- Efficient Sendai Virus Mediated CRISPR/CAS9 Gene Editing to Protect Hemotopoietic Stem Cells from HIV, Principal Investigator Dr. Dong Sung An
Agency: NIH National Institute of Allergy and Infectious Diseases Project Number 1R01AI138921-01A1
Finding a new HIV cure therapy is a major focus of NIH HIV research program. Our Sendai virus vector can genetically modify hematopoietic stem cells to confer HIV-resistance at unprecedented efficiencies. This overcomes the major obstacles in the field for anti HIV stem cell based gene therapy, and allows for the possibility of a HIV cure – the successful long-term drug-free control of HIV disease.
- Genetic Protection of Hematopoietic Stem Cells for Stable HIV Control. Principal Investigator: Dr. Dong Sung An
Agency: NIH National Institute of Allergy and Infectious Diseases Project Number: 1R01AI100652-01A1
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."
- Understanding Self and Family Management in HIV-positive Asian Americans in New York. Principal Investigator: Dr. Wei-ti Chen
Agency: NIH National Institute on Minority Health and Health Disparities Project Number R03
In this pilot project, we aim to improve the understanding of self-management barriers and facilitators among HIV-positive Asian Americans. This includes better understanding how they manage their physical and psychological discomforts, ART adherence, and quality of life, and how clinicians assess the need and readiness for self- and family-management intervention.
- Relationships Between Brain Tissue Integrity and Self-Care Abilities in Adults with Type 2 Diabetes. Principal Investigator: Dr. Sarah Choi
Funding Agency: NIH National Institute of Nursing Research Project Number:1R01NR017190-01A1
Over 26 million persons have Type 2 diabetes (T2DM), and poorly managed T2DM contributes to early morbidity and mortality; therefore, improving T2DM Fhealth outcomes and preventing T2DM-related complications through excellent self-care is a public health priority. Effective T2DM self-care requires intact cognition and mood, which are linked to brain structural changes. We will examine brain structural status between T2DM patients and non-diabetic healthy subjects, as well as gender differences, and investigate relationships between brain changes and self-care, mood, cognition, and impact of A1C levels in T2DM subjects, which could impact clinical practice and self-care of T2DM patients through the identification and testing of novel therapeutic interventions to protect or restore the brain, minimize or prevent cognitive and mood dysfunction, and thus, improve T2DM self-care and health outcomes in this high-risk patient population
- Feasibility testing of a randomized controlled trial of acupuncture to improve symptoms for stable angina (AIMS-A). Principal Investigator: Dr. Holli DeVon
Funding Agency: NINR Project Number R21 NR017705
- Characterizing prehospital delay and outcomes in patients treated for potential acute coronary syndrome in the emergency department. Principal Investigator: Dr. Holli DeVon
Agency: NHLBI Project Number R21 HL140277
- Feasibility of a Nursing Intervention to Reduce Pain, Fatigue and Depression in Pancreatic Cancer Patients and their Caregivers. Principal Investigators: Dr. Lynn Doering and Dr. Eunice Lee
Agency: Hirshberg Foundation for Pancreatic Cancer Research
Depression is common among both pancreatic cancer (PC) patients and caregivers, and impacts PC symptoms and quality of life (QOL). Access to effective depression treatment may be challenging. The goal of this proposal is to test the feasibility of an online nursing intervention to reduce overall suffering for PC patients and caregivers. Study aims are: Test practicality and acceptability of an online cognitive behavioral therapy led by cancer nurses along with education and coaching (iCBT-PLUS) for PC patient/caregiver pairs; In PC patients, determine the size of changes in pain, fatigue, and depression after iCBT-PLUS; In PC caregivers, determine size of changes in fatigue after iCBT-PLUS; Explore relationships of QOL to pain, fatigue, depression in PC pairs; Explore trends over time in severity and frequency of symptoms among non-depressed pairs via a novel smartphone application (chemowave.com). Fifty PC pairs will enroll in a 2-group study lasting 12 weeks. If at least of each pair has at least moderate depressive symptoms, the pair will be assigned to receive a nursing intervention using a well-established “talk therapy” for depression, delivered online, with 1) education regarding PC symptoms and treatment, and 2) communications coaching by trained cancer nurses regarding communication with healthcare providers. Non-depressed pairs will use a novel smartphone application at least weekly. Innovation: This study will test both a novel, multimodal online nursing intervention and a unique cancer-specific smartphone application to address depressive symptoms and overall QOL in PC patients and caregivers.
Study webpage: https://www.nursing.ucla.edu/node/511
- Development of a Connect: A Social Media Intervention for Depressed Cannabis Users. Principal Investigator: Dr. Suzette Glasner
Agency: NIH National Institute on Drug Abuse Project Number: 5R21DA042627-02
The proposed research is of considerable public health significance in that it will provide foundational information on the use of social media (i.e., Facebook) as a delivery medium for behavioral support for depressed adults with cannabis use disorders, a serious problem with extensive impacts. If proven effective, the protocol could be useful in reducing cannabis use and improving depressive symptomatology as well as depression treatment regimen adherence among treated individuals, thereby efficiently reducing drug abuse and related consequences such as criminal activity, social disruption, and high rates of health service utilization. This investigation will establish the clinical utility and mechanisms of action of an innovative social media-assisted intervention with potential for rapid and broad deployment to cannabis users with concomitant major depression.
