Arizona State University-Tempe Campus

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Neointimal hyperplasia (NIH) is a significant issue that arises from vascular damage during interventions, leading to arterial wall thickening and lumen loss. This condition is primarily caused by the phenotypic transition of vascular smooth muscle cells (VSMCs). Excessive migration and proliferation of these dysfunctional VSMCs contribute to NIH, which ultimately causes stenosis and restricts blood flow. Preventing or reversing this pathological transition in VSMCs could be a promising strategy to mitigate NIH following interventions. Recent studies have identified a long noncoding RNA called cardiac mesoderm enhancer-associated noncoding RNA (CARMN), which plays a critical role in VSMC differentiation and maintenance of contractile functions. Disruptions in CARMN regulation have been linked to VSMC dysfunction and NIH. Decreased expression of CARMN has been observed in dedifferentiated VSMCs and diseased blood vessels. Furthermore, studies have shown that genetic ablation of CARMN exacerbates neointima formation, while CARMN overexpression attenuates NIH in mouse and rat models of vascular injury. These findings strongly suggest that restoring CARMN regulation in dysfunctional VSMCs could be a viable strategy to mitigate NIH and improve the outcomes of vascular interventions. Based on these insights, our research project aims to develop a lesion- targeted nanotherapeutic that utilizes CARMN transcripts as the pharmaceutical agent for the treatment of VSMC dysfunction and NIH. Building on our prior successful research with platelet membrane-cloaked nanoparticles (PNP) as an efficient targeted delivery system for injured vasculature, we have integrated in vitro transcribed (IVT) CARMN RNA into PNP, creating PNP-CARMN. Our preliminary findings demonstrate that PNP significantly increases the uptake of CARMN by cultured VSMCs and improves targeted delivery of CARMN in the denuded mouse artery. Importantly, in mice subjected to a wire-injury procedure, PNP-CARMN effectively mitigates arterial wall thickening compared to those loaded with GFP mRNA. These preliminary results indicate that PNP-CARMN has the potential to address VSMC dysfunction and prevent NIH. The research project will test the overall hypothesis that CARMN transcripts delivered by PNP would selectively accumulate in the vascular injury sites and promote VSMC contractile gene expression and functions, there mitigating NIH. The proposed studies involve three Specific Aims, including (1) optimize PNP-CARMN for nuclear delivery and assess its in vitro effects, (2) investigate the pharmacokinetics and toxicity of PNP-CARMN, and (3) evaluate the pharmacological responses and therapeutic efficacy of PNP-CARMN against VSMC dysfunction and NIH. Successful completion of these Aims will provide insight into the therapeutic role of CARMN and contribute to the development of a new avenue for CVD treatments that can benefit millions of Americans.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Chronic low back pain associated with disc degeneration is a leading cause of chronic pain and has a substantial economic impact in the United States. Treatments for discogenic low back pain exhibit poor long-term efficacy highlighting an important unmet medical need. However, efforts to improve pain management are hampered by limited knowledge of the mechanisms underlying low back pain. Improving our understanding of the mechanisms driving these chronic pain states is hampered by a lack of well characterized and validated preclinical models. The current unmet need is a model of chronic low back pain that robustly mimics human presentation and etiology. To develop a robust model of chronic discogenic low back pain, this proposal brings together experts in orthopedics and animal models (Wachs) with neuroscience and behavioral measures of chronic pain (King). The overarching goal of this proposal is to reproduce and validate a recently published rat model of disc degeneration induced low back pain developed in Dr. Wachs’ lab. For the R61 portion of this proposal, we will establish that this model can be reproduced in a second laboratory (King lab) to demonstrate external replication of this new model of discogenic low back pain. To ensure consistency, Dr. Wachs and her veterinary surgeon will both go to the King lab prior to the study start to train the King lab in the surgery and assays. Concurrent animal studies will then be performed in the Wachs and King labs using the single puncture method in both sexes of animals over an 18-week time course. Real-time disc degeneration will be monitored using either µCT or high- speed x-ray. Pain-like behavior will be assessed using grip strength (evoked) and open arena (non-evoked) testing. Post-processing will include histological analysis of disc degeneration, nerve growth, and inflammation. Quantitative measures will be used to compare results between the Wachs and King labs to ensure robust model reproducibility and provide tangible milestones for progression to the R33 phase. The R33 phase will consist of external validation to establish face, construct, and predictive validity. Concurrent studies will be performed in the Wachs and King labs over an 18-week time course. In this phase, we will increase resolution, frequency, and quantification of assays to more accurately compare to human disease. For example, MRI will be used to examine changes in disc degeneration and water content over time which, although more expensive, is more directly comparable to the gold standard in human disease assessment. In addition, we will perform behavioral analyses every three weeks to compare with the time course in humans. Histological analyses will be broadened to include more robust analysis that will determine specific localization of nerves, blood vessels, and inflammatory cells to allow comparison to previously published data of human biological features of discogenic pain. Finally, we will use conditioned place preferences (CPP) testing in conjunction with administration of anti- inflammatories to test predictive validity. The outcomes of this work have the potential to create a robust model of discogenic pain with high translational potential.

