Title: GENETIC PROTECTION OF HEMATOPOIETIC STEM CELLS FOR STABLE HIV CONTROL
Agency: NIH National Institute of Allergy and Infectious Diseases, Project Number 1R01AI100652-01A1
DESCRIPTION (provided by applicant): Hematopoietic stem/progenitor cell (HSPC) based gene therapy holds great promise to provide long-term control of HIV with a single treatment. Like HAART, it is essential to combine multiple drugs to effectively suppress HIV and prevent drug resistant HIV escape mutants. The overall hypothesis of this proposal is that stable introduction of highly potent combinations of anti-HIV genes capable of inhibiting multiple early and late steps of HIV viral lifecycle into HSPC will provide lifelong protection from HIV infection The safety and efficacy of anti-HIV HSPC gene therapy strategies, including inhibition of HIV, lowering of viral load and selective growth advantage of protected cells and prevention of resistance will be evaluated in the recently developed human bone marrow, liver and thymus (BLT) transplanted mouse model. Specific aims are 1) To develop novel multi-pronged anti-HIV gene therapeutic lentiviral vectors and characterize therapeutic reagents to inhibit HIV infection in HSPC and their progeny in vitro 2) To determine the long-term anti-gene expression and stable control of HIV through genetically engineered human HSPC transplant in the BLT mouse model. The approach is innovative because it focuses on novel HIV-1 target HSPC protection and the development of novel potent, broad-range early stage and late stage anti-HIV combinations, maximizing the potential to HIV replication not only in HSPC but also all potential target cells. The proposed research is significant because the results may ultimately lead to an innovative, more effective, more convenient, less toxic, safe and more cost effective way of controlling HIV infection than is currently available. The long-term goal is to advance HSPC based gene therapy research and make rapid progress towards providing a new therapy that leads to stable control of HIV by a single treatment. PUBLIC HEALTH RELEVANCE: Our proposed research will positively impact public health with the development of an anti-HIV gene therapy by blocking the multiple early and late stages of the HIV infection. Ultimately, HIV infection will be controlled with a single treatment by protecting the hematopoietic stem cells and their progeny. This research will provide significant knowledge towards the long-term goal of the NIH "HIV cure."
Title: HOME ECG MONITORING TO DETECT ALLOGRAFT REJECTION FOLLOWING HEART TRANSPLANTATION
Agency: NIH National Institute of Nursing Research, Project Number 1R01NR012003-01A1
DESCRIPTION (provided by applicant): The long-term goal of this research is to apply novel technology for detection of donor organ (allograft) 3 rejection to improve patient outcomes following heart transplantation. The specific goal of this study is to 4 determine whether daily monitoring of the transplant recipient's electrocardiogram (ECG) using a simple home 5 device with transmission to an ECG Core Laboratory would provide an early biomarker for acute rejection. 6 Despite routine immunosuppressant drug therapy, acute rejection is common, especially within the first 6 7 months following transplant surgery. To detect rejection, frequent endomyocardial biopsies of heart tissue are 8 performed. An endomyocardial biopsy is a costly and invasive procedure performed in a hospital cardiac 9 catheterization laboratory that has associated risks. Recent evidence suggests that acute allograft rejection 10 causes delays in ventricular repolarization resulting in a longer QT interval on the ECG. The specific aims of 11 the study are to: 1) determine whether an increase in the QT interval during the first 6 months following heart 12 transplant is a sensitive and specific biomarker for acute rejection; and 2) determine the timing of QT interval 13 increases relative to biopsy-diagnosed stages of mild/moderate/severe rejection. Secondary aims are to: 3) 14 determine whether an increase in the QT interval predicts 1-year mortality; and 4) explore additional ECG 15 measurements that might predict rejection or death. 16 A prospective, double-blind, descriptive and correlational research design is planned. Investigators who 17 analyze ECG data will be blinded from biopsy results; healthcare providers will be blinded from QT 18 measurements. A sample of 325 adult heart transplant recipients will be recruited from 3 transplant centers: 19 Columbia University-New York Presbyterian Medical Center; University of California, Los Angeles and Cedars- 20 Sinai Medical Center, Los Angeles. Each subject will record a 30-second ECG daily using the HeartOneTM 21 device; the device will automatically transmit the ECG to an ECG Core Laboratory at the University of 22 California, San Francisco. For Primary Aim #1, a log regression analysis will be performed with the 23 independent variable being presence /absence of the ECG criteria ( QTC e25 milliseconds X 3 days) and the 24 dependent variable being presence /absence of acute allograft rejection. Odds ratios and confidence intervals 25 will be reported, as well as established evaluative criteria for new diagnostic instruments (sensitivity, specificity, 26 positive /negative predictive value, predictive accuracy). For Primary Aim #2, descriptive statistics will be used 27 to report the average time period between the development of the ECG criterion and biopsy evidence of 28 rejection. The potential benefit of finding a simple ECG biomarker of allograph rejection that could be 29 measured at home is that it might yield earlier detection of rejection, allow more timely therapy and reduce 30 mortality from acute allograft rejection. PUBLIC HEALTH RELEVANCE: The goal of this research is to identify changes in a heart transplant patient's electrocardiogram (ECG) that indicate donor organ rejection, a major cause of death in the first year. Patients will record their ECG daily using a simple home device combined with novel mobile phone technology that will automatically send their ECG to the researchers. The public health benefit of detecting a simple ECG marker of heart transplant rejection is that it might yield earlier detection, allow more timely initiation of medical therapy and reduce mortality from acute rejection.