- Depolarization-Induced Tau and Exosome Release from Synapses in AD. Principal Investigator: Dr. Karen Gylys
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.
- Targeting IGF2 and Adrogen Receptors for TNBC Therapy. Principal Investigator: Dr. Nalo Hamilton
Funding Agency: California Breast Cancer Research Program
Among women, receiving a diagnosis of breast cancer (BC) raises serious concerns regarding prognosis and survival. Indeed, certain types of BC are more-well studied and successfully treated than others. Specifically, unlike women with estrogen receptor-α (ERα) positive BC whose survival outcomes can be positively impacted by successful endocrine therapy, women with triple-negative breast cancer (TNBC) have not benefited from these advances. Women with TNBC cannot be treated with current endocrine therapies and though initially responsive to chemotherapy, frequently women with TNBC have early relapse and metastasis. Thus, women with TNBC continue to account for almost half of all breast cancer deaths. This disparity is concerning because those most often diagnosed with TNBC are women in their reproductive years and/or women who are African American. In light of this, our research priority is to identify prognostic/therapeutic targets that can be used to develop more effective treatments for women with TNBC.
- Metformin and analogues in triple-negative breast cancer immunotherapy. Principal Investigator: Dr. Nalo Hamilton
Funding Agency: NIH/NCI U54 CDU/UCLA Cancer Center Partnership Grant
The objective is to develop potent antitumor analogues of metformin that are safe for therapeutic treatment of patients with triple-negative breast cancer (TNBC).
- GABA and Glutamate Changes Underlying Altered Autonomic Function in Obstructive Sleep Apnea. Principal Investigator: Dr. Paul Macey
Funding Agency: National Institutes of Health National Heart, Lung and Blood Institute Project Number: 1R01HL135562-01A1
Obstructive sleep apnea (OSA) occurs in approximately 10% of the adult population, and patients experience changes to the brain that may contribute to increased illness and death, but we do not know the cause of those changes. In this project, we will relate levels of neurotransmitters, chemicals help control brain function, to structure and function in regions that regulate blood pressure and mood. The findings from this project will guide treatments to prevent, treat or recover impaired brain function in people with OSA.
- Sex-Specific Brain Injury and Symptoms in Sleep Apnea. Principal Investigator: Dr. Paul Macey
Funding Agency: National Institues of Health National Institute of Nursing Research Project Number: 1R56NR017435-01A1
Obstructive sleep apnea (OSA) occurs in over 10% of the adult population, and people with the disorder show changes to the brain that may contribute to more illness and lower quality of life. While OSA is less common in women, symptoms like difficulty thinking and feeling depressed are especially prominent and difficult to treat in females. In this project, we will determine separately in men and women whether brain injury may be contributing to the psychological problems, and whether the usual OSA treatment will resolve the brain injury.
- Cerebral Artery Integrity Linked to Brain Injury and Cognition in Congenital Heart Disease. Principal Investigator: Dr. Nancy Pike
Agency: NIH National Institute for Nursing, Project Number 1R01NR016463-03
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.
- Investigating the Cardiovascular Toxicity of Exposure to Electronic Hookah Smoking. Principal Investigator: Dr. Mary Rezk-Hanna
Funding Agency: National Institutes of Health National Heart, Lung and Blood Institute Project Number: 1R21HL145002-01
Narrative Hookah (water-pipe) smoking has quickly grown to become a major global tobacco epidemic among youth; with electronic hookahs more recently increasing in popularity especially among young female adults, who endorse marketing claims that these products are a safer alternative to traditional hookah, but scientific evidence is lacking. Our study aims to elucidate the comparative effects of traditional hookah smoking vs. electronic hookah inhalation on human vascular and endothelial function; and examine the role of inflammation and oxidative stress as likely mechanisms in hookah-related cardiovascular disease pathogenesis. Findings will: 1) provide rigorous scientific evidence to clarify the vascular effects, and the potential mechanisms, of traditional versus e-hookah exposure on known cardiac risk factors; and 2) provide a scientific basis needed to inform FDA tobacco regulatory science for the development of hookah policy regulation.
- Effect of Walnuts on Prostrate Health. Principal Investigator: Dr. Wendie Robbins
Agency: Walnut Commission
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.
- A Dyadic Sleep Intervention for Alzheimers Disease Patients and their Caregivers. Principal Investigator: Dr. Yeonsu Song
Funding Agency: NIH National Institute on Aging Project Number: 5K23AG055668-02
Poor sleep in both Alzheimer's disease (AD) patients and their caregivers is associated with adverse health outcomes, and increases risk of institutionalization in individuals with AD. This proposal will pilot test an innovative sleep intervention targeting both groups simultaneously. Improved sleep in AD patients and their caregivers may improve health and quality of life, and may prevent or delay admission of AD patients to institutional settings, potentially leading to decreased healthcare costs.
- Improving Screening Tools to Better Predict High-Grade Anal Dysplasia For MSM. Principal Investigator: Dr. Dorothy Wiley
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.
- Blood-Brain Barrier Dysfunciton and Brain Injury in Heart Failure. Principal Investigator: Dr. Mary Woo
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 effective 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.