University Of California, San Diego

NIH Research Projects · FY 2025 · 2022-09

Program Summary Nigeria has one of the largest HIV epidemics in the world with 1.8 million people living with HIV infection. With an estimated female population of 102 million and HIV prevalence of 1.6% among adult females, Nigeria has the largest population of women and the 4th largest number of women living with HIV (WLHIV) in Africa. Although access to antiretroviral therapy (ART) among WLHIV in Nigeria has increased over the years, with over 98% of the 960,000 WLHIV on ART, AIDS-related mortality remains high. In 2020, 16,000 WLHIV died from AIDS- related illnesses including cervical cancer. A pilot implementation program in Nigeria demonstrated that leveraging the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) supported HIV programs for the provision of evidence-based cervical cancer screen-and-treat interventions in WLWH is feasible. The pilot program demonstrated, however, that tailored implementation strategies will be needed to address specific multilevel barriers along the cancer control continuum in order to address adoption, reach, and sustainability that are necessary for successful scale-up. However, in many African countries with a high burden of both HIV and cervical cancer, there is a paucity of evidence-based implementation strategies to inform effective integration of HIV and cervical cancer services delivery. Objectives of this proposal are to: 1) Refine strategies to integrate cervical cancer screening, treatment and management within existing comprehensive HIV treatment programs and determine implementation readiness; 2) Determine the comparative effectiveness of a Core set of implementation strategies versus Core+ enhanced implementation strategies; and 3) assess sustainment of the integration of cervical cancer screening, treatment, and management intervention into HIV programs. We have assembled a strong team from University of California San Diego; University of Nigeria, Nsukka and John Hopkins University with expertise in implementation science, HIV care and research, and cancer care and research. Our proposal is responsive to the NCI RFA and consistent with the World Health Organization global plan of elimination of cervical cancer by 2030. If effective, the proposed project will result in a set of feasible, culturally adaptable, and sustainable implementation strategies to integrate evidence-based cervical cancer screening and treatment into HIV programs in order to improve the health and life expectancy of WLHIV.

NIH Research Projects · FY 2024 · 2022-09

PROJECT SUMMARY Persistent immune activation is the defining feature of HIV-1 infection in vivo and a driver of progression to end-stage AIDS. Systemic immune activation in people living with HIV has been hypothesized to account for higher incidence of chronic inflammatory diseases, including HIV-associated neurocognitive disorders (HAND). While significant neurological complications associated with HIV-1 infection occur years after seroconversion and is commonly coincident with progressive immunosuppression and high viral loads, establishment of a virus reservoir in the CNS occurs with primary infection. Furthermore, acute infection in the CNS is thought to initiate a cascade of pro-inflammatory events that result in inflammation- induced neuronal injury and associated neurocognitive disorders that are evident even in the present combination antiretroviral therapy (cART) era. Approximately 12 million people inject drugs globally, 13% of these are people living with HIV. Opioid misuse is a route of HIV acquisition and a barrier to effective antiretroviral therapy (ART). However, it is unclear whether opioid misuse changes the course of HIV pathogenesis, especially on HIV-associated neurocognitive disorders. Our central hypothesis is that opioid misuse exacerbates HIV pathogenesis in the CNS by dysregulating the glial population in the brain. Our overall objective is to exploit cell type specific transcriptomic information at the single nuclei level from patient brain samples to characterize the effects of opioid use disorder on CNS neuronal and glial cells, HIV infection and HANDs. We will characterize single nuclei gene expression and identify dysregulated gene regulatory networks in each of the neuronal and glial populations associated with opioid misuse in HIV infected individuals and/or with HANDs. We will also perform computational analysis to identify neuronal and glial cell regulatory networks altered by opioid misuse. In the validation component, we will select the top 20 targets from single cell transcriptomics profiles, first validating with immunohistochemistry with fixed brain tissue, then selecting a few top targets and using 2D and 3D cultures of iPS derived neurons, microglia and astrocytes to characterize functionality with CRISPR knockout. Successful completion of these aims will have significant research and clinical impact by 1) elucidating how opioid misuse alters HIV/HAND pathogenesis in the CNS, and 2) discovering candidate molecules to regulate HIV infection or persistence in the CNS in the context of opioid misuse.

NIH Research Projects · FY 2025 · 2022-09

SUMMARY This application will study a novel role of the enzyme phosphatidylinositol-glycan-specific phospholipase D (GPLD1) in relation to physical activity (PA), cognitive outcomes, and relevant mediating pathways, including inflammation, coagulation, mitochondrial indices and vascular remodeling in aging people with HIV (PWH). Although PA promotes better cognitive function and quality of life in HIV, PA is problematic for many aging PWH due to physical limitations from neuropathy, cardiopulmonary disease, and other conditions. Systemic GPLD1 was recently shown to recapitulate the neurogenic and cognitive benefits of exercise and may represent an alternative approach to gain neural benefits of exercise for those with physical limitations. In an existing cohort of 100 PWH (50 participating in a PA intervention and 50 controls), we will quantify how GPLD1 levels change before and after the PA intervention and how these levels associate with plasma markers of inflammation, clotting, vascular remodeling, mitochondrial indices and neurocognitive (NC) performance. We propose PWH with higher levels of PA documented by Fitbit and accelerometer monitoring will show greater increases in GPLD1 than those with lower PA. We hypothesize that higher GPLD1 at baseline will associate with improved markers of inflammation, abnormal clotting, mitochondrial indices and vascular remodeling and that greater increases in GPLD1 during the PA intervention will correlate with larger improvements in these indices. Additionally, we expect that higher baseline GPLD1 will associate with better NC performance and that GPLD1 increases during the 6-month PA intervention will associate with improving NC performance. In addition to human studies, we will perform translational work to evaluate mechanisms by which GPLD1 exerts salutary effects. These will include studies in an animal model of virally suppressed PWH on antiretroviral therapy (ART), the EcoHIV mouse model. In these animals, we will measure the effects of GPLD1 administration on cognition and markers of inflammation and clotting, including evaluating if the beneficial effects of GPLD1 are blocked by an inhibitor (phosphatidic acid). In addition, we will characterize inflammation, mitochondrial indices and synaptodendritic integrity in brain tissue from GPLD1-treated mice. We expect GPLD1 treatment in EcoHIV mice will improve behavioral performance, reduce brain tissue inflammation and improve synaptodendritic integrity and mitochondrial indices. In service of future Phase 1 clinical trials, we will examine GPLD1 effects on liver toxicity in mice. We will also evaluate neuronal cultures for GPLD1 effects on mitochondrial biogenesis and neurogenesis by exposing cultures to plasma from humans in the PA intervention. We expect PWH plasma with higher PA will stimulate hippocampal mitochondrial biogenesis and neurogenesis compared to lower PA, and will determine if serum GPLD1 associates with these outcomes. Examining GPLD1 effects in PWH, our translational design, and extension of prior works into brain mechanisms of GPLD1, including inflammation and mitochondrial function, which is impaired by antiretroviral therapy (ART)-related neurotoxicity, are innovative.

NIH Research Projects · FY 2024 · 2022-09

Bilinguals have remarkable control abilities to prevent interference between languages in production and comprehension, two modalities that have different goals and go through different pathways. However, it still remains unclear if and to what extent language control mechanisms are shared or different across these two modalities. The proposed project will systematically compare language control mechanism in production versus comprehension at different processing levels. We will combine ERP (Event-Related Potential in the brain) measures and the mixed-language paragraph reading paradigm to reveal the neuro-cognitive processes of language switching in sentence context, modulating syntactic and phonological constraints. Bilinguals will read the same mixed-language paragraphs in production and comprehension tasks, with the only difference being if articulation is required. ERP measures will provide detailed information about how language control works as the language-switching event unfolds in real time. My Specific Aims are: Aim 1 (K99): to investigate the role of syntactic constraints in language control during production vs. comprehension by measuring bilinguals' ERPs on language switching with content vs. function words, which carry more semantic vs. syntactic information, respectively. In production, I expect larger costs switching function words, as these need more inhibition and monitoring, revealed by N2 and ERN respectively. If syntactic constraints equally affect production and comprehension, function switches should be more costly than content switches also in comprehension, revealed by P600/LPC, or even N400 as well. Alternatively, content switches might be more costly in comprehension, revealed by P600/LPC and N400, due to vague syntactic analysis and the priority to integrate semantic information. Aim 2 (R00): to investigate how phonological constraints influence language control during production vs. comprehension by measuring bilinguals' ERPs on intra-sentential language switches with cognates vs. noncognates. Cognates are words with cross-language phonological overlap (e.g., lemon-limón). I expect larger costs with cognate than noncognate switches in production, as more inhibition and monitoring are needed for cognates, revealed by N2 and ERN respectively. For comprehension, if language selection is also critical, switch costs with cognates may be larger than noncognates, revealed by N400 and/or P600/LPC. Otherwise, switch costs may be smaller with cognates than noncognates due to easier semantic integration with cognates, revealed at least by N400, or even by P600/LPC as well. My training in the K99 phase will include structured mentorship by my advisory committee on both theoretical framework (language production and comprehension, as well as bilingual language control) and the training of new methodology (ERP measures). It will also include formal course work, workshops, and a program of career transition. This career plan and research project will ensure my successful transition to independent research, fulfilling my career goal of understanding bilingual language processing in a comprehensive view. !

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY/ABSTRACT Research Plan: Worldwide, one in 8 adults has obstructive sleep apnea (OSA) which results in disturbed sleep, daytime sleepiness, and increases the risk for many health issues including cognitive impairment, heart attacks and strokes. Unfortunately, half of OSA patients are unable to use continuous positive airway pressure therapy, and due to limited alternative options, most remain untreated. But OSA is a heterogenous condition, and mechanisms underlying OSA in individual patients (“endotypes”) can now be quantified, allowing targeted manipulation and providing a clear avenue to develop OSA drug therapy as an alternative for such patients. Ventilatory instability (“high loop gain”) contributes to OSA pathogenesis in one third of patients. The PI’s data suggests that acetazolamide—a safe, low-cost ($0.66/day), once daily drug which lowers loop gain—can markedly improve OSA and its sequelae in some patients, and may be particularly beneficial for patients with a high loop gain endotype. However, prior studies generally did not measure loop gain and data on clinically important outcomes are scarce. To define better acetazolamide’s value for patient-care, the PI will conduct a randomized, placebo-controlled, crossover trial, testing if 4 weeks of acetazolamide in general OSA patients improves OSA severity (aim 1) and clinically important outcomes (aim 2), and assess predictors/mechanisms (including loop gain) of changes in these outcomes (aim 3) to help identify likely responders more precisely. Career Development Plan: The PI, Dr Chris Schmickl MD/PhD, has a strong background in epidemiology, biostatistics and clinical sleep medicine. This K23 award will provide him with the protected time and training to achieve his long-term goal of becoming an independent physician-scientist, translating physiological insights into precision pharmacotherapy for patients with OSA who are unable to use current therapies. To achieve this long-term goal Dr Schmickl will develop advanced skills in three key domains which perfectly align with the expertise of his diverse and outstanding mentor/advisor team from UC San Diego: 1) OSA patho- physiology (Drs Malhotra/Owens/Nemati); 2) Designing/executing clinical trials (Dr Jain); and 3) Assessing clinically important outcomes (Drs Banks/Taub). Based on a gap analysis, a comprehensive training plan was designed which carefully balances hands-on research experiences with complementary coursework, and emphasizes the importance of a responsible conduct of research. Clear objectives and milestones have been defined to track progress during the award. The acquired data and skills will allow the PI to expand on this work with an R01 studying the long-term effects of acetazolamide (and/or other interventions) in patho- physiologically defined subgroups of likely responders. More broadly, this award will enable him to develop novel, high-impact, precision interventions for the many currently untreated OSA patients, thereby joining the NHLBI mission to enhance the health of all individuals so that they can live longer and more fulfilling lives.

NIH Research Projects · FY 2025 · 2022-09

Project Summary Individuals with advanced glaucomatous damage have markedly impaired visual function resulting in a decreased quality of life. This proposal will provide the longitudinal follow-up to fill in important gaps in our knowledge about monitoring eyes with advanced open angle glaucoma (OAG). Monitoring of the disease in its advanced stages is challenging because the visual field island shrinks to such an extent that only the central visual field survives and measurement of the retinal nerve fiber layer thickness reaches a floor, after which more thinning is not detectable. The overall objectives of this application are (i) to characterize the macular structural (microvasculature and thickness) and functional changes in eyes with advanced OAG and (ii) to develop novel models that can detect and predict progression in these eyes. The central hypothesis is that novel statistical and artificial intelligence-based analyses of central visual field functional status and recently developed macular optical imaging measurements will improve monitoring of disease in advanced OAG eyes. There is a critical need for models that can predict glaucomatous progression in advanced OAG eyes and to characterize longitudinal loss of macular structure and function in order to advise clinical decision making. The central hypothesis will be tested by 3 Specific Aims. Aims 1 and 2 will develop and validate models for detection of OAG progression using the central 10 degree visual field and characterize patterns of the longitudinal changes in the central visual field and retina. Cluster-based progression methods will be applied in vulnerable and less vulnerable zones of the 10-2 visual field. Nested multivariable linear mixed effects models will be used to compare rates of macula structure (ganglion cell layer and vessel density) and functional change (in eyes with Mean Deviation <-8 dB) and to characterize the relationships between baseline patterns of visual field and structural loss and glaucoma progression while adjusting for inter-eye correlation. In Aim 3, we will apply novel deep learning techniques to macular function and recently developed optical imaging measurements to improve the prediction accuracy of glaucomatous progression in advanced disease. Complex functional and structural tests in daily use by eye care providers contain hidden information that is not fully used in the current analyses and advanced pattern recognition/machine learning-based analysis techniques can find and use that hidden information. We will use mathematically rigorous unsupervised techniques such as archetypal analysis and multimodal deep learning to discover patterns of defects and assess the risk of changes in longitudinal series of perimetric and optical imaging data from >500 patients, available in our NIH-supported glaucoma database. The proposed work is significant because it will lead to development of more effective mathematically-based, validated methods of detecting OAG progression in eyes with advanced disease. Moreover, it will reduce the cost of glaucoma care by identifying high-risk patients that require more aggressive treatment, thus decreasing disability and reducing the burden of glaucoma blindness.

NIH Research Projects · FY 2025 · 2022-09

As part of the NIH Common Fund’s Bridge2AI program, the CM4AI data generation project seeks to map the spatiotemporal architecture of human cells and use these maps toward the grand challenge of interpretable genotype-phenotype learning. In genomics and precision medicine, machine learning models are often "black boxes," predicting phenotypes from genotypes without understanding the mechanisms by which such translation occurs. To address this deficiency, project will launch a coordinated effort involving three complementary mapping approaches – proteomic mass spectrometry, cellular imaging, and genetic perturbation via CRISPR/Cas9 – creating a library of large-scale maps of cellular structure/function across demographic and disease contexts. These data will broadly stimulate research and development in "visible" machine learning systems informed by multi-scale cell and tissue architecture. In addition to data and tools, this project will implement a standards data management approach based on FAIR access and software principles, with deep provenance and replication packages for representation of cell maps and their underlying datasets; initiate a research program in ethical AI, especially as it relates to how maps will be used in genomic medicine and model interpretation; and stimulate a diverse portfolio of training opportunities in the emerging field of biomachine learning.

NIH Research Projects · FY 2025 · 2022-09

Project Summary/Abstract The interaction between our diet, metabolism by the microbiome, and the downstream biological effects on the host are key foundational knowledge that will guide the development of precision medicine integrated with nutrition. To characterize the function of these individual metabolites that are transformed from foods or fully synthesized by the microbiome will improve the mechanistic understanding of Microbe-Diet-Host interactions. Despite this importance, the community lacks a knowledge management center that centralizes and aggregates bioactivity and function of these metabolites that hinders the ability of researchers to reuse knowledge in a high throughput fashion and build off the discoveries of others. The proposed “Collaborative Microbial Metabolite Center” or CMMC proposed here will fill this void in the scientific landscape, aiming to integrate microbial metabolite discovery and activity from PAR-21-253 grantees and the broader microbial metabolomics community. The CMMC will build a centralized microbial metabolites bioactivity knowledge base that aims to work with the grantees and community to define standards to represent bioactivity, handle community depositions of knowledge and supporting raw data, aggregate depositions into corroborated knowledge, apply knowledge to new data, propagate knowledge into previous uncharacterized molecules, and integrate with other community knowledgebases that host complementary knowledge for microbial metabolites. All data, knowledge, and tools will be made findable, accessible, interoperable, and reusable (FAIR). This proposal will 1) Build the web portal for microbial metabolites with search, export, and analysis functions. 2) Build a microbial metabolite knowledgebase with the accompanying R01 grantees, NIDDK, and the larger scientific community. 3) Coordinate data sharing activities, training and technical support and organize a yearly meeting. The PIs and Co-Is are well suited to address the needs and build the proposed knowledge base, due to their expertise in microbial metabolomics (Dorrestein), microbiome (Dorrestein, Knight), knowledge base creation (Dorrestein, Wang, Knight, Bandeira), community outreach (Dorrestein, Wang), platform training (Dorrestein, Wang), community tool integration (Wang), community knowledgebase integration (Dorrestein, Wang, Knight, Bandeira), scalable tool development (Wang, Bandeira), and data resiliency (Wang, Bandeira).

NIH Research Projects · FY 2026 · 2022-09

PROJECT SUMMARY Alzheimer’s disease (AD) and other tau-mediated neurodegenerative diseases are characterized by aggregation and spread of pathological tau protein in the brain. Despite decades of research, effective interventions to these diseases are still lacking. It is well-evidenced that women typically show greater tau pathology than men on the AD trajectory; yet the reason for such sex differences is poorly understood. A better understanding of the mechanisms underlying the greater tau deposition in women can benefit all by informing causal pathways of disease and therapeutic targets and strategies that are optimal for each sex. Clinical evidence suggests that low testosterone levels correlate with poorer cognitive function and greater risk for AD. In particular, a recent study in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) revealed that women with lower testosterone tend to have higher levels of phosphorylated tau (p-tau) in cerebrospinal fluid (CSF), particularly among ApoE4 carriers. This suggest that lower testosterone levels that typically characterize women may predispose them to pathological tau, and contribute to sex differences observed in AD. To take these correlative findings to the necessary next step, our overall objectives are to establish the causal relationship between testosterone and tau in females, to explore the clinical applicability of testosterone therapy, and to elucidate the underlying molecular mechanisms. Given testosterone’s anti-inflammatory actions and neuroprotective effects on AD-related outcomes, we hypothesize that pharmacological induction of high testosterone protects against pathological tau accumulation and spread, diminishes neuroinflammation and ameliorates cognitive deficits associated with tau pathogenesis, particularly in ApoE4 females. Based on published preclinical studies on testosterone, we further hypothesize that the protective effects of testosterone are linked to androgen receptor signaling in astrocytes and neurons, leading to enhanced neuronal survival, synaptic integrity and reduces neuroinflammation. This project is a new direction in our research program: In collaboration with experts on reproductive biology and gene expression, we will combine our expertise in tau biology, sex hormones and transcriptomics to determine how testosterone modulates tau pathogenesis in a sex-specific manner. We will: 1) Determine how increase of testosterone levels affects tau pathogenesis in female tau transgenic mouse models with human ApoE4/E3 knock-in; 2) Elucidate the molecular mechanism underlying the protective effects of testosterone in ApoE4 females by single nucleus RNA sequencing, and determining the involvement of neuronal and astrocytic androgen receptor signaling. This project aims to close critical gaps in our understanding of mechanisms underlying sex differences in tau pathophysiology, and provide novel insights into the influence of androgen on molecular mechanisms central to AD pathogenesis. Results from the proposed research will address NIA strategic goals: understand the progression of Alzheimer’s (A), and identify potential therapeutic targets for the development of precision medicine treatments for men and women (D).

NIH Research Projects · FY 2024 · 2022-09

SUMMARY This application will study a novel role of the enzyme phosphatidylinositol-glycan-specific phospholipase D (GPLD1) in relation to physical activity (PA), cognitive outcomes, and relevant mediating pathways, including inflammation, coagulation, mitochondrial indices and vascular remodeling in aging people with HIV (PWH). Although PA promotes better cognitive function and quality of life in HIV, PA is problematic for many aging PWH due to physical limitations from neuropathy, cardiopulmonary disease, and other conditions. Systemic GPLD1 was recently shown to recapitulate the neurogenic and cognitive benefits of exercise and may represent an alternative approach to gain neural benefits of exercise for those with physical limitations. In an existing cohort of 100 PWH (50 participating in a PA intervention and 50 controls), we will quantify how GPLD1 levels change before and after the PA intervention and how these levels associate with plasma markers of inflammation, clotting, vascular remodeling, mitochondrial indices and neurocognitive (NC) performance. We propose PWH with higher levels of PA documented by Fitbit and accelerometer monitoring will show greater increases in GPLD1 than those with lower PA. We hypothesize that higher GPLD1 at baseline will associate with improved markers of inflammation, abnormal clotting, mitochondrial indices and vascular remodeling and that greater increases in GPLD1 during the PA intervention will correlate with larger improvements in these indices. Additionally, we expect that higher baseline GPLD1 will associate with better NC performance and that GPLD1 increases during the 6-month PA intervention will associate with improving NC performance. In addition to human studies, we will perform translational work to evaluate mechanisms by which GPLD1 exerts salutary effects. These will include studies in an animal model of virally suppressed PWH on antiretroviral therapy (ART), the EcoHIV mouse model. In these animals, we will measure the effects of GPLD1 administration on cognition and markers of inflammation and clotting, including evaluating if the beneficial effects of GPLD1 are blocked by an inhibitor (phosphatidic acid). In addition, we will characterize inflammation, mitochondrial indices and synaptodendritic integrity in brain tissue from GPLD1-treated mice. We expect GPLD1 treatment in EcoHIV mice will improve behavioral performance, reduce brain tissue inflammation and improve synaptodendritic integrity and mitochondrial indices. In service of future Phase 1 clinical trials, we will examine GPLD1 effects on liver toxicity in mice. We will also evaluate neuronal cultures for GPLD1 effects on mitochondrial biogenesis and neurogenesis by exposing cultures to plasma from humans in the PA intervention. We expect PWH plasma with higher PA will stimulate hippocampal mitochondrial biogenesis and neurogenesis compared to lower PA, and will determine if serum GPLD1 associates with these outcomes. Examining GPLD1 effects in PWH, our translational design, and extension of prior works into brain mechanisms of GPLD1, including inflammation and mitochondrial function, which is impaired by antiretroviral therapy (ART)-related neurotoxicity, are innovative.

NIH Research Projects · FY 2026 · 2022-09

PROJECT SUMMARY This is the initial submission of a K01 application by Lindsay Miller Ph.D., under the mentorship of Joachim Ix M.D., at the University of California, San Diego (UCSD). This proposal will establish Dr. Miller as an independent investigator and will leverage large-scale proteomics to understand the association and predictive ability of the proteome with cognitive impairment (CI), a clinical symptom of Alzheimer’s Disease and Related Dementias (ADRD) in older adults with chronic kidney disease (CKD). Candidate: Dr. Miller’s training objectives and career goals through this proposal include: 1) to become an expert in CKD and CI in older adults 2) to develop skills in advanced methods for the application to proteomic data, and 3) to develop skills in grant writing, lab management and career development. Dr. Miller will accomplish these objectives through mentorship, coursework, and workshops. She has assembled a multidisciplinary mentorship team comprised of her primary mentor, Dr. Ix, an established leader in nephrology, and the following co-mentors: Dr. Marquine, an expert in neuropsychology; Dr. Scherzer, the Director of Biostatistics at the Kidney Health Research Collaboration at the University of California, San Francisco. Research: CI is a clinical symptom of ADRD, with mild CI being often a precursor to the development of ADRD. CI is common among patients with CKD; however, CI has received much less investigation than complications such as CVD and end-stage kidney disease. Studies have primarily used estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (ACR) to evaluate the relationship between CKD and CI. However, in recent work the applicant demonstrated that a panel of markers reflecting kidney tubule health was associated with CI independent of eGFR and ACR in older adults, indicating that these markers of kidney health do not fully explain its link with CI. Still, the relationship is likely more complex that what can be identified using a few targeted biomarkers. Thus, Dr. Miller proposes to utilize large-scale proteomic data to understand the multifactorial relationship between CKD and cognition with the long-term objective that these insights might lead to novel approaches and therapies to prevent or ameliorate the development of CI in the CKD population. Next, while large-scale proteomics is optimally suited to understand biological pathways between CKD and CI, it will not be feasible to utilize in clinical practice to identify individuals at highest risk for CI. As such, variable selection methods are needed to identify and validate subsets of proteins that will allow clinical prediction of cognitive impairment. In aim 1, she will identify protein clusters and biological pathways that associate with CI. This aim will be conducted in 3419 adults with CKD in the Chronic Renal Insufficiency Cohort Study (CRIC). In aim 2 she will test different penalized variable selection methods to identify a panel of proteins that predict CI in the same CRIC cohort. In aim 3, Dr. Miller will determine if the clusters and proteins identified in CRIC externally validate among 1076 older adults with CKD in the Cardiovascular Health Study.

NIH Research Projects · FY 2025 · 2022-09

ABSTRACT For the first time in decades, HIV incidence is increasing among people who inject drugs (PWID). Pre- exposure prophylaxis (PrEP) is a safe, effective, evidence-based HIV prevention strategy recommended for at- risk PWID. However, despite the acceptability of PrEP among PWID, access remains low, and uptake has lagged far behind that observed in other vulnerable populations. Our preliminary research demonstrates that syringe service programs (SSPs) are uniquely poised to improve PrEP access, and many already provide some services along the PrEP delivery cascade, including PrEP education, HIV testing, and linkage to onsite and external medical services. Despite being ideal venues for improving PrEP access among PWID, our data demonstrate that these agencies need additional support to optimally implement the SSP-based PrEP delivery cascade. This novel randomized controlled trial (RCT) uses an interrupted time series design to test whether an evidence-based, organization-level intervention, the Systems Analysis and Improvement Approach (SAIA), can improve the delivery of PrEP services among 32 SSPs located in Ending the HIV Epidemic priority jurisdictions. After a 3-month run-in period, SSPs will be randomized to receive SAIA (n=16) versus treatment as usual (n=16). SAIA will be delivered by trained specialists through five cyclical steps over 12 months: (1) analyze SSPs’ PrEP delivery cascade to identify priority areas for system improvements, (2) map processes and build consensus around programmatic modifications to address priority areas, (3) implement programmatic modifications, (4) assess effects of programmatic modifications on delivery of cascade services, and (5) repeat steps 1-4 as needed. SSPs will use an electronic data collection system to report on outcomes including numbers of SSP clients receiving (1) PrEP education, (2) HIV testing, (3) PrEP linkage, and (4) PrEP initiation verification. Data will be collected during the 3-month run-in period prior to randomization, and then for an additional 24 months, allowing us to identify initial impacts of SAIA after 12 months (Aim 1) and sustained impacts at 24 months (Aim 2). Outcomes will be disaggregated by sex and race/ethnicity to allow for process monitoring of programmatic changes to address equity in service delivery. We will also estimate the cost and cost-effectiveness of SAIA relative to treatment as usual using an activity-based costing approach (Aim 3). To our knowledge, this will be the first RCT of an organizational-level intervention to optimize the SSP-based PrEP delivery cascade. If successful, SAIA could be disseminated to the ≥430 SSPs nationally and in global settings, carrying the potential for exceptional impact amidst persistent HIV transmission in PWID.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY A central goal of neuroscience is to understand animal behavior in the context of the information processing properties of neuron ensembles. Neurons are circuit nodes in the brain information processing network, but they are also cells that express hundreds of genes that may make important contributions to determining their activity patterns. The relationship between gene expression, neuron projections, neuron activity, and behavior have been, individually, major avenues for investigation in both molecular and systems neuroscience. Integrating these levels of investigation would greatly advance understanding the influence of molecular properties on neuron information processing characteristics in healthy brains and disease states. In this project, which we refer to as CaRMA 2.0, we propose to develop and democratize methodologies to integrate measurements of transcriptomics, projectomics, calcium dynamics, and behavior in deep-brain structures. This proposal builds on our past success to develop and implement Calcium and RNA Multiplexed Activity (CaRMA) imaging, which combines these levels of investigation into a single large-scale experiment. This is achieved by deep-brain two-photon calcium imaging in a behaving mouse, followed by removing and sectioning the brain, aligning the ex vivo image volume with the in vivo-imaged neurons, and then performing multiple rounds of RNA-fluorescence in situ hybridization (FISH) on the same tissue. To reliably produce these high dimensional, multi-modal datasets requires significant advancements for “Optimization of Transformative Technologies for Large Scale Recording and Modulation in the Nervous System” as indicated in this RFA-NS-18-019 program announcement. We will develop improved technologies for deep-brain calcium imaging as well as highly multiplexed gene expression analysis on the same cells and apply this pipeline to investigate the mPFC, hindbrain, and the role of the lateral hypothalamus in hunger, thirst, and fear.

NIH Research Projects · FY 2025 · 2022-09

Reinforcement learning (RL) is a fundamental learning process that is common across species and essential for cognitive flexibility and survival. In addition to neuroscience and psychology, RL also has proved valuable in the field of artificial intelligence (AI), achieving super-human performance in complex tasks. Understanding of the neural mechanism of RL would facilitate not only the development of diagnosis and treatment for learning and cognitive disorders but also development of novel deep RL architectures in AI. In this proposal, we aim to gain insights into how different brain areas work together to support RL. To tackle this problem, we use a behavioral task that entails two layers of RL at different timescales: fast RL to solve the task within a session and slow RL to learn the fast RL strategy over weeks/months of training. By leveraging mouse genetics and cutting-edge technology such as longitudinal two-photon calcium imaging of neural population activity and dopamine signaling, optogenetics, plasticity perturbation, and modeling with artificial deep RL networks, we will investigate the neural mechanisms of the fast and slow. In particular, we hypothesize that synaptic plasticity in the orbitofrontal cortex (OFC) plays a central role in slow RL. We will investigate the functions of OFC and its dopamine signaling in RL in Aims 1 and 2. In Aim 3, we will examine how OFC interacts with other cortical areas in RL. These aims will uncover the large-scale circuit basis of different aspects of RL and offer a novel conceptual framework to understand how RL is implemented in the brain.

NIH Research Projects · FY 2026 · 2022-09

ABSTRACT The prevalence of chronic pain is higher among American Indian/Alaskan Native (AI/AN) people than any other group in the United States. Although a number of psychosocial interventions for chronic pain are well-established as effective, there are no culturally adapted interventions for AI/AN individuals. This proposed study aims to begin the process of developing a culturally-adapted psychosocial pain intervention for AI/AN individuals at the Portland Area Indian Health Service – Yakama Service Unit. The K99 phase focused on the development of the intervention and the R00 will entail a feasibility randomized pilot trial. During the K99 phase, focus groups aided in the development of a treatment manual, workbooks, and procedures for a culturally appropriate psychosocial pain intervention (Specific Aim 1). After developing a prototype intervention during the K99 phase, focus groups then provided feedback to improve the intervention (Specific Aim 2). Specific Aim 3 (R00) is to assess the feasibility of conducting a future randomized controlled trial with the developed intervention from the K99 phase. This research will provide pilot data for an NIH R01 proposal which will be prepared and submitted towards the end of the R00 phase. The long-term objective of the proposed Pathway to Independence Award is to support the applicant in transitioning into an independent research scientist who studies chronic pain and conducts intervention research in AI/AN communities. The candidate’s prior research in chronic pain in low-income communities in Alabama, community-based participatory research, and clinical trials are a strong match for this current proposed project. With the K99 training plan, she has expanded her knowledge and expertise into an important new area of research that has largely been understudied, has strengthened skills in cultural competency in working with AI/AN individuals (Training Goal 1), gained skills in conducting community-based participatory research with AI/AN communities (Training Goal 2), and fostered skills in the development, adaptation, implementation, and dissemination in clinical trials (Training Goal 3). Drs. Jensen, Rhudy, Fuentes, and Johnson-Jennings will continue to serve as mentors and offer expertise in the areas of chronic pain intervention research, cultural adaptations for psychosocial interventions for AI/AN individuals, tribal based research, and community-based research methods with AI/AN communities. The University of Washington training environment provided significant resources and support that facilitated the development of skills and expertise needed for the applicant to transition into an independent research scientist. The University of California San Diego provides excellent resources and support for early career development during the R00 as an independent research scientist. The Yakama Service Unit is strongly committed to this proposed study and will provide critical support in recruitment, retention, and space for treatment. Because each tribal community has their own values, traditions, and culture, the proposed study will offer a step-by-step process for culturally adapting chronic pain interventions that may extend to tribal communities across the country.

NIH Research Projects · FY 2026 · 2022-09

Project Summary/Abstract In late 2019, the SARS-CoV2 virus emerged as a global pandemic, causing the severe respiratory disease COVID-19 and resulting in millions of deaths worldwide. As a coronavirus, SARS-CoV2 host interactions are dictated through the Spike proteins that encompass the virion. The Spike protein of SARS-CoV2, is a highly glycosylated trimer that interacts with the ACE2 receptor on host cells via the receptor binding domain (RBD) to facilitate viral entry. As a key player in viral infection, the Spike trimer, and the RBD, have become the target for a majority of approved therapeutics and vaccines used to treat or prevent SARS-CoV2. In this proposal, the PI uses a novel antiviral lectin, BOA, which he has demonstrated that BOA binds glycans on the spike protein, and inhibits SARS-CoV2 viral entry. To understand how BOA inhibits viral entry, during the K99 phase of the award, the PI will determine the mechanism by which BOA inhibits in SARS-CoV2 viral infection using a combination of viral inhibition assays, biophysical assays, and electron microscopy. Subsequently the PI will test the ability of BOA to inhibit emerging SARS-CoV2 variants of concern that have accumulated mutations to various regions of the spike protein that facilitate immune escape. Expanding upon these findings during the independent R00 phase of this award, the PI will use skills developed during the K99 phase to establish his own independent research group, where they will test the ability of the BOA lectin to inhibit viral entry of Beta- Coronaviruses known to infect humans. Successful completion of these aims could provide a bona fide broad spectrum coronavirus inhibitor to be further developed as a therapeutic or diagnostic for the next coronavirus that emerges. The proposed research, will provide the PI with new and exciting training in virology as well as electron microscopy which he intends to pass on to his future trainees. The proposed work will be completed at The University of Pittsburgh, where the Department of Structural Biology and Center for Vaccine Research will provide unmatched access to resources, instrumentation, and experts in the field. The PI has assembled an exciting mentorship team of virologists and biophysicists who he will meet with monthly to receive advice, discuss results, designed new experiments, and prepare for transitioning into an independent career. To aide in his career development, the university offers numerous workshops to develop skills such as grant writing and mentorship. The PI will also attend conferences to give presentations and hone his science communications skills. In Summary, the proposed training and career development plans will prepare the PI to lead his own independent research group and become a leader in his field.

NIH Research Projects · FY 2025 · 2022-09

CYTOSCAPE: AN ECOSYSTEM FOR NETWORK GENOMICS PROJECT SUMMARY Cytoscape is an open source software platform for biological network analysis, visualization and modeling. It is a critical bioinformatics resource in academia and industry, with 300,000+ downloads per year and 25,000+ citations. The widespread adoption of Cytoscape is due mainly to its utility in diverse biological analyses, its sustainable open development model, and its extensible architecture, which enables anyone to add algorithmic functionality and has attracted hundreds of third-party developers. Access to network analysis tools is particularly important now, at a time when network knowledge and concepts are increasingly central to genomics research. Cytoscape is in an excellent position to address this need and serve as a hub for knowledge-based genome analysis. In this application to support Cytoscape as a U24 Genomic Community Resource, we will work towards four specific aims. First, we will maintain our longtime substantial commitment to produce Cytoscape software as a critical research resource. Second, we will complete our ongoing development of Cytoscape as an ecosystem of tools and services on the web, so that key network biology tools are more accessible to biomedical researchers and can readily access big biomedical datasets and interoperate in cloud computing environments. Immediate targets of these developments will be resources in which federal organizations are already making substantial investments, including AnVIL, BioData Catalyst and Cancer Genomic Data Commons. Third, we will work collaboratively with outside tool developers to promote a constellation of leading tools for network-based genomic analysis, including both existing and nascent approaches emerging from the data science community. Finally, we will continue to offer a rich set of Cytoscape training programs, including new material that actively guides users through analysis workflows, updating content based on input they provide. In summary, these activities will support not only production of the Cytoscape resource– they will create a next generation desktop, web and cloud-based ecosystem for using knowledge networks in genomic data science.

NIH Research Projects · FY 2026 · 2022-09

ABSTRACT Chronic low back pain (cLBP) is the most common clinical pain condition worldwide, and the top chronic non-cancer condition for which opioids are prescribed. The current opioid crisis in the U.S. emerged in large part from overuse and misuse of opioids by patients with cLBP. Yet, there are few evidence-based interventions to reduce opioid use and misuse among patients with cLBP. Faced with a lack of effective treatment options, some cLBP patients become ensnared in a downward spiral of opioid dose escalation. Mindfulness-based interventions reduce chronic pain and opioid dosing. However, lack of mechanistic data has limited the deployment of these cost-effective and non-pharmacological treatment approaches. Multiple clinical trials indicate that Mindfulness-Oriented Recovery Enhancement (MORE), a novel mind-body therapy that integrates mindfulness with other affect regulation techniques, alleviates chronic pain symptoms as well as opioid use among people with cLBP. Yet, the active brain mechanisms of action underlying MORE’s analgesic and opioid sparing effects remain unknown. Further, no known placebo-controlled studies have disentangled the specific neural mechanisms of MORE or other mindfulness-based interventions for cLBP from nonspecific therapeutic factors like beliefs, expectancy, and social support. As such, the proposed study will employ one of the most rigorous control conditions in the mindfulness literature to date—a validated sham-mindfulness meditation technique combined with supportive psychotherapy (Sham-MORE). Integrating functional neuroimaging and psychophysics (noxious heat and behavioral pain ratings), the overarching aims of the proposed R01 study are to a) identify the neural mechanisms supporting the immediate analgesic effects of MORE (versus Sham-MORE and treatment-as- usual), and b) to determine if changes in default mode network functional connectivity predict individual differences in cLBP relief and opioid dose reduction following treatment with MORE. Ultimately, the proposed work will yield insight into the fundamental neuro-functional processes mediating the therapeutic effects of mindfulness-based interventions for cLBP, thereby facilitating the optimization of novel biobehavioral treatments for this highly prevalent and disabling chronic pain condition that helped to fuel the ongoing opioid crisis.

NIH Research Projects · FY 2025 · 2022-09

Project Summary The overall objective of this proposal, “Multimodal Artificial Intelligence to Predict Glaucomatous Progression and Surgical Intervention”, is to use multimodal artificial intelligence (AI) and deep learning strategies to predict which glaucoma patients will need glaucoma surgery and which are likely to have progressive visual field loss in the future. This study is designed to leverage longstanding well characterized clinical and research cohorts of glaucoma patients and its validated decision support AI infrastructure to predict which glaucoma patients will progress and which will need surgery. The proposal includes the following two Specific Aims. Aim 1 will use baseline electronic health records (EHR), optic nerve head (ONH) optical coherence tomography (OCT) imaging, visual field (VF) data, intraocular pressure (IOP) and central corneal thickness (CCT) in a multimodal DL model to predict the likelihood of surgical intervention for glaucoma. Aim 2 will use baseline EHR, ONH OCT imaging, VF data, IOP and CCT in a multimodal DL model to predict the likelihood of fast glaucomatous visual field progression. To address these aims, existing data from glaucoma patients 1) enrolled in the National Eye Institute funded Diagnostic Innovations in Glaucoma Study (DIGS 1995-present) and African Descent and Glaucoma Evaluation Study (ADAGES 2009-2021), and 2) managed at the UCSD Viterbi Family Department of Ophthalmology will be used in the AI model development and testing. We will also leverage UCSD's existing cloud-based AI pipeline to build a glaucoma-specific platform to train, test and in the future, update the deep learning models developed. In the future, this infrastructure can be used to support randomized clinical trial testing of AI guided glaucoma management and enable real-time decision support for clinicians.

NIH Research Projects · FY 2025 · 2022-08

Summary This R01, submitted to the Toward Translation of Nanotechnology Cancer Interventions (TTNCI) program, is a continuation of our successful U01 CA218292 (09/2017-07/2022), funded through the NCI Alliance for Nanotechnology in Cancer program. During the U01 project period, we demonstrated that our nanoparticles derived from the plant virus cowpea mosaic virus (CPMV) stimulate a potent antitumor immune response against multiple tumor mouse models. Additionally, trials in companion dogs with melanoma, sarcoma, and breast cancer demonstrate potent antitumor efficacy with our unique immunotherapy approach. CPMV is an intratumoral injected in situ vaccine (ISV) technology, with an ability to induce durable immune-mediated antitumor efficacy against treated and untreated tumors as well as immunological memory against recurrence. Mechanistically, CPMV activates the innate immune system to improve processing of tumor-associated and neoantigens, thereby resulting in a more functional adaptive antitumor immunity against antigens expressed by the tumor. This results in remissions of treated and untreated malignant tumors, and protection from recurrence via the adaptive arm and immune memory. Building on this strong foundation of data as well as intellectual property, this project will focus on optimizing GMP manufacturing and pharmacology in murine tumor models and canine patients to provide the foundational basis of future human oncology trials. The multi-PI leadership team Steinmetz (UC San Diego), Fiering (Dartmouth) and Ranjan (OSU) brings complimentary expertise in plant virus-based CPMV nanotechnology, cancer immunology, and veterinary oncology/immunotherapy trials. Our team is also supported by a group of consultants with expertise in regulatory (Garnick, Mosaic IE Inc.), pharmacology/toxicology (Luksic, Intrinsik), clinical (Garovoy, Mosaic IE Inc.) affairs, as well as experience in vertical farming (Eisenberg, OPO). We believe that our strong team of collaborators can help establish the future manufacture of the plant-derived biologic. We will fulfil the following Specific Aims: (1) Chemistry, Manufacturing, and Control (CMC) method development for scalable manufacture and QAC of the CPMV- ISV, (2) Pharmacology: Determine biodistribution, dosing, and toxicology of the CPMV-ISV drug candidate in orthotopic and metastatic mouse models of melanoma; and (3) Canine trials: establish dosing and safety in canine oncology trials in varying tumor types amenable for in situ vaccination (melanoma, sarcoma, and mast- cell tumor). Through parallel trials in murine tumor models and dog patients, we will identify biopsy or blood biomarkers for longitudinal monitoring of treatment response. Successful completion would position us for good manufacturing practice (GMP) production of this plant virus-based biologic nanotechnology and to continue the developmental path, e.g. through the NCI Experimental Therapeutics (NExT) program, thereby translating the CPMV-based drug candidate into a human clinical trial and practice.

NIH Research Projects · FY 2025 · 2022-08

Summary/Abstract The mechanism by which transcription factors assemble active transcription complexes on specific DNA sequences does not appear to follow a simple recognition code. Direct readout, wherein specific residues in the transcription factor “read” the specific DNA sequence through direct interactions is most often assumed to apply due to an oversimplified view of DNA as a rigid molecule. However, subtle, and not-so-subtle, structural changes occur when DNA binds to transcription factors. In addition, the DNA binding domains of transcription factors exhibit a large range of flexibility and often contain intrinsically disordered regions. These elements of flexibility endow the problem of transcription factor-DNA molecular recognition with many of the features of the protein folding problem. Our overall hypothesis is that transcription factor-DNA binding would instead be better described by similar principles as have been elucidated for the protein folding problem. Here, we will focus on the stress-response transcription factor, nuclear factor κB (NFκB), which activates hundreds of genes involved in growth regulation and the immune response. We will combine rigorous theory with molecular biophysical experiments to study the assembly kinetics of NFκB transcriptosome complexes. We will investigate coupling between DNA and NFκB as it relates to tandem κB sites, nucleosomal DNA, and the DNA-binding co-activator, RPS3. We predict that NFκB and additional nuclear proteins assemble into specific NFκB transcriptosomes on κB-DNA sites via a cooperative assembly process. We will test this hypothesis with the following aims: Aim 1 Determine the role of DNA context in NFκB binding. We will test the hypothesis that DNA context plays a key role in determining which NFκB binding events result in transcription activation by studying the binding of NFκB to a series of bona fide NFκB promoter and enhancer sequences both theoretically and experimentally. Aim 2 Explore how NFκB interacts with nucleosomal DNA and can invade or unwind nucleosomal DNA. We will test the hypothesis that NFκB is capable of disrupting nucleosome stability in a manner dependent on NFκB concentration and the sequence of DNA that is wrapped by the nucleosome, thereby exposing DNA for the initiation of transcription. Atomic force microscopy and computational modeling of the NFκB interaction with nucleosomes will be pursued. Aim 3 Determine how the ternary interaction between DNA, NFκB and the transcription co-activator, RPS3 forms. The NFκB coactivator, RPS3, associates with, and activates, subsets of NFκB transcription activation sites forming higher-order NFκB transcriptosome complexes. We will use the AWSEM-Suite code to predict the structures of these larger protein complexes and will verify the predicted long-range contacts between proteins and domains by NMR paramagnetic relaxation, SAXS, and HDX-MS experiments.

NIH Research Projects · FY 2025 · 2022-08

Recently developed CRISPR-based systems permit precise genome editing by inducing targeted DNA breaks at specific sites in the genome. Cellular DNA repair machinery can restore genome integrity by copying information from the intact homologous chromosome at the cleavage site via homology directed repair (HDR). While precise HDR-mediated DNA repair is the predominant pathway active during meiosis, the competing and potentially mutagenic non-homologous end-joining pathway (NHEJ) is typically thought to prevail in somatic cells. One reason for this bias is that the NHEJ pathway is active throughout somatic cell cycles, while HDR is primarily restricted to post-replicative S and G2 phases. Thus, achieving efficient HDR-based gene editing in somatic cells has proven challenging, which limits the in vivo use of this technology for human gene therapy. My group has contributed to developing the first CRISPR-based gene-drive (or active genetic) systems in flies, mosquitoes, mammals, and bacteria that bias germline inheritance of genetic elements programmed to cut the genome at their site of insertion. We also pioneered allelic-drive systems designed to promote biased inheritance of a favored allelic variant at a separate genetic locus. These germline drive systems also produce somatic phenotypes, which have generally been attributed to mutations induced by the NHEJ pathway. Recently, we developed genetic elements we refer to as “CopyCatchers” that permit visualization of HDR- mediated copying of gene cassettes. These studies have revealed an unexpectedly high frequency of somatic gene conversion (SGC) events in Drosophila (30-50%) wherein the chromosome homolog serves as a DNA repair template. Rates of SGC can be improved further by optimizing delivery of CRISPR components, or by reducing the expression of various genes encoding factors involved in DNA repair or chromosome pairing. Preliminary experiments indicate that interhomolog SGC can also take place in human cells and point to untapped strategies for repairing disease-causing mutations using intact sequences from the homologous chromosome. In this grant we propose to explore SGC repair mechanisms mediated by Cas9 and Nickase in somatic cells of Drosophila and then extend analysis of this interhomolog repair process to human cells. First, we will analyze the mechanisms underlying CRISPR dependent copying of gene cassettes or allelic variants to optimize their activities. Next, we will develop and optimize Drosophila models for homolog-based repair of disease-causing mutations in the Notch locus affecting mitotically active stem cells or in post-mitotic cells in the adult gut epithelium using a humanized Drosophila CFTR–/– disease model. Finally, we will assess whether insights gained in Drosophila are portable to human somatic cell lines, and whether interhomolog SGC can restore native gene activity in human cell-based models for cystic fibrosis. Enhancing homolog-based repair in mammalian cells could offer transformative possibilities for next-generation gene therapy strategies.

NIH Research Projects · FY 2025 · 2022-08

ABSTRACT Approximately 1 in 54 children in the United States is diagnosed with autism spectrum disorder (ASD). Among children with ASD, estimates of overweight and obesity (OW/OB) range from 19% to as high as 55% with the majority of studies reporting OW/OB rates equal to or greater than typically developing children. OW/OB in childhood tracks well into adulthood and is associated with negative health and psychosocial consequences. To date, the most successful treatment for typically developing children with OW/OB is family-based behavioral treatment (FBT), which delivers weekly group-based treatment to the parent and child separately over a 6- month period. However, children with ASD are typically excluded from these trials and given their unique presentation, require a tailored treatment program. FBT programs for parents without their child (Parent-based treatment [PBT]) are more appropriate for families with a child with ASD and OW/OB, as the functioning and language levels of the children can impact their ability to directly participate in an intensive group-based program. Research shows that PBT is noninferior to FBT on child weight loss and is less costly to implement. Our group has developed and pilot tested a PBT group for children with ASD and OW/OB (called PBT-ASD). Our pilot data showed that the PBT-ASD program was feasible, acceptable and showed initial efficacy on child weight loss. This project is the next step in this program of research, and we will recruit 150 youth with OW/OB and ASD and their parent and randomize them to a 6-month telehealth PBT-ASD or active health education comparator (HE). We will assess main outcomes in children and parents at five time points; baseline, mid- treatment (month 3), post-treatment (month 6), 6-month follow-up (month 12) and 12-month follow-up (month 18). The primary aim of this study is to compare the effect of PBT-ASD and HE on the target child’s weight (BMIz/%BMIp95) over the 18 months of the study. The secondary aim is to determine the extent to which the PBT-ASD and HE affect parent BMI, parent and child physical activity and dietary intake, child mealtime behavior, parenting style and self-efficacy. As an exploratory aim, we will evaluate moderators (e.g. parent and child gender, parent and child age, parent educational level, parent baseline BMI, child baseline BMIz/%BMI p95, parent executive functioning, parenting, child symptom severity, child adaptive behavior skills) and mediators (e.g. parenting, child symptom severity) of the PBT-ASD and the HE treatment on child BMIz/%BMI p95 over time. This program of research could advance the standard of practice for children with ASD, and could result in a tailored intervention for children with both ASD and OW/OB. We believe that by working with parents using a telehealth model, we can potentially provide an effective and durable treatment, which can easily be disseminated to parents with children with both ASD and OW/OB.

NIH Research Projects · FY 2025 · 2022-08

Despite higher rates of incident or recurrent MI and fatal coronary heart disease (CHD) among women aged 85 and older (120/1000) than men (85/1000), and the disproportionate burden of disability and co-morbidity in aging women related to diagnosed and occult cardiovascular disease (CVD), prevention of CVD in this vulnerable population is vastly understudied. This application builds upon the now completed Objective Physical Activity and Cardiovascular Health (OPACH) Study (NHLBI R01 HL105065), ancillary study embedded in the Women’s Health Initiative Long Life Study led by Dr. LaCroix. The OPACH team studied accelerometer-measured physical activity (PA) and sedentary behavior (SB) in relation to incident CVD among 7048 women ages 63-99. Our primary results showed a statistically significant, dose responsive, 20% reduction in incident CHD, a 10% reduction in incident CVD, and a 24% reduction in all-cause mortality for every additional hour spent in light PA (1.6-2.9 METs) in older women; and a 12% increased risk of CVD for every additional hour spent sedentary. To classify light PA, the OPACH team conducted a laboratory calibration study (200 OPACH women) to determine accelerometer cutpoints for absolute intensity relevant to the usual daily PA habits of older women. Age-specific classification of PA intensity is critical because resting metabolic rate and maximal aerobic capacity decline with aging, whereas the energy cost of aerobic activity increases with age. Because of these age-related changes and the heterogeneity in how they occur in older adults, the 2018 PA Guidelines Evidence Report urged researchers to: “Conduct prospective cohort studies of PA and physical function in older adults that include objective measures (e.g., heart rate monitors) of relative intensity of PA.” The term “relative” in this context refers to the maximal exercise capacity of individuals. OPACH2 and the OPACH2 Calibration Study are designed specifically to derive validated accelerometer- measured PA relative intensity and determine its association with incident CVD (CHD, heart failure, stroke) and mortality through 2027. To do this, we will obtain a second accelerometer measurement of PA and SB with contemporaneous measurement of heart rate (a physiological measure of PA intensity) using a non-invasive cardiac monitor patch (Cardea SOLO) in 4200-5000 surviving OPACH women. We will also investigate cross- sectional associations at the second accelerometer wear (2022-2023) of relative and absolute PA intensity with indicators of underlying CV health including traditional risk factors (lipids, glycemia, inflammation, blood pressure, adiposity), novel biomarkers of CVD pathology (cardiac troponin, brain natriuretic peptide, galactin- 3), heart rate variability (from Cardea SOLO patch), and physical performance. Finally, we will determine the association of changes in accelerometer-measured PA and SB over ≈10 years with changes in traditional cardiovascular risk factors, novel biomarkers, and physical functioning during the same interval, and with incidence of clinical CVD events and mortality through 2027.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY/ABSTRACT Candidate. Dr. Meyers-Pantele applies for this K01 mentored training award with the independent career goal of attaining a productive and independent research career as a health behavior interventionist focused on reducing HIV disparities among women who use drugs (WWUD). Her current training, however, does not extend beyond the secondary analysis of stigma, and substance use data, and is insufficient for in-depth instruction on the theoretical and practical methods required for the development and implementation of health behavior interventions for racially and ethnically diverse WWUD. Specifically, the K01 training will support her transition to an independent career scientist by: (1) developing proficiency in intersectionality theory to inform an intervention targeting HIV prevention service engagement and intersectional stigma for racially diverse WWUD, (2) gaining expertise in mHealth intervention design and development to create the proposed mHealth intervention, (3) building proficiency in the implementation of randomized controlled trials to pilot the developed intervention, (4) strengthening her skill base in implementation science to design an intervention that has the potential for adoption and implementation, and (5) fostering the personal development skills necessary for a successful academic career. These training aims will be accomplished through didactic courses, training workshops, participation in professional research networks, hands-on research, and mentored training. Research and Environment. WWUD are at increased risk for HIV and have low levels of pre-exposure prophylaxis knowledge and acceptance. Additionally, racially and ethnically diverse WWUD experience intersectional stigma due to gendered and racialized social norms surrounding womanhood, motherhood, morality, substance use, and criminality, all of which have important implications for women’s engagement with HIV prevention services. Mobile health (mHealth) interventions and interventions that target intersectional stigma have the potential to increase HIV prevention service engagement, but there is a dearth of interventions tailored toward racially diverse WWUD. The proposed research will provide Dr. Meyers-Pantele with the training to address this critical gap in HIV prevention research. She will employ qualitative methods to identify key experiences with HIV prevention services and intersectional stigma, and potential barriers and facilitators to intervention adoption and implementation, to inform the development of potential theory-driven mHealth intervention components. This information will be used to develop and test the usability of the mheaLth interventiOn To redUce Stigma (LOTUS) intervention to improve HIV prevention service engagement and intersectional stigma for racially and ethnically diverse WWUD. Lastly, she will conduct a pilot RCT to assess the feasibility, acceptability, and preliminary impact of the LOTUS intervention. This training will uniquely position her as one of few mHealth interventionists specializing in intersectional stigma for WWUD at UCSD.