Title: VULNERABLE POPULATIONS/HEALTH DISPARITIES RESEARCH
Agency: NIH National Institute of Nursing Research, Project Number 2T32NR007077-16
DESCRIPTION (provided by applicant): This application is designed to continue our long trajectory of recruiting and training nurse scholars in pre- doctoral and postdoctoral education emphasizing methods and measures for ameliorating health disparities experienced by vulnerable populations (VPs). This training program began at the UCLA School of Nursing (SoN) in1994. Since then 23 pre-doctoral and 11 postdoctoral students were trained and supported in their VP- related research. Our program, VP/HD, is supported by the SoN's long history of working with VPs, expertise in research methods and measures, the SoN's research centers that includes research targeting the elderly, homeless, vulnerable and Indigenous populations, and a history of interdisciplinary faculty and community investigators. An improved curriculum targets methods and measures specific to vulnerable group research, as well as a summer Internship/immersion program that provides expanded experience in health disparities in rural and urban sites (such as among the homeless and Indian reservations). The strengths of this application are the long-term experience of the training program and the (1) Transition to new Program Director, (2) Significant numbers of new/continuing key faculty supporting trainee research, (3) Recruitment of trainees who reflect the ethnic make-up of the region, (4) A well-funded faculty research grant support program and research centers targeting VPs, (5) A well-designed curriculum on VP research methods and measures, and (6) a VP focused summer program to provide pre-doctoral students with expanded hands-on experience in VP settings and healthcare needs.
Title: HOME VISITATION PROGRAM
Agency: DHHS/ADMINISTRATION FOR CHILDREN AND FAMILIESSub-Contract Number
DESCRIPTION (provided by applicant): The project assists in the development and evaluation of a home visitation program in American Indian communities in two counties for children 0-5 years of age. The intervention targets American Indian families during the perinatal and early childhood periods of life. This is a five year program consisting of planning and training of the Riverside San Bernardino Counties Indian Health, Inc. (RSBCIHI) program staff. (1) Program technical and evaluative support includes modifying the training for cultural appropriateness and test measurement of mandated benchmark constructs. Bench mark measures to be reported to demonstrate improvement are: (a) Maternal, Newborn, and Child Health, (b) Child Injuries, Child Abuse, Neglect or Maltreatment, and Emergency Department Visits, c) School Readiness and Achievement, d) Domestic Violence, 5) Family Economic Self-Sufficiency, and e) Coordination and Referrals for Other Community Resources and Supports. Other activities include: (2) To develop an ongoing Continuous Quality Improvement programs, in identify critical areas for improvement and preparing a Quality Improve Plan, and (3) To develop and host a Geographic Information System for resource management enhancement. We developed a geographic information system locating tribal, county, state, and private resources accessible by home visitors. The GIS resource management system is an enhancement of the home visiting program that will facilitate appropriate referrals and improve coordination with non-RSBCIHI services, and is hosted at the Charles Drew Medical Geographic Information Systems Laboratory., and (4) Finalize the evaluation plan for the RSBCIHI Outreach Home Visiting Program.
Title: EXAMINING TYPE 2 DIABETES AMONG CALIFORNIA AMERICAN INDIANS
Agency: UCLA INSTITUTE OF AMERICAN CULTURES
Description: The study explores important research hypotheses through the use of an existing dataset that has several important features. A key CHIS sampling goal was to produce data that reflected California’s ethnic and racial diversity. The 2011-12 survey cycle included a supplemental sample of AI/ANs to ensure that both urban and rural residents are adequately represented. Also, the ability to compare the population over time, from a data set collected in 2001 through 2011-12 is valuable leading important information on the changing demographics of AI/ANs in California, and the epidemic of diabetes that may be shifting with the population from rural to urban locations and from adult to younger cohorts. A better understanding of social cohesion, connectivity, access to care, and healthy behaviors will provide much needed information to tailor culturally-specific interventions in high-risk groups. The CHIS dataset has not been utilized in this manner before. Furthermore, the regression models that are planned will be able to simultaneously consider and adjust for the multiple factors previously mentioned (risk behaviors, social connectivity, etc.). We would be able to test hypotheses regarding behaviors and barriers to prevention and treatment that have not been adequately examined. Therefore, both the utilization of this dataset and methodology for this particular topic are novel.
The following are study aims:
AIM 1. To identify the prevalence of and distribution of borderline, gestational, and type 2 diabetes and by age and urban – rural reservation residents in the 2001 and 2011-2012.
AIM 2. To identify the statistical association of high risk factors associated with type 2 diabetes, such as obesity, suicide ideation, and depression.
AIM 3. To assess social cohesion and connectivity as protective factors against diabetes.
Data analysis using epidemiologic research is designed to investigate diabetes among AI/AN groups by age, gender and by residence. We will identify rates of diabetes by urban-rural residency, risk factors (obesity, depression, etc.) and potential protective factors such as social cohesion (social bonding) and connectivity (self-identity and connection with community).
Title: Xiangya-UCLA HIV/AIDS Nursing Research Initiative
Agency:Fogerty International Center, NIH Project Number 1D43TW009579-01
DESCRIPTION (provided by applicant): The long-term objective of the Xiangya-UCLA HIV/AIDS Nursing Research Initiative is to enhance capacity at Xiangya School of Nursing (Central South University, Hunan, China) and affiliated institutions to conduct research addressing questions in HIV/AIDS nursing with a focus on mental health and management of cognitive/affective symptoms of HIV and concomitant conditions. Specific aims include 1) development of research expertise in a cadre of Chinese nurses and psychologists who will conduct collaborative HIV/AIDS behavioral research; and 2) enhancement of the institutional capacity for nursing, mental health and behavioral HIV/AIDS research, including rigorous measurement of biological outcomes. The research training plan comprises 1) long-term (9 month) post doctoral training in HIV behavioral studies for 8 Chinese investigators at UCLA; 2) medium term training (6 months) in measurement of biological outcomes for 1 Chinese laboratory fellow at Yale and UCLA; 3) part-time, long term, in-country training in behavioral research methods for a cohort of 20 Chinese nurses and psychologists; and 4) mentored research projects. The proposed program responds to and extends ongoing HIV/AIDS collaborations which have demonstrated the need for additional post doctoral training in order to conduct rigorous studies of emerging questions related to mental health and behavioral aspects of HIV/AIDS in China including measurement of biological outcomes. The rationale for the program is that while Xiangya has strengthened its doctoral studies program for nurses and psychologists, local expertise is limited regarding the behavioral research methods that are key to high quality investigations of psychosocial and self-management issues of interest to nurse-researchers and psychologists. The program links nursing and psychology in recognition of common academic interests and the existing relationship between these two disciplines among the partner institutions. The program design builds in collaboration, long term mentorship and ongoing support of trainees as they design, implement, and evaluate mentored research of immediate relevance to China and by extension to similar countries faced with maturing HIV epidemics. It is anticipated that this program will substantially increase the number of young and mid career nurse-scientists, psychologists, and others conducting research related to the mental health and behavioral aspects of HIV/AIDS. Increased capacity will be measured by the number of research projects conducted by trainees; peer reviewed publications and professional presentations; successful applications for external funding; and number of courses taught and individuals mentored by trainees. PUBLIC HEALTH RELEVANCE: This project will provide advanced training in HIV/AIDS research with a focus on mental health and management of cognitive/affective symptoms of HIV and concomitant conditions for nurses and psychologists at Xiangya School of Nursing in Hunan, China. The training will improve the ability of researchers at Xiangya to conduct studies of behavioral interventions for HIV/AIDS with benefits for patients in both the developed and developing world.
Title: ApoE and Cholesterol Effects on Amyloid Beta in Synaptic Terminals in AD
Agency: NIH, National Institute on Aging
Description: Most workers in the field consider loss of synapses to be the earliest correlate of cognitive loss in AD. Meanwhile, although APOE4 is the largest risk factor for Alzheimer’s disease (AD), the mechanisms by which it increases risk are not understood. Similarly, the mechanisms for protection by APOE2 remain unknown. The present project is aimed at understanding APOE mechanisms in a key neuronal compartment, synaptic terminals. Synaptic terminals are not well-resolved at the level of light microscopy, which makes accurate determination of synaptic pathways technically difficult; therefore, my laboratory has developed methods for flow cytometry analysis of synaptosomes prepared from cryopreserved human and rodent tissue. This technique is used together with more routine biochemical assays and allows 1) study of populations of individual terminals (5-10,000 particles/sample) and 2) absolute quantification of synaptic AB, phosphorylated tau (p-tau), and lipid and mitochondrial markers in postmortem human cases and in transgenic disease models. The long term goal of this project remains to determine APOE genotype effects on synaptic pathways leading to Ab accumulation and clearance. Our working hypothesis is that synaptic Ab in surviving, ‘sick’ synaptic terminals represents a pre-deposit accumulation that contributes to synaptic dysfunction, and that APOE modulates clearance vs. early deposition pathways within synapses. Synaptosomes from three model systems will be used for Aims 1 and 2: i) postmortem staged AD cases and aged control cases, ii) young targeted replacement (TR) mice expressing human apoE2,3, and 4, and iii) aged TR mice. Young TR mice have low levels and aged TR miced have moderate levels of diffuse Ab, avoiding confounds from the high Ab level in some mouse models. Aim 1 will determine the effect of APOE on Ab level, apoE level and lipidation, and on synaptic lipids in cortical synapses. Aim 2 will determine the effect of APOE and Ab level on mitochondrial function, downstream tau pathology and autophagic flux. Aim 3 is in vitro, and will examine the contribution of APOE genotype and apoE level and lipidation to mitochondrial function and Ab levels in cortical synaptosomes from aged TR mice. Synaptosomes will be treated with highly lipidated vs physiologically lipidated apoE, with and without Ab42. Because apoE is a promising therapeutic target, the proposed experiments to clarify the role of APOE in the synaptic compartment are urgently needed in order to understand and predict the effects of apoE-directed therapeutics.
Title: Depolarization-Induced Tau and Exosome Release from Synapses in AD
Agency: NIH, National Institute of Aging
Description: Extracellular tau has been shown to be toxic and evidence supports regional trans-synaptic spread of tau pathology but the process is poorly understood. Moreover, tau immunotherapeutic approaches have been shown to be effective but progress is slow because the exact peptide released is not known. Based on recently published evidence that C-terminal truncated and intact tau is released by depolarization in Alzheimer’s disease (AD) synaptosomes, the present project has the goal of understanding how synaptic release and accumulation of tau contributes to disease progression and whether tau release is modulated by Ab. The general hypothesis is that synaptic C-terminal truncated tau peptides impact synaptic function and regional spread of tau pathology, and that released tau is carried on exosomes. Synaptosomes from cryopreserved AD and aged control cases will be studied; cases are staged and genotyped and will include a high pathology control group. A tauopathy mouse model that expresses human tau will also be studied. Aim 1 will characterize the specific tau peptides that are released along with neurotransmission and endocytic mechanisms, and will determine stage and APOE effects on release. Aim 2 will quantify exosome release from synapses and determine its association with disease stage and APO, and will determine the extent of tau association with exosomes and other pathology-related cargos. This proposal will directly address mechanisms related to synaptic release of tau peptides in AD.