NIH Research Projects · FY 2026 · 2024-09

PROJECT SUMMARY/ABSTRACT Type 2 diabetes (T2D) is an important public health challenge associated with significant morbidity, mortality, and increased healthcare costs. Low-income populations are 2.5 times more likely to have T2D and experience a disproportionate burden of poor health outcomes. Diabetes Self-Management Education and Support (DSMES) is an evidence-based program recommended for every person newly diagnosed with T2D with proven efficacy for improving health behaviors and outcomes. However, <5% of low-income individuals with T2D engage in DSMES within the first year of diagnosis, further exacerbating disparities. Multilevel and multidimensional barriers contribute to DSMES underutilization in this high-risk population, and these must be considered in order to promote health equity. Digital health interventions show promise for increasing access, uptake, and relevance of health promotion interventions among underserved communities where the ubiquitous nature of cell phones can also be leveraged to enhance engagement. To our knowledge, there are no digital health interventions tailored to low-income people newly diagnosed with T2D in the US. The first year of diagnosis is a critical window for establishing and sustaining self-management behaviors that promote health across the lifespan. This K99/R00 proposal is guided by the National Institute on Minority Health and Health Disparities Research Framework to support research, mentorship, training, and community-engagement activities that will foster the growth and trajectory of an early-stage health equity scholar focused on improving T2D-related health among low-income populations. The K99 research goal is to co-create a user-informed, digitally enhanced DSMES tailored to the education and support needs of low-income adults newly diagnosed with T2D. The R00 research goal is to establish the feasibility, acceptability, and preliminary effects of the intervention in a Federally Qualified Community Health Center on engagement in DSMES, changes in self-management behaviors, and improvements in health outcomes (A1c, weight, and quality of life). The proposed research sets the stage for a full-scale R01 that will test the efficacy of the digitally enhanced DSMES intervention to improve health outcomes among low-income patients newly diagnosed with T2D. The PI has established a transdisciplinary mentorship team of NIH-funded health disparity scholars and a comprehensive training plan guided by an individual development plan to expand her skills, knowledge, and professional network to support a career focused on advancing health equity through accessible, sustainable, and scalable system-level interventions for underserved populations. The applicant’s long-term goal is to become an independent, NIH-funded scientist with a research program focused on developing and implementing community-informed, culturally- and contextually relevant interventions that improve diabetes-related health outcomes among underserved populations.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY/ABSTRACT Type 2 diabetes (T2D) is an important public health challenge associated with significant morbidity, mortality, and increased healthcare costs. Low-income populations are 2.5 times more likely to have T2D and experience a disproportionate burden of poor health outcomes. Diabetes Self-Management Education and Support (DSMES) is an evidence-based program recommended for every person newly diagnosed with T2D with proven efficacy for improving health behaviors and outcomes. However, <5% of low-income individuals with T2D engage in DSMES within the first year of diagnosis, further exacerbating disparities. Multilevel and multidimensional barriers contribute to DSMES underutilization in this high-risk population, and these must be considered in order to promote health equity. Digital health interventions show promise for increasing access, uptake, and relevance of health promotion interventions among underserved communities where the ubiquitous nature of cell phones can also be leveraged to enhance engagement. To our knowledge, there are no digital health interventions tailored to low-income people newly diagnosed with T2D in the US. The first year of diagnosis is a critical window for establishing and sustaining self-management behaviors that promote health across the lifespan. This K99/R00 proposal is guided by the National Institute on Minority Health and Health Disparities Research Framework to support research, mentorship, training, and community-engagement activities that will foster the growth and trajectory of an early-stage health equity scholar focused on improving T2D-related health among low-income populations. The K99 research goal is to co-create a user-informed, digitally enhanced DSMES tailored to the education and support needs of low-income adults newly diagnosed with T2D. The R00 research goal is to establish the feasibility, acceptability, and preliminary effects of the intervention in a Federally Qualified Community Health Center on engagement in DSMES, changes in self-management behaviors, and improvements in health outcomes (A1c, weight, and quality of life). The proposed research sets the stage for a full-scale R01 that will test the efficacy of the digitally enhanced DSMES intervention to improve health outcomes among low-income patients newly diagnosed with T2D. The PI has established a transdisciplinary mentorship team of NIH-funded health disparity scholars and a comprehensive training plan guided by an individual development plan to expand her skills, knowledge, and professional network to support a career focused on advancing health equity through accessible, sustainable, and scalable system-level interventions for underserved populations. The applicant’s long-term goal is to become an independent, NIH-funded scientist with a research program focused on developing and implementing community-informed, culturally- and contextually relevant interventions that improve diabetes-related health outcomes among underserved populations.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY The development of Alzheimer's Disease (AD) and AD Related Dementias (ADRD) is impacted by biological, clinical, socio-demographic, and lifestyle factors. Therefore, training the workforce for AD/ADRD research requires an interdisciplinary approach that is informed by community and clinical need, which is in turn critical to rapid translation of fundamental research into practice and communities. This proposal aims at developing an interdisciplinary training program for nurturing 9-10 predoctoral trainees annually (6 of 10 in years 1-4 and 5 of 9 in year 5 trainees will be supported by NIH, and 4 each year will be supported by Arizona State University (ASU), who will be mentored by a team of faculty from different units/schools at ASU and clinicians/researchers from Mayo Clinic, Banner Alzheimer Institute, Barrow Neurological Institute, and TGen, with diverse expertise covering AD/ADRD clinical science, diagnostics and engineering, disease biology, data science, and drug discovery/development. The training program will leverage AD/ADRD resources in Arizona and actively engage the Arizona Alzheimer’s Consortium (AAC) and the Arizona Alzheimer's Disease Research Center (ADRC). The program is in a unique position to partner with Mirabella, a senior living community on the ASU campus, and Hospice of the Valley, Arizona's leading provider of end-of-life care, and other community partners to provide the trainees with real-life experiences. The team has designed a unique program with well-rounded training opportunities covering the following four dimensions: curriculum-based training, research training, career development, and community-based real-world experiences. Recognizing the exponentially increasing amount of data in all disciplines involved in AD/ADRD research and the critical and often enabling role that Artificial Intelligence (AI) plays in data-intensive research, the proposed training program employs a data-centric approach with AI being a bridge serving to connect all the involved disciplines through its role as a data processing and inference engine. Accordingly, the focus of the proposed curriculum-based training and research training is on helping the trainee to gain the fundamental knowledge and research skills in employing AI for AD/ADRD research. The training faculty have established track records, not only for pursing AI and AD/ADRD research, but also for doctoral student mentoring. Further, there are active collaborations among the training faculty, which have helped to shape the design of the initial set of research projects that are ready to be deployed for the choice of the first batch of trainees.

NIH Research Projects · FY 2024 · 2024-09

Although the majority of AD patients are sporadic (SAD), numerous studies have implicated biological sex and variation in the Apolipoprotein E (APOE) gene as two of the strongest factors that modulate risk of AD onset and age-related progression. Specifically, compared to the APOE3 allele, individuals carrying one copy of APOE4 have an increased AD risk by 4-fold and individuals carrying two copies have up to 15-fold higher probability of developing AD. Conversely, individuals with the APOE2 allele are 40 percent less likely to develop AD. Moreover, the risk-inducing effects of APOE4 have been shown to be augmented in female patients. Despite these interactions, the cellular and molecular mechanisms of sex-based differences in APOE-related AD risk have not been precisely determined. Previously, we used isogenic human induced pluripotent stem cells (hiPSCs) to investigate the mechanisms by which APOE genotypes influences AD risk. In this proposal, we will build upon this work to dissect the role sex plays as it relates to these APOE genotype-dependent effects. To that end, in the first aim of this proposal will use our highly efficient gene editing technology to introduce various APOE genotypes into isogenic hiPSC lines with different sex chromosome complements derived from the same genetic background. In the second aim, we will employ these isogenic hiPSC lines in the context of neuronal, astrocytic, and microglia culture systems to determine the manner in which APOE and sex interact to (i) influence Aβ processing, secretion, and uptake, (ii) alter tau hyperphosphorylation, and (iii) regulate global transcriptional changes that would influence AD risk. Overall, a more thorough understanding of the mechanisms by which APOE and biological sex interact to modulate likelihood of AD onset will have a significant impact on the design of therapeutic interventions.