Title: OBSTRUCTIVE SLEEP APNEA, GENDER BIOLOGY AND AUTONOMIC REGULATION
Agency: NIH National Institute of Nursing Research, Project Number 1R01NR013693-01A1
DESCRIPTION (provided by applicant): Obstructive sleep apnea (OSA) occurs in close to 20% of men and 10% of women in the adult population, and is an independent risk factor for cardiovascular disease and death. Despite the lower prevalence in women, female OSA patients show more severe cardiovascular and neuropsychological consequences than men with the disorder. The causes of the health problems associated with OSA are unclear, and there are few clinical guidelines for treating symptoms other breathing support with positive airway pressure (PAP); that support assists ventilation, but does little to restore sympathetic dysfunction, one factor that likely contributes to hypertension and other cardiovascular sequelae in the syndrome. Since sympathetic outflow is regulated by the brain, a possible contribution to the cardiovascular sequelae is impaired regulation due to neural injury from the intermittent hypoxia and other characteristics of OSA. We showed such injury in OSA together with deficient cardiovascular control in many brain regions, including the insular cortex, an area that integrates higher brain processing and sensory input to modulate brainstem and hypothalamic autonomic outflow. Our R21 data show that female OSA patients have an even greater extent of insular cortex injury and dysfunction than male OSA patients. We therefore hypothesize that in OSA patients, the insular cortex has impaired function due to injury, resulting in less effective cardiovascular regulation, and these effects are especially severe in female OSA patients. We will evaluate brain structure with diffusion tensor imaging, brain function with functional magneti resonance imaging (fMRI), and cardiovascular function with heart rate measurements during three autonomic challenges, an inspiratory apnea, Valsalva maneuver, and static hand grip. We will localize the insular cortex subdivisions involved in sympathetic modulation from high-resolution MRI scans. We will study 144 people across four age-matched groups: newly-diagnosed OSA females and males matched for disease severity, and healthy control females and males. Females will be assessed for menopausal and hormonal status, with the aim of balancing the numbers of pre- and post-menopausal women, and including hormonal factors in statistical models. In males and females, the findings will show whether disrupted neural regulation of sympathetic activity occurs in OSA, whether that dysfunction is paralleled by brain injury, and whether cardiovascular responsiveness is also impaired. We will also perform an exploratory assessment of the effects of 3 months of PAP treatment on autonomic function in 15 male and 15 female patients, and gather evidence as to whether autonomic central function can recover, at least in the short term. A lack of recovery would suggest additional treatments to PAP should be investigated. Findings of worse effects of OSA in women would highlight the need to broaden OSA treatment, which currently solely focuses on resolving breathing disruptions for moderate and severe OSA, and is typically ignored in mild OSA in women, despite evidence that mild OSA in females is accompanied by severe cardiovascular characteristics. PUBLIC HEALTH RELEVANCE: We will investigate a possible cause of the cardiovascular and neuropsychological symptoms that women with Obstructive Sleep Apnea (OSA) show to a greater degree than men. We will test whether brain function in the insula, a region controlling blood pressure and mood, is abnormal in female OSA patients by using magnetic resonance imaging, and look at brain damage as a possible cause of this dysfunction, as well as looking at the cardiovascular consequences, and in a subset of patients the influence of treatment. This study will help show whether impaired brain function in the insula due to injury is associated with poor cardiovascular control, whether women are more physically affected by OSA than men, and whether treatment for the sleep disorder may improve brain and cardiovascular function
Title: UCLA/CDU PARTNERSHIP FOR ENHANCING DIVERSITY OF NURSES WITH RESEARCH CAREERS
Agency: NIH National Institute of General Medical Sciences, Project Number 1R25GM102777-01
DESCRIPTION (provided by applicant): Health disparities for individuals from under-represented minority groups (URMGs) continue to plague the US population. The roots of this problem are many and complex, but of great relevance is the dearth of individuals from URMGs in the health professions workforce, with serious disparities in the ethnic/racial composition of the workforce being particularly pronounced in nursing. The 2008 NSSRN survey showed 32.1% of Black/African American nurses and 39.4% of Latino nurses had baccalaureate degrees; for all racial/ethnic groups combined, only 11.4% had graduate degrees including PhDs. This state exists at a time when the US population is becoming older and more ethnically diverse. Given this dire state of affairs, we are proposing to enhance an existing relationship between the Schools of Nursing at the University of California, Los Angeles (UCLA) and Charles R. Drew University of Medicine and Science (CDU), an Historically Black Graduate Institution and Hispanic Serving Institution, for the purpose developing and implementing an integrated plan of individual and institutional activities to prepare masters students from URMGs to make a seamless transition to doctoral education. The long term goal of this project is to increase the ethnic/racial diversity of those prepared to pursue research careers in nursing focusing on research about aging adults (45+ years) by (1) increasing involvement of master's students and faculty at CDU SON in the scientific enterprise through structured development activities; (2) enriching the research course offerings and scientific environment at CDU SON to prepare master's students to seamlessly transition to doctoral education; and (3) facilitating student advancement to the UCLA SON via systems that facilitate student enrollment and scientific exchange between faculty at UCLA and CDU. PUBLIC HEALTH RELEVANCE: Health disparities persist despite efforts to curb them. Encouraging more diverse, underrepresented minority individuals to pursue doctoral education in the health care field, such as nursing, is one documented way to reduce health disparities. This application proposes collaboration between University of California Los Angeles and Charles Drew University to provide the supportive and educational activities required to prepare a more diverse nursing workforce at the doctoral level, who will ask the relevant research questions and develop the science that will ultimately reduce health disparities.
Title: CO:ADVOCATE: A PROGRAM TO PREVENT ETHICAL CONFLICTS AND MORAL DISTRESS IN ICU
Agency: American Association of Critical Care Nurses
DESCRIPTION: Ethical conflicts are among the most challenging situations faced by patients with life-threatening conditions, their families, healthcare providers, and the healthcare system. Ethical conflicts are particularly relevant during care of critically ill patients near the end of life. These conflicts can occur between patients, families, and healthcare teams or within healthcare teams, or within families. Regardless of origin, ethical conflicts threaten patient safety and quality care. For clinicians, ethical conflicts can lead to recurring and increasing moral distress which the American Association of Critical-Care Nurses (AACN) identifies as a critically important topic for critical care nurses. Moral distress may result in disengagement, medical errors, absenteeism, and burnout. Healthcare systems also suffer increased organization costs with ethical conflicts. In a recent consensus statement, the American College of Critical-Care Medicine (ACCM) asserted that effective team communication plays a crucial role in preventing and managing ethical conflicts during end-of-life care.32 However, both the ACCM and the AACN acknowledge a lack of proven strategies that decrease the risk for ethical conflicts, moral distress, and burnout. This research proposal builds on the investigators' previous work that evidenced nurses' awareness of moral concerns and impending ethical conflicts regarding treatment decision making; however this awareness was often accompanied by reluctance to initiate discussion about their concerns. The purpose of the proposed study is to to evaluate the effectiveness of an ethics educational program called CO:ADVOCATE in ICU settings in three institutions: University of California Los Angeles Medical Center, Mayo Clinic, and Massachusetts General. Our working hypothesis is that educational programs aimed at improving interdisciplinary teamwork will facilitate timely interdisciplinary goals-of-care conversations, increase family satisfaction, improve ethical climate, and decrease clinicians' moral distress. CO:ADVOCATE has the potential for creating safer and more effective systems of care for seriously ill patients and their families.
Title: Decision Making on Aramatase Inhibitors in Breast Cancer Survivors 65 and Older
Agency: NCI (National Cancer Institute) Project Number 1R21CA167218-01A1
DESCRIPTION (provided by applicant): Age is a strong and independent risk factor for dying from breast cancer (BC) in and of itself. This becomes highly significant when considering that BC is the most commonly diagnosed cancer in women and the second most deadly. Hormone positive BC is especially common among older women. While adjuvant hormonal treatment is proven to dramatically reduce the risk of cancer recurrence and mortality for hormone- sensitive BC, evidence shows that about half of all women 65 years discontinue this life-saving treatment. What contributes to discontinuation is poorly understood. Aromatase inhibitors (AIs) are associated with adverse side effects such as an arthralgia syndrome, hot flashes, loss of bone density, and cardiovascular events which may influence whether women persist with the treatment. Although the numbers of older women with BC is growing and this population has disproportionately high mortality rates compared with younger women, little or no research has explored the processes by which women 65 years decide to continue or discontinue AI treatment. Our multidisciplinary study will elicit in-depth narratives to explore what influences te trajectory of continuing or discontinuing an AI in the context of the lives of women 65 years and above. We will gain understanding of how women 65 years interpret, and act upon information that they have received about AIs. In addition, based on the pragmatic evidence in the women's own words, we will develop a novel descriptive framework of the decisional processes about using AIs within the context of the women's lives. The choice of research method is constructivist grounded theory, providing a methodology to access and understand meanings and decisional processes from a personal perspective. Approximately 50 personal interviews with 40 women, 65 years who were treated for primary, invasive loco-regional BC and are either taking an AI or have discontinued the treatment will supply the data. A focused interview guide has been developed from preliminary findings including the PI's research with women 70 years who recently completed treatment for early stage BC. The interview guide will extend previous research to include questions about preferred ways to receive information about AIs and what the women did to self-manage the modifiable factors of side effects. Furthermore, from the perspective of cancer survivorship science, the interview guide contains questions about the role of family and support people. A novel framework will result from this study to provide the foundation to design and test an age- appropriate and cost-effective supportive intervention to improve informed decision making and increase continuation with AIs. We also foresee that the findings may be transferable to women 65 years in other contexts of geriatric oncology and other areas of oncology such as the use of an AI to reduce the relative risk of a first time invasive BC in healthy postmenopausal women. PUBLIC HEALTH RELEVANCE: Despite progress in early detection and treatment, breast cancer is the second most deadly cancer and women 65 years are even more likely than younger women to die from breast cancer itself. Aromatase inhibitors, a proven effective treatment to prevent deadly complications of a first-time breast cancer, are discontinued by an estimated 50% of all women who stand to benefit from this treatment. Using the women's own words, our research will assess what comprises the decisions of women 65 years to continue or discontinue this potentially life-saving treatment towards the goal of developing an intervention for improved decision-making.
Title: Cerebral Artery Integrity Linked to Brain Injury and Cognition in Congenital Heart Disease
Agency: NIH National Institute for Nursing, Project Number 1R01NR016463-01
Adolescents with congenital heart disease (CHD) show brain injury in regions (hippocampus, frontal cortex, temporal, and parietal), which control cognition. Abnormalities in these sites are associated with cognitive deficits. However, the underlying cause of brain injury in these areas in CHD is unclear. Alteration in cerebral artery integrity (measured by arterial transit time [ATT]), which is associated with neural injury in other diseases, is a potential cause of brain injury in CHD. However, there are no published reports of cerebral artery integrity in CHD or regarding any associations between cerebral artery integrity, brain injury, and cognition in this condition. We will use a comparative study design, 80 subjects (40 CHD / 40 Healthy controls), with inclusion criteria for CHD will be subjects between 14-18 years of age, have undergone surgical repair or palliation, and controls will be age- and gender-matched to CHD subjects. Using non-invasive brain magnetic resonance imaging (MRI) procedures, our preliminary study is the first to report abnormalities in ATT values (via diffusion-weighted pseudo-continuous arterial spin labeling [pCASL] procedures) in CHD and that these changes are associated with brain injury (as examined by diffusion tensor imaging based mean diffusivity [MD], an MRI measure of tissue integrity) in the hippocampus, frontal cortex, temporal, and parietal regions in CHD subjects compared to controls. However, while promising, the sample size in this preliminary study was quite small and did not allow us to control for important covariates, such as age and gender. Therefore, the specific aims of this proposal are to: 1) compare ATT values (calculated from diffusion-weighted pCASL) between CHD and age- and gender-matched control subjects; 2) compare regional MD values, derived from diffusion tensor imaging data and cognitive scores (measured by the total Montreal Assessment of Cognition [MoCA] and general memory index (GMI) score from the Wide Range Assessment of Memory and Learning [WRAML2]) between CHD and age- and gender-matched control subjects; 3) examine the relationships between altered ATT (indicating cerebral artery integrity), regional MD values (assessment of injury), and cognitive scores in CHD patients. In summary, CHD patients show significant brain injury in areas that control cognition. These deficits are associated with poor school performance, increased morbidity and mortality, and poorer quality of life. A potential cause of this brain injury may be compromised cerebral artery integrity; however, status of the artery integrity and its association with brain injury and cognition has not been reported in CHD. Information from this study has the potential to disclose a process contributing to brain injury in CHD. Thus, it has important implications on identification of effective treatments for CHD by repairing cerebral artery integrity as used in other conditions (such as stroke and traumatic brain injury), which could dramatically improve cognitive function, reduce mortality and morbidity, and increase quality of life in this high risk patient population.
Title: MEMORY AND BRAIN STRUCTURE IN ADOLESCENTS WITH SINGLE VENTRICLE HEART DISEASE
Agency: NIH National Institute of Nursing Research Project Number: 1R01NR013930-01A1
DESCRIPTION: Cognitive impairment, especially short-term memory, [is] prevalent in adolescents with single ventricle congenital heart disease (CHD), [which] can deleteriously impact one’s ability for self-care. To date, no research team has reported a link between memory loss and brain structural changes in this high risk, vulnerable population. Therefore, the specific aims for this study are to: 1) Compare brain [structural integrity] of regions which control memory (hippocampus, mammillary bodies [controlling for global cerebral volume and with other relevant cofactors]) between CHD adolescents and age- and gender-matched healthy controls, and 2) Examine the relationship between clinical/questionnaire measures of memory and [volumes of] brain structure[s that control memory function] [ controlling for global cerebral volume] in adolescents with single ventricle CHD and healthy controls. Using a comparative [research] design, 20 single ventricle CHD subjects and 40 age- and gender-matched healthy controls will undergo [high-resolution T1-weighted] structural brain [magnetic resonance imaging] and have memory testing using the Montreal Assessment of Cognition (MoCA) and the Wide Range Assessment of Memory and Learning (WRAML2). Inclusion criteria [for CHD] will be subjects between the ages of 14 to  years, single ventricl heart disease, and have undergone Fontan surgical completion, [and for controls will be age (+1 year) and gender-matched to CHD subjects and without any condition that may affect the brain.] [Magnetic resonance imaging] analysis will consist of volumetric measures of [bilateral] hippocampus and mammillary bodies of each subject. Statistical tests will consist of Spearman’s Rho and [MANCOVA with age, gender, and global cerebral volume] as covariates with significance set at p < 0.05. In summary, the overall purpose of the study is to identify the association between memory and structural brain injury in adolescents with CHD after staged surgical palliation. [The proposed study] has the potential to dramatically impact clinical practic, as information from this study can guide clinicians toward improved patient education/self-management strategies and assist researchers in the identification and testing of innovative interventions to improve memory and self-care in this growing [patient] population of single ventricle CHD survivors. PUBLIC HEALTH RELEVANCE: Cognitive deficits, particularly memory loss, are common in adolescents with single ventricle congenital heart disease and can impact their ability for self-care; [however, it] is uncertain if these memory deficits are associated with brain injury. This study will be the first to examine the relationship between memory loss and structural brain injury in adolescents with single ventricle congenital heart disease. The [proposed] study has the potential to dramatically impact clinical practice, as information from this study can guide clinicians toward improved patient education/self-care strategies and test innovative interventions to improve memory in this growing [patient] population.
Title: EFFECT OF WALNUTS ON PROSTATE HEALTH
Agency: Walnut Commission
DESCRIPTION: Having children is an important part of life, yet many couples struggle with this milestone due to infertility. Worldwide ~70 million couples suffer from infertility. In the USA infertility affects ~one in seven couples and has led to a steady increase in the number of couples seeking infertility services. In vitro fertilization and other assisted reproductive technologies now account for ~3 in every 100 live births. A more natural first step toward dealing with infertility would be to focus on factors we know are associated with good health, for example diet. As described below, walnuts provide a rich dietary source of nutrients needed for male reproductive health.
The male partner is responsible for about 30 – 50% of all cases of infertility. Although the underlying causes of most male infertility are not known, the clinical hallmark is poor semen quality (low sperm count, poor sperm motility, abnormally shaped sperm, fragmented sperm DNA). There are multiple reports of declining semen quality in specific geographic locations around the world, usually associated with industrialized nations. Some research suggests environmental pollutants and a trend toward a more Western diet (laden with saturated fats, refined sugars, low fruit and vegetable intake) are to blame.
It is logical to think that Western diets are not healthy for semen quality. Sperm need very flexible plasma membranes in order to swim and fuse with ova. Sperm require membranes that are highly enriched with beneficial polyunsaturated fatty acids. If polyunsaturated fatty acids are low in sperm, fertility is low. Decreasing the ratio of omega-3 to omega-6 polyunsaturated fatty acids in the diet has been shown to improve male fertility. Selenium is also critical to normal sperm development and function and if not adequate in the diet, sperm swim in circles and suffer damage to their membranes and DNA. A recent study has shown that increased folate in the diet reduces the number of sperm carrying too many or too few chromosomes. Sperm with an altered number of chromosomes can lead to disorders such as Down syndrome or spontaneous abortion. However, walnuts provide a rich dietary source of all the factors above needed for healthy semen quality. Walnuts contain beneficial lipids, selenium, folate, and antioxidants to protect sperm membranes and sperm DNA. Walnuts have been shown repeatedly to improve lipid profiles in published dietary studies. Based on this, we propose a study to examine whether enriching the diet with walnuts might improve semen quality.
We will combine two respected research laboratories at UCLA to accomplish the research. One laboratory has a long history of conducting male reproductive health studies and the other a long history of conducting diet and nutrition research.
The plan is to enroll 120 men who habitually eat Western diets and then randomly assign half to eat their usual diet supplemented with walnuts (3 ounces per day) and the other half to eat their usual diet excluding nuts. At the beginning of the study we would collect full dietary histories, blood measures of omega-3 and omega-6 fatty acids, selenium, anti-oxidants and folate (the factors critical to sperm). We would also directly measure the semen quality including sperm count, motility, shape, chromosome number, and DNA fragmentation (the factors necessary to male fertility). After three months on the diets, we would collect the same measures again and look for changes in those measures. Throughout the study the research team would be available to monitor and assist study participants with the diets and other study procedures.
We have designed the study to be able to detect beneficial effects of walnuts on male reproductive health. If couples planning pregnancies could enhance their fertility with a natural dietary source like walnuts, it would be preferable to taking supplements or rushing into in vitro technologies. Similar to the health information given on benefits of walnuts for cardiovascular health, information on benefits of walnuts for male reproductive health would be very beneficial to couples of reproductive age.
Title: PHARMACOGENETICS OF DONEPEZIL IN MILD COGNITIVELY IMPAIRED PATIENTS
Agency: NIH National Institute of Aging, Project Number 1K23AG051416-01A1
DESCRIPTION (provided by applicant): The purpose of this application for a K23 award is to provide additional training to Dr. Sokolow to establish herself as a successful independent investigator in patient-oriented research focusing on the pharmacogenomics (PGX) of Alzheimer's Disease (AD). Dr. Sokolow's academic background includes an advanced degree in pharmacy practice and a doctorate in Biomedical Sciences with specialization in molecular biology and mouse genetics. For the past seven years, her research program at the UCLA School of Nursing has focused on the neurobiology of AD. Her training plan includes a cross-training in bioinformatics, biostatistics and statistical genomics. In addition to her training pla, she has assembled an outstanding mentoring team with expertise in clinical phenomenology of AD, genome-wide association studies (GWAS) and PGX. The collaborative environment of the UCLA School of Nursing, the UCLA Mary S. Easton Center for AD Research and the Institute for Translational Genomics and Population Sciences – Los Angeles Biomedical Research Institute is ideal for developing her new research program focusing on the investigation of genetic factors affecting the response to donepezil (DPZ) in MCI individuals. MCI is a syndrome characterized by a memory deficit which differs from normal age-related changes in memory and dementia. There is no pharmacotherapy approved for the treatment of cognitive symptoms in MCI patients; however DPZ is the most commonly prescribed medication for this disorder. Existing neuropsychological testing and GWAS data collected from 3 previously conducted studies [i.e. Alzheimer’s Disease Neuroimaging Initiative study (ADNI); Alzheimer’s Disease Cooperative Study (ADCS) trial of MCI and the Imaging and Genetic Biomarkers for Alzheimer’s Disease study (ImaGene)] will be used to address 3 complementary specific aims. In Aim 1, we will impute the existing GWAS against the 1000 genome project and we will perform association studies to test the interactions between DPZ response and candidate genetic polymorphisms associated with AD susceptibility/endopehenotype and/or with DPZ response in AD. DPZ response will first be estimated with existing Clinical Dementia Rating sum of boxes scores. Follow-up of the top PGX markers will be assessed with 5 other measures of cognition and executive function. In Aim 2, we will use the same resources and we will apply pathway-based association analyses of DPZ response in MCI to identify new PGX markers. In Aim 3, we expect to validate the associations between DPZ response and the strongest candidate for the actual predisposing SNPs at the top genetic loci discovered in Aims 1&2 using existing Whole-genome sequence (WGS) data from ADNI study. Overall, we expect to demonstrate the usefulness of PGX testing in clinical practice and in clinical trials to identify the individuals who are most liely to benefit from the pharmacotherapy. At the conclusion of this award, Dr. Sokolow will have the necessary skill sets to compete effectively for future NIH support and to propel her to an independent career in AD PGX.
Title: Improving Screening Tools to Better Predict High-Grade Anal Dysplasia For MSM
Agency: NCI (National Cancer Institute) Project Number 1R01CA169508-01A1
DESCRIPTION (provided by applicant): Invasive anal cancer (IAC) is a health crisis for gay, bisexual, transgender & other men who have sex with men (MSM), where risk for disease is now 20-40-fold higher than all U.S. males.9-12 Thirteen human papillomaviruses (high-risk HPVs) cause most invasive cervical cancers (ICC) in women & likely cause most IACs.13 High-risk HPV infections are sexually transmitted between partners. Persistent infections, together with their associated high-grade dysplasias, strongly predict ICCs.14-17 Recent data suggests we poorly understand HPV infections in men, especially among MSM who are at highest risk for IAC.18-25 Cervical cytology using Papanicolaou's staining (Pap test) significantly reduced ICC beginning in the mid-1950's; & cytology specimens are currently collected using cytobrush, a tool poorly adapted to anal sampling.26,27 Experts now recommend anal Pap test for MSM every 1-2 years, using Dacron swab passed blindly through the anal verge.28 Dacron-cytology specimens are marginally sufficient & require diagnostic follow-up for any detected abnormalities, a lower threshold than used for cervical cytology. Our pilot data show that sensitivity & specificity of anal cytology to predict HG-AIN is improved 1.5-fold using nylon-flocked swab, but only improved specificity 1.3-fold to 73%. Although most IACs test positive for HPV using PCR, the high prevalence of infection among MSM without cancer makes HPV PCR genotyping a poorly specific screening test, with low positive predictive value (PPV). High-threshold, nucleic acid HPV assays (molecular HPV tests) are calibrated to better predict high-grade cervical dysplasia in older females without atypias & to triage women to colposcopy with atypical squamous cells on cytology; they are not calibrated for IAC screening. Two molecular HPV tests that detect viral DNA & -mRNA may be relevant for IAC screening: HPV-Hybrid-capture II (HC-2) & -APTIMA. Both tests detect the 13 highest-risk HPVs; APTIMA detects HPV66, additionally. HC-2 detects HPV-DNA >1 pg/mL.29 HPV E6/E7 are often detected at higher levels where HPV is integrated into human DNA, a hallmark of cancer.30 Molecular HPV tests significantly reduce diagnostic follow-up referrals for women with equivocal cytology, limiting costly & invasive procedures, & while these tests improve detection of in situ & ICCs, they have not been explored as adjunctive tests for IAC screening. Also, sufficient attention has not been paid to improving the quality of anal Pap test specimens. This study seeks to evaluate two Pap test collection protocols & molecular HPV tests, as biomarker assays, using specimens collected at a single examination visit & randomized controlled study design. Optimizing the sequence of biomarker assays & cytology to predict HG- AIN will decrease morbidity & mortality, & lower use of costly & invasive diagnostic testing. We will evaluate the contribution that molecular HPV testing makes when simultaneously or sequentially positive tests, with or without (anal) cytology, are used to predict HG-AIN. Sensitivity, specificity, & PPV for anal cancer screening algorithms & their cost-effectiveness to prevent invasive anal cancer will be evaluated to inform practice. PUBLIC HEALTH RELEVANCE: Invasive anal cancer (IAC) is a health crisis for gay, bisexual & other men who have sex with men & male-to- female transgender females who have sex with men (MSM), especially where men are infected with HIV. Improved Pap test specimen collection together with properly calibrated laboratory biomarker tests will improve the accuracy of IAC screening strategies. Improved IAC screening will better drive research to develop better precancer treatments, decreasing the number of cancer cases & improving costs, the number of years lived & the quality of life for affected individuals.
Dr. Mary Woo, presented the third NINR Director's Lecture on May 21, 2013. Dr. Woo discussed her research on brain-heart interactions in a lecture entitled "It's All in the Mind: Heart Failure and the Brain." Watch here:
Title: BLOOD-BRAIN BARRIER DYSFUNCTION AND BRAIN INJURY IN HEART FAILURE
Agency: National Institute of Nursing Research, Project Number 1R01NR014669-01
DESCRIPTION (provided by applicant): Heart failure (HF) patients show brain injury in regions which control the autonomic (insular lobes), cognition (hippocampus, frontal cortex), and breathing (cerebellum) functions. Abnormalities in these sites are associated with symptoms which are linked to increased morbidity and mortality and decreased quality of life in HF. However, the underlying cause of brain injury in these areas in HF is unclear. Alteration in blood- brain barrier (BBB) function is a potential cause of brain damage in HF, as functional changes in the BBB are associated with neural injury in other diseases. However, there are no published reports of BBB changes in HF or regarding any association between BBB function and brain damage in this condition. Using non-invasive brain magnetic resonance imaging (MRI) procedures, our preliminary studies are the first to report BBB abnormalities (via diffusion-weighted pseudo-continuous arterial spin labeling [pCASL] procedures) in HF and that these BBB changes are associated with brain injury (as examined by diffusion tensor imaging based mean diffusivity [MD], an MRI measure of tissue integrity) in the insular lobes, hippocampus, frontal cortices, and cerebellar regions in HF subjects compared to controls. However, while promising, the sample size in this preliminary study was quite small and did not allow us to control for important covariates, such as age and gender. Therefore, the specific aims of this proposal are to: 1) compare global BBB function (calculated from diffusion-weighted pCASL) between HF and age- and gender-matched control subjects; 2) compare regional brain injury (assessed by MD) in the insular lobes, hippocampus, frontal cortices, and cerebellum between HF and age- and gender-matched healthy controls; 3) examine the relationship between altered BBB function (as indicated by diffusion-weighted pCASL data) and insular, hippocampal, frontal, and cerebellar injury (as indicated by MD measures) in HF patients. In summary, HF patients show significant regional brain injury in areas that control autonomic, cognitive, and breathing functions. A potential cause of this brain injury may be alterations in the BBB function. Abnormal BBB activity has not been reported previously in HF, but our preliminary studies have shown that BBB function is compromised and that this alteration is associated with brain injury in areas which control autonomic, cognitive, and breathing functions. The proposed study will examine global BBB function, assess regional tissue injury, and evaluate the relationships between BBB function and brain injury. Information from this study has the potential to disclose the processes contributing to brain injury in HF. Thus, it has important implications on identification of effectve treatments for HF by repairing BBB function, as used in other conditions (such as stroke), which could dramatically improve the mortality, morbidity, and quality of life in this high risk patient population.