NIH Research Projects · FY 2024 · 2024-09

Stress-related psychiatric disorders (SRPDs) are now the leading disease burden worldwide and diagnoses are increasing in both adolescents and adults. High rates of trauma in the US, especially for women and marginalized racial, ethnic, and sexual minority groups, ensures continued high rates and health disparities in SRPDs. Provided the biological complexity, symptom heterogeneity, and high comorbidity of these disorders, the search for biomarkers has been difficult. Additionally, current gold-standards for clinical research entails comparing a clinical group to a control group. However, this design is less than ideal for SRPDs as the risk factors (genetic and environmental), potential biomarkers, and collection of symptoms are on a continuous spectrum; not a dichotomy like other conditions. Biologically, and statistically, SRPD biomarkers and symptoms should be treated as continuous variables. The last couple decades have produced convincing evidence regarding the impact of adverse childhood experiences (ACE) on the epigenome and brain structure in regions regulating stress, mood, reward, and cognition - the very pillars of SRPD symptom clusters. An individual’s ACE history, genome, epigenome, and brain metrics should be used in combination to reveal biocomposites of SRPDs. The objective of this New Innovator Award is to test my newly developed model, The GEAN Model of mental health (Genetics, Epigenetics, ACE, and Neurobiology) designed to identify SRPD biocomposite clusters based on continuous individual-level endophenotypes to better understand risk and heterogeneity SRPDs. Using advanced computational approaches, we will 1) identify epigenetic sites and brain regions most responsive to the environment, 2) identify genetic and endophenotype clusters that mediate the relationship between ACE history and SRPD symptoms in a prospective cohort, and 3) validate this same model in a separate clinical cohort. This project is innovative because it is truly transdisciplinary and bridges the fields of psychiatry /psychology, (epi)genomics, and neuroscience with powerful computational models to address the biological underpinnings of SRPDs. The proposed studies directly tackle many of the issues around the sheer complexity of SRPDs by integrating trauma and multiple biological measures, using a multidimensional phenotype measure, and using person-centered analyses in both prospective and clinical cohorts. Importantly, these studies address the challenge of diversity by employing state-of-art mobile imaging methods for at-home data collection. Further, by including a genetically informed design, we specifically tackle the challenges of genetic-confounding. The results of these studies represent major acceleration within the field of mental health and will inform better predictions of long-term outcomes following ACEs, biocomposites of SRPD risk and diagnoses, and treatment targets for precision medicine. We anticipate that the results will create a new paradigm for SRPDs and inform research and clinical care for years to come.

NIH Research Projects · FY 2025 · 2024-09

Abstract Type 1 diabetes (T1D) is a multifactorial disease caused by a complex interplay of genetic and environmental factors. The genes that mediate disease susceptibility have largely been discovered. The importance of environmental factors is widely acknowledged but their identification has been challenging. Virus infections have long been among the prime candidates, but progress has been hindered by the narrow “candidate microbe” approach and limited availability of large prospective studies. The present study fills this major knowledge gap by combining the tremendous power of modern immunoproteomics technologies to detect antibodies against a wide range of different microbes with world largest prospective birth cohort study evaluating the role of environmental factors in the pathogenesis of T1D (the TEDDY study). The goal is to obtain a comprehensive and holistic picture on microbial infections which are associated with increased or decreased risk of islet autoimmunity (IA) and T1D. This goal directly addresses the founding aims of the TEDDY study. We have assembled a highly integrative multi-disciplinary team with synergizing expertise in T1D, immunoproteomics, high throughput arrays, virus diseases, metagenomics, virome analyses and advanced statistics. We use three supplementary high-throughput arrays with full proteins as antigens to enable the detection of antibody responses against both structural and linear antigen epitopes to increase the screening sensitivity. First, the highest protein capacity Nucleic Acid Programmable Protein Array (NAPPA) technology is used to carry out a wide screening of antibodies against 2000 different whole microbial proteins representing 171 viruses, bacteria, and parasites selected specifically for their relevance to T1D at a critical time-point of T1D pathogenesis, the serum sample where IA was first detected (600 TEDDY IA+ children and 600 matched control children); Second, the quantitative Multiplexed In-Solution Protein Array (MISPA) technology is used to identify infections and their timing in childhood by analyzing antibodies to 400 best microbial protein candidates selected based on Aim 1 results from all prospective serum samples from infancy through IA (the same 600 cases plus 1200 HLA matched controls at ~7 time points ≈ 12,600 samples). Third, widely used commercial Meso Scale Discovery (MSD) and other technologies are employed to confirm the microbe-IA associations observed on the MISPA platform (the same cohort as used on MISPA plus additional samples after the initiation of IA to study accelerants of progression to clinical T1D). Overall, the results from this well-powered study will shape the landscape in this field as this study represents the largest and widest screening of infections in children who develop IA/T1D. This information is not only crucial for the understanding of T1D pathogenesis and for opening new possibilities to prevent and treat the disease by vaccines or other antimicrobial strategies but will also provide valuable information on the timing of infectious exposures in the early development of children in general.

NIH Research Projects · FY 2025 · 2024-09

Leveraging Community-Engaged Research to Co-Create Youth Vaping Prevention with Urban Indigenous Communities of the Southwest ABSTRACT The prevalence and early initiation of nicotine vaping among Indigenous youth surpass that of all other racial/ethnic groups. This concerning trend is prominent in urban environments, where approximately 60% of Indigenous youth reside. In urban settings, multilevel influences heighten risks for nicotine and cannabis vaping among Indigenous adolescents, including the intricate navigation of ethnic identity, which can compound challenges these youth face. Preventing adolescent nicotine and cannabis vaping is further complicated by the unique characteristics of vaping products. Their ease of concealability, the ability to purchase online, and the lower perception of adverse health consequences contribute to their attractiveness. Even among youth who successfully avoid traditional cigarette smoking, vaping nicotine remains a risk due to misinformation, misconceptions, and misperceptions. Therefore, interventions that have demonstrated efficacy in preventing the use of alcohol and other drugs may need to be adapted to specifically address the risks associated with vaping. Tailoring interventions to these unique challenges is crucial to achieve the intended impact and reduce the prevalence of vaping among Indigenous youth. However, no evidence-based interventions exist for urban Indigenous youth. For over a decade, our team has collaborated with Phoenix Indian Center to adapt and test substance use interventions for urban Indigenous youth. Now, Phoenix Indian Center has prioritized nicotine and cannabis vaping as the most problematic substances in the local urban Indigenous community. To address this community-driven priority with our long-term community partner, we now propose to build upon our extensive experience to rigorously test the efficacy of the evidence-based substance use prevention intervention, Living in 2 Worlds, adapted to include salient multilevel risk and protective factors for vaping for urban Indigenous adolescents. We will also examine barriers and facilitators of implementation to increase sustainability and the likelihood of real-world impact in eliminating racial and ethnic disparities in substance use. To further ensure that the Living in 2 Worlds intervention is designed, implemented, evaluated, and disseminated for cultural relevance and community specificity, we will engage an Indigenous Youth Advisory Board throughout the research process. Our long-term goal is to build the evidence to scale preventive vaping interventions across urban Indigenous communities in the U.S. As the next step towards this goal, we propose the following: Aim 1: Identify multilevel risk and protective factors for nicotine and cannabis vaping among urban Indigenous youth to adapt the Living in 2 Worlds intervention. Aim 2: Test the efficacy of the adapted Living in 2 Worlds intervention for preventing initiation and reducing use of nicotine and cannabis vaping, decreasing key risk factors for vaping initiation, and increasing skills that protect against vaping. Aim 2b. Identify implementation barriers and facilitators of Living in 2 Worlds. Aim 3: Advance the science for engaging youth throughout the research process.

NIH Research Projects · FY 2024 · 2024-09

Project Summary Recent nationally representative data show that 76% of adolescents experience digital dating abuse. Digital dating abuse is the use of technology to threaten, harass, monitor, control, pressure, or coerce a romantic partner. It is a cause for serious concern; adolescents who experience digital dating abuse are more likely to experience mental health problems (depressive symptoms, anxiety, and suicidal ideation). Yet, the reciprocal nature between digital dating abuse and mental health problems is unclear due to a lack of longitudinal research. Adolescents are prolific technology users and constantly connect with romantic partners via texting and social media. Furthermore, characteristics of media, such as the lack of non-verbal cues, publicness, and permanence of communication, make for an easily accessible yet harmful context that possibly amplifies the adverse effects of digital dating abuse on adolescents' mental health. Therefore, it is timely to investigate the relational and digital mechanisms that underlie the reciprocal influences of digital interactions between romantic partners and mental health problems. First, we will identify how adolescents with mental health problems experience increased daily relationship threats and negative mood, leading to digital dating abuse among couples. Second, we will investigate whether daily supportive parent and peer relationships are protective factors for the emergence of digital dating abuse and mental health problems. At the same time, certain media characteristics (lack of non- verbal cues, publicness, permanence) are likely to exacerbate the effects of digital dating abuse on adolescents' mental health problems. Third, we will examine the long-term bidirectional impact of digital dating abuse and mental health problems. Despite a higher risk for in-person dating abuse and mental health problems for Latinx adolescents, research has yet to examine the impact of the sociocultural context on digital dating abuse. Therefore, we will include a primary sample of Latinx adolescents and investigate how Latinx adolescents' cultural competencies will protect against the long-term consequences of DDA on mental health problems. We propose to follow 300 couples (N = 600 adolescents) in a dyadic, observational, and longitudinal study. In addition to adolescents' daily self-reports, we will objectively code for digital dating abuse from screenshot uploads of their digital relationship interactions. We will also measure negative mood and mental health problems with passive sensing of sentiment derived from mobile phone text input. Following couples day-to-day and longitudinally will capture the full range of digital interactions, varying from minor conflicts to digital dating abuse. This approach will allow us to examine how, in which contexts, and when adolescents with mental health problems engage in digital dating abuse and, in turn, investigate its long-term consequences on mental health problems. Findings have real-world implications by identifying intervention points to break the vicious cycle between digital dating abuse and adolescents' depressive symptoms, anxiety, and suicidal ideation.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Cryogenic electron microscopy (cryo-EM) is indispensable for structural biology studies. Arizona State University (ASU) has a long history of leadership in the electron microscopy field. ASU has been expanding and promoting cryo-EM research for biomedicine and fundamental biology since establishing its cryo-EM facility in 2017. ASU has a large pool of researchers utilizing cryo-EM to study biomolecular structures and their action mechanisms and to develop new medical applications, such as rational drug design and nanomedicine. However, the hardware for cryo-EM imaging has dramatically advanced in recent years, and the ASU cryo-EM instrument has been outdated, presenting challenges in imaging thick specimens for electron tomography or achieving high- quality data of membrane or small proteins. This limits the productivity of scientific studies and prohibits the advancement of knowledge in this field at ASU. To this end, ASU requests an energy filter to upgrade the cryo-EM capability, aiming to improve cryo-EM data quality and research productivity in structural biology. An energy filter can filter the inelastically scattered electrons and reduce the background noise, thereby boosting the data quality and improving the resolution of the target structure. This energy filter is equipped with a new-generation direct electron detect (DED) camera, which enhances the image signal-to-noise ratio (SNR) and records the data at full temporal resolution. The proposed energy filter system is fully compatible with the current cryo-EM setup at ASU and will be operated by the natively supported software. The new cryo-EM workflow with the proposed instrument is expected to improve the resolutions of crystallographic reconstruction of micro-crystals and image reconstruction of single particles. It will also allow imaging of thick samples for cell biology studies, enabling in situ structural investigation of protein complexes. ASU has a complete and existing management system for multiple electron microscope instruments. The cryo-EM instruments are managed and maintained by the ASU Eyring Materials Center (EMC), which has extensive long-term experience and a thorough framework in managing electron microscopes and related instruments. ASU also contains a pool of electron microscopy experts who can provide expertise and suggestions in research and administration of these instruments. Overall, the addition of the proposed cryo-EM upgrade will significantly benefit NIH-funded biomedical research at ASU and the broader community in the Southwestern region.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Recent nationally representative data show that 76% of adolescents experience digital dating abuse. Digital dating abuse is the use of technology to threaten, harass, monitor, control, pressure, or coerce a romantic partner. It is a cause for serious concern; adolescents who experience digital dating abuse are more likely to experience mental health problems (depressive symptoms, anxiety, and suicidal ideation). Yet, the reciprocal nature between digital dating abuse and mental health problems is unclear due to a lack of longitudinal research. Adolescents are prolific technology users and constantly connect with romantic partners via texting and social media. Furthermore, characteristics of media, such as the lack of non-verbal cues, publicness, and permanence of communication, make for an easily accessible yet harmful context that possibly amplifies the adverse effects of digital dating abuse on adolescents' mental health. Therefore, it is timely to investigate the relational and digital mechanisms that underlie the reciprocal influences of digital interactions between romantic partners and mental health problems. First, we will identify how adolescents with mental health problems experience increased daily relationship threats and negative mood, leading to digital dating abuse among couples. Second, we will investigate whether daily supportive parent and peer relationships are protective factors for the emergence of digital dating abuse and mental health problems. At the same time, certain media characteristics (lack of non- verbal cues, publicness, permanence) are likely to exacerbate the effects of digital dating abuse on adolescents' mental health problems. Third, we will examine the long-term bidirectional impact of digital dating abuse and mental health problems. Despite a higher risk for in-person dating abuse and mental health problems for Latinx adolescents, research has yet to examine the impact of the sociocultural context on digital dating abuse. Therefore, we will include a primary sample of Latinx adolescents and investigate how Latinx adolescents' cultural competencies will protect against the long-term consequences of DDA on mental health problems. We propose to follow 300 couples (N = 600 adolescents) in a dyadic, observational, and longitudinal study. In addition to adolescents' daily self-reports, we will objectively code for digital dating abuse from screenshot uploads of their digital relationship interactions. We will also measure negative mood and mental health problems with passive sensing of sentiment derived from mobile phone text input. Following couples day-to-day and longitudinally will capture the full range of digital interactions, varying from minor conflicts to digital dating abuse. This approach will allow us to examine how, in which contexts, and when adolescents with mental health problems engage in digital dating abuse and, in turn, investigate its long-term consequences on mental health problems. Findings have real-world implications by identifying intervention points to break the vicious cycle between digital dating abuse and adolescents' depressive symptoms, anxiety, and suicidal ideation.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY ABSTRACT African Americans are at a significantly elevated risk of Alzheimer’s disease (AD) compared to the non-Hispanic white population. Yet, the underlying mechanisms of this health disparity are significantly understudied. Recently, a variant in Apolipoprotein E (APOE), APOE R145C, was identified as significantly increasing the risk of AD among individuals of African ancestry. Despite this association, the underlying mechanisms of how the presence of this APOE variant exacerbates AD onset and progression in aging adults have yet to be elucidated. As such, we will use our collective experience in stem cell bioengineering, neurodegenerative disease modeling, and genome editing to elucidate the potential mechanisms by which the APOE R145C variant modulates AD risk. To that end, in the first aim, we will use our recently developed highly efficient gene editing approach to introduce the APOE R145C variant into isogenic human induced pluripotent stem cells (hiPSCs) from both non-demented control (NDC) and AD patients including those derived from African American subjects. In turn, in the second aim, biochemical, cellular, and genetic analysis of neuronal, astrocytic, and microglia cultures will be used to determine the effect of the APOE R145C variant on the presence of AD-related phenotypes. In particular, we will determine if APOE R145C exerts its risk modifying effects through (i) modulation of Aβ processing, secretion, or uptake and (ii) alteration in tau hyperphosphorylation and uptake. In addition, whole transcription analysis will be used to identify signaling pathways and transcriptional targets that are modified by the presence of the APOE R145C variant and disease status. Overall, the data obtained as part of this proposal will set the stage for future hypothesis-testing studies to probe the mechanisms by which the African American-associated APOE R145C variant accelerates AD onset. Such investigations will have a significant impact on the design of molecularly targeted therapies to treat AD in the high-risk African American population.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY The long-term goal of this line of research is to improve physical therapy for fall prevention in people with Parkinson’s disease (PD). Falls place an enormous burden on people with PD, leading to injury, isolation, and often, death. Physical therapy can improve balance; however, its effect on falls is often limited. Barriers to developing effective rehabilitative approaches include a lack of knowledge regarding 1) which specific aspects of balance should be targeted to reduce falls in this group, and 2) how neural deficits contribute to altered balance. For example, therapists are aware that reactive stepping (i.e., the quick steps to regain balance after a loss of balance) are related to falls. However, there is limited evidence directly relating reactive stepping responses to falls in people with PD, and no evidence regarding which aspects of stepping (e.g., size, speed, latency) should be targeted during therapy to have the greatest impact on falls. Similarly, while there is some evidence that standing balance (i.e., sway) relates to falls, the specific aspects of sway (e.g., area, relation to base of support) most related to falls in people with PD are unclear. Finally, the brain changes that lead to altered sway and reactive balance deficits in people with PD are poorly understood. These gaps impede our ability to deliver effective fall-prevention interventions and develop targeted neurostimulation protocols to improve balance in people with PD. This project will identify the specific aspects of reactive and standing balance that are related to prospectively measured falls, as well as the brain regions that contribute to altered balance. These data are necessary to design effective clinical trials to test rehabilitation approaches for fall reduction. The goals of this project will be achieved by assessing reactive & standing balance, as well as neuroimaging outcomes in 100 people with PD at risk for falls. We will then follow these individuals for 12 months to prospectively track falls. Aim 1 will assess the individual relationship between 1) reactive and 2) standing balance to prospectively assessed falls. Balance outcomes will be collected under dual-task conditions, given that falls often occur when attention is divided. Aim 2 will assess the relative and cumulative importance of reactive and standing balance for fall prediction in 1 model. To facilitate a better understanding of the PD-specific pathophysiology leading to poor balance in people with PD, exploratory Aim 3 will identify the neural correlates of poor reactive and standing balance in this cohort. This work is a critical step in understanding and treating balance deficits & falls in people with PD; addressing the question: “Which aspects of balance should clinicians target for fall-prevention therapy in people with PD?” Data will provide information to clinicians regarding rehabilitative targets for fall-prevention balance interventions, as well as a deeper understanding of the neural signatures of balance deficits in people with PD.

NIH Research Projects · FY 2025 · 2024-08

Young adults (age 18-35) living with psychosis (YA-P; schizophrenia spectrum disorders) have high rates of heavy cannabis use that are associated with long-term deleterious mental health and functional outcomes. Those early in the course of psychotic illness are especially vulnerable to the negative impact of cannabis on future recovery. There are no effective interventions that reduce cannabis in this group. Clinicians agree that heavy cannabis use is a significant problem for YA-P patients and report that effective, evidence-based interventions are sorely needed. Families have been identified as effective and influential treatment allies for YA-P, but often, cannabis is a highly contentious topic that can lead to interpersonal conflict. Such conflict increases risk for psychotic relapse and is associated with non-change of substance use. The goal of this study is to develop and pilot test an intervention for families of YA-P who use cannabis to teach them skills to increase motivation among their YA-P to reduce their cannabis use. Relevant skills from motivational interviewing and the community reinforcement and family training interventions as well as psychoeducation centered on risks of cannabis to psychosis will be core elements of the intervention. Phase 1 will focus on the development of the Cannabis Conversation Skills for Families (CCSF) intervention material through the application of recently collected qualitative (focus group) data. Specific adaptations will include: the development of intervention content specific to YA-P such as education around the differential effects of THC potency on psychosis, and the impact of cannabis misuse on psychosis intervention outcomes. Materials will be iteratively adapted over the course of Phase 1 through pretesting the intervention with 10 families of YA-P who frequently use cannabis. Phase 2 will include the conduct of a randomized controlled pilot trial to assess feasibility, acceptability and preliminary effectiveness of the CCSF with 40 relatives of YA-P who frequently use cannabis and are engaged in coordinated specialty care. Participants will be randomly assigned to receive a 6- session group delivered CCSF or treatment as usual (TAU) intervention and will be assessed at baseline, and 3-month follow-up. The specific aims are: 1) develop the CCSF for relatives of heavy cannabis using YA-P; 2) conduct a 1-arm pretest (n = 10) and counselor training trial; and 3) assess the feasibility, acceptability and preliminary effectiveness of CCSF in a randomized pilot trial and assess target mechanisms of expressed emotion, caregiver burden and self-efficacy.

NIH Research Projects · FY 2024 · 2024-08

Abstract Aging exhibits remarkable individual heterogeneity as exemplified by the varying health trajectories and outcomes experienced by people of the same chronological age. Much of this variability is due to different live experiences and environments. Understanding the impact of environmental factors on aging is essential because it holds the key to unlocking strategies for promoting healthier and more equitable aging experiences for individuals across diverse backgrounds. The F99 phase of this project explores the interplay between environmental adversity, epigenetic shifts, and aging, using a cohort of 1,000 dogs from the Dog Aging Project. The goal is to understand how environmental factors modulate the epigenome, potentially accelerating aging and influencing health and lifespan. Specifically, I am analyzing associations between age, sex, weight, and site-specific and global DNA methylation changes, alongside validating a DNA methylation-based 'epigenetic clock' associated with chronological age, and assessing whether environmental adversity mirrors molecular aging. At the end of the F99 phase, I will have revealed mechanisms behind environmentally-induced aging in dogs, and gained training and expertise that will serve as a bridge to the postdoctoral, K00 phase. In the K00 phase, my research will expand to explore molecular determinants of aging in women, with an emphasis on understanding how specific environmental adversities impact their aging processes. Utilizing data from extensive cohort studies like the Study of Women's Health Across the Nation study (SWAN), a long-term cohort study that investigates the physical, psychological, and social aspects of women's health during the menopausal transition and beyond, involving a diverse group of women across different racial and ethnic backgrounds. I aim to uncover how epigenetics, and gender-specific environmental adversity intertwine to define aging trajectories in women, with the goal to identify high-risk groups and develop targeted interventions, thereby ameliorating age-related disparities and enhancing health and longevity in women.

NIH Research Projects · FY 2025 · 2024-08

Abstract (Overall) Living alone has emerged as a risk factor for Alzheimer’s disease (AD) and related dementias (ADRD) that will affect 14 million Americans, particularly African and Hispanic Americans. A third of community-dwelling older adults with ADRD live alone, but there are limited interventions to help them live alone safely and for as long as they desire. Growing research have shown that behavior and lifestyle Interventions can improve cognition, physical function, and quality of life (QoL) in older adults with cognitive decline (defined as subjective cognitive decline [SCD], mild cognitive impairment [MCI], or ADRD). However, the real-life uptake of these interventions has been low because the interventions did not target Mechanisms of Behavior Change (MoBC) and older adults living alone with cognitive decline and minorities were often excluded by clinical trials. These issues can be addressed with technology. Hence, the goal of the Arizona State University Roybal Center for Older Adults Living Alone with Cognitive Decline (ASU Roybal) is to develop infrastructure and conduct clinical trials of MoBC-driven, technology-enabled interventions to delay ADRD and improve quality of life (QoL) in older adults living alone with cognitive decline. It is guided by a conceptual framework integrating the NIH’s Stage Model, MoBC, Symptom Science Model, and NIA’s Health Disparities Research Framework. It hypothesizes that technology-enabled interventions driven by MoBC (e.g., stress) or biological targets (e.g., inflammation) can improve proximal (e.g., cognition, emotional wellbeing) and long-term outcomes (e.g., ADRD prevention) in older adults living alone with cognitive decline. For example, Trial 1 (Stage IB) will focus on MoBC targets of social support and stress to increase physical activity in older adults living alone with SCD and Trial 2 (Stage I) on MoBC targets of interpersonal/social processes to improve emotional wellbeing in those with early AD. ASU Roybal will be co-led by experienced senior scientists who are experts in ADRD, MoBC, behavioral trials, technology, and administration. The Administrative Core will develop infrastructure, administer Call for Trials, and evaluate and sustain ASU Roybal’s long-term impact. The Behavioral Intervention Development (BID) Core will support the design, conduct, and advancement of 12 trials. The Specific Aims are to 1) build the infrastructure to conduct clinical trials of MoBC-driven, technology-enabled interventions for behavior and lifestyle change and across the NIH’s Stage Model in older adults living alone with cognitive decline; 2) facilitate the design and conduct of 12 trials to test interventions’ effects on mechanistic, proximal, and long- term outcomes in older adults living alone with cognitive decline; and 3) sustain the long-term impact of MoBC- driven, technology-enabled intervention research on older adults living alone with cognitive decline. ASU Roybal matches the FOA Thematic Area in targeting MoBC to promote behavior and lifestyle change and is in line with the National Research Summit recommendations. It will test innovative technology-enabled interventions in a growing but overlooked population—older adults living alone with cognitive decline.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT Intimate partner aggression (IPA) is a prevalent public health concern that has been tied to numerous negative consequences. Alcohol use is a well-established contributing cause of IPA. Traditionally conceptualized as a private form of aggression, most IPA research has focused on risk factors lying within individuals (e.g., personality) or within couples (e.g., communication). However, more recently, the need to look at couples' social contexts has been emphasized, suggesting that alcohol use may interact with couples' contexts to increase risk for IPA. The proposed project builds directly upon this foundation to test the possibility that aggression in intimate relationships is governed by the social connections that partners create and maintain. Specifically, we aim to examine how social isolation and social norm perceptions in in-person versus virtual social networks moderate the association between alcohol use and IPA. To do so, we will make use of a validated approach that assesses social networks at the dyadic level, thereby allowing us to capture both partners' individual social networks as well as the specific ways in which partners' networks overlap or fail to overlap. We locate our study among couples from low-income communities who do not only represent an understudied segment of the population, but who also have fewer resources and thus tend to rely more heavily on their social networks for support. Two-hundred couples (N = 400 individuals) will complete an online survey on alcohol use and IPA (along with other demographic measures). In addition, each partner will provide the names of 20 people in their in-person and virtual social networks (network “alters”), information about each alter, and information about the relationships between each unique pair of alters. These raw data will allow us to calculate measures of social isolation and social norm perceptions related to alcohol use and IPA. Aims of the current project are to examine whether associations between alcohol use and IPA will be stronger when couples are in networks that are more socially isolated (H1a) and when couples hold greater social norm perceptions for alcohol-related IPA (H1b). Moreover, we will examine whether the effect of social norm perceptions on the association between alcohol use and IPA depends on social isolation such that couples in high-density networks with social norms supportive of alcohol-related IPA will report more frequent/severe alcohol-related IPA (H2a) and couples in high-density networks with social norms NOT supportive of alcohol- related IPA will report less frequent/severe alcohol-related IPA (H2b). Finally, we aim to explore whether associations among social isolation, social norm perceptions, alcohol use, and IPA differ as a function of the proportion of alters who belong to in-person vs virtual social networks. Understanding alcohol-related IPA within the context of couples' social networks has the potential to make a significant public health impact by developing an evidence base for interventions that address social networks themselves as a target of change.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY The objective of the proposed project is to develop and evaluate an online contraception decision aid, ContraceptionForAll, for transgender or gender-nonconforming (TGNC) persons assigned female at birth (AFAB). The specific aims are: (1) build the ContraceptionForAll tool by engaging the TGNC AFAB individuals in participatory design to enhance the platform, system function, and usability of an existing prototype developed by our group; (2) assess the usefulness and usability of ContraceptionForAll in a series of mixed- methods studies with cognitive walkthrough, usability testing, simulated test cases, a user survey, and follow- up interviews; and (3) conduct a randomized controlled trial to use ContraceptionForAll as a digital intervention to improve contraceptive decision-making, sexual health knowledge, and mental health for TGNC AFAB people. The proposed research fills the current knowledge gap in characterizing the structure and process of contraceptive decision-making among the TGNC AFAB individuals. It directly addresses the unmet health needs of the TGNC AFAB population and advocates for health and healthcare equity for this gender-minority group. It has the potential to advance culturally appropriate healthcare as well as to fight against potential biases, stigma, and discriminations. From the technology perspective, it will develop guiding principles for engaging gender-minority groups in participatory design of digital health tools as part of the efforts to build cultural competence for the biomedical informatics and health IT workforce. It builds on: (1) our team’s expertise and experiences in health information dissemination research, clinical decision support systems and patient decision aids, design and evaluation of information systems, gender-minority health, reproductive health, behavioral and mental health, clinical trials, and biostatistics; and (2) our preliminary work in development and evaluation of online contraceptive decision aids for both cisgender women and TGNC AFAB individuals. The digital intervention developed from this project will directly serve the TGNC AFAB population and has the potentials to enhance their sexual health education, to facilitate contraception decision-making, and to improve their sexual and mental health. The proposed research is highly responsive to AHRQ’s priorities in: (1) study of decision making tailored to the needs of disadvantaged populations; and (2) advancing health and healthcare equity. The success of the proposed research will lay out a foundation for dissemination of the digital intervention to the TGNC AFAB population in the next stage.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT Physical inactivity is a leading risk factor for obesity and cardiovascular disease across age groups. Numerous studies across the lifespan have found cross-sectional associations indicating neighborhood environment features (e.g., walkability) are favorably related to both physical activity and BMI/weight status. Though there was evidence from prospective studies supporting what has been found in cross-sectional studies, important gaps remain. Many prospective studies did not allow for interpretation of the magnitude of changes in outcomes, have focused on a single age group, and included short durations of follow-up, precluding examination of long-term impact of neighborhood environments on development of regular PA habits and weight status across the lifespan. This proposed study addresses these limitations by efficiently leveraging existing data from 5 existing NIH-funded studies to investigate prospective associations between neighborhood environment features and physical activity in 4 age groups (children, adolescents, adults, and older adults). A key innovation is the ability to examine similarities and differences in environment—health associations across the lifespan. Each existing study involves cross-sectional data but the shared participants and measures across studies allows for the investigation of long-term prospective associations over two assessment time points 5-15 years apart. We will investigate in 1083 participants whether and how baseline neighborhood environment features (using GIS-based and reported measures) and changes in reported neighborhood environment features over time relate to changes in participants’ accelerometer-derived total physical activity, self-reported physical activity for transport and leisure, and weight status. The GIS-based measures are based on best practices in neighborhood walkability research and include residential density, land use mix, street connectivity, retail floor area ration, and a walkability index, as well as park density (playability) and transit density (transitability). The self-report measures capture additional widely used constructs such as pedestrian facilities, crime safety, traffic safety, and aesthetics. The age groups captured involve critical transition time points (e.g., into adolescence, young adulthood, and retirement) when understanding predictors of changes in physical activity are particularly important. The analytic approaches used will identify whether associations differ across age groups, sex, race/ethnicity, and education status. The findings will be critical in strengthening the evidence base on neighborhood environment impacts on health to better guide policy and practice around cardiovascular disease prevention and control. Results will be widely communicated to researchers as well as practice and policy audiences.

NIH Research Projects · FY 2026 · 2024-08

SUMMARY/ABSTRACT Approximately 85% of the proteome is considered undruggable by traditional, occupancy-driven pharmacology employing small molecular inhibitors. Proteolysis-targeting chimeras (PROTACs) and associated molecules that induce targeted protein degradation via the ubiquitin–proteasome system have emerged as a revolutionary strategy for addressing “undruggable” targets. However, despite the groundbreaking advances and entry of some PROTACs into clinical trials, substantial challenges and considerable room for further development remain. Limitations of current PROTACs include poor cell permeability, limited availability of E3 ligands, and poor selectivity, highlighting a critical need for ongoing innovations in Targeted Protein Degradation (TPD) technology. To address these issues, the possibility of developing an efficacious drug delivery system, coupled with conditional activation of target protein degradation, stands out as a pivotal enhancement. In this context, nucleic acid-based modalities offer considerable promise for advancing TPD, building on the successful biomedical applications of nucleic acid-based drugs like antisense oligonucleotides (ASOs). The programmable and addressable nature of DNA or RNA nanostructures has been successfully harnessed, allowing for functional integration with small molecules, proteins, and peptides to realize applications in drug delivery, vaccines, and biosensors, among others. Based on these prior successes, we hypothesize that by leveraging the inherent programmability and addressability of DNA, precise and effective delivery of protein degradation modalities into cells and conditional activation of degradation can be achieved. For proof-of-concept validation, we have established an efficient cytoplasmic delivery platform utilizing a multifunctional DNA nanodevice and developed a DNA-based target protein degradation system (DTAC) capable of degrading CDK4/6 proteins at nanomolar concentrations. Building on these accomplishments, we intend to integrate our delivery platform with the DNA- based protein degradation system, aiming to pioneer the next generation of TPD technologies. Our approach aims to 1) optimize the programmability of our DNA duplex-based protein degradation system by transitioning from DNA duplex structures to multitargeting DNA nanostructures; 2) assess protein degradation variations caused by spatial distances and evaluate the efficiency of multi-target degradation; 3) integrate and optimize the cytoplasmic DNA nanostructure delivery system with the DNA-based protein degradation system; and 4) validate and optimize the conditional activation of protein degradation through two distinct design approaches: i) toehold mediated conditional activity of DTAC and ii) allosteric mediated conditional activity of DTAC.

NIH Research Projects · FY 2026 · 2024-07

PROJECT SUMMARY: Chronic pain affects over one third of the U.S. population and is a leading cause of disability. Hence, there is pressing need for developing innovative, safe, and accessible non-opioid treatments that effectively alleviate chronic pain. Mindfulness-based therapies (MBTs) have emerged as widely used mind-body interventions for chronic pain, focusing on enhancing present-moment attention, non-judgmental awareness, and acceptance. Despite their popularity, the overall effects of MBTs on pain-related outcomes remain modest. Recent mechanistic studies have shed light on the fact that mindfulness meditation does not modulate the endogenous opioid system, a crucial player in pain relief. This revelation underscores the potential for improving the efficacy of an MBT by integrating it with a safe, non-opioid intervention capable of directly modulating endogenous opioid system. Open-label placebo (OLP), a non-deceptive placebo, presents a promising, safe, and ethical intervention for chronic pain that can be combined with an MBT. Research has indicated that placebo-induced analgesia is mediated by the release of endogenous opioids. Consequently, there is a strong rationale to hypothesize that the combined application of an MBT and OLP treatment may yield more potent and enduring effects in alleviating chronic pain than either treatment used in isolation. This R34 study proposes a single-site three-arm randomized-controlled trial to evaluate the feasibility and acceptability of combining Mindfulness-Based Stress Reduction (MBSR), one of the most established and extensively studied MBTs for chronic pain, with OLP treatment for individuals living with chronic pain. A total of 45 participants will be randomly assigned to one of the following three conditions for an 8-week trial with a 3- month follow-up period: (1) MBSR-only; (2) OLP-only; and (3) a combination of MBSR and OLP treatment. The feasibility of conducting the proposed trial will be determined by several metrics, including: (1) the rate of participant enrollment, (2) participant retention from baseline to 3-month post-treatment follow-up, (3) adherence to the MBSR program, (3) adherence to OLP treatment monitored using a smart pillbox and the detection of urinary riboflavin tracer in mid- and post-treatment sessions; and (5) compliance with daily diary assessments. The acceptability of combining MBSR and OLP treatment will be determined by self-report ratings regrading (1) treatment satisfaction, (2) intervention effectiveness, (3) intervention convenience, (4) side effects, (5) appropriateness of intervention and daily diary assessment length and frequency; and (6) appropriateness of other study measures. The ultimate goal of this study is to advance chronic pain management strategies for millions of individuals with chronic pain. The proposed study will serve as a pivotal initial step in establishing procedures and strategies necessary for a comprehensive evaluation of combined MBSR and OLP treatment in a future fully-powered multi-site clinical trial.

NIH Research Projects · FY 2026 · 2024-07

Project Summary/Abstract The prevalence of obesity has reached alarming levels, impacting approximately one-third of the adult population in the United States. This epidemic poses a significant risk to individuals, increasing the susceptibility to metabolic syndrome. In most cases, obesity is characterized by hypothalamic resistance to the anorexigenic hormone leptin. Leptin resistance impedes the efficacy of leptin therapy in addressing obesity and metabolic syndrome. While several regulators have been implicated in leptin resistance, it is critical to identify additional regulators of leptin signaling to gain a full understanding in the development of leptin resistance, particularly nuclear factors that influence the epigenetic landscape of chromatin architecture, which can be susceptible to obesogenic environmental factors. Aberrant epigenetic modifications are increasingly recognized to trigger the onset of numerous diseases, including metabolic diseases. However, the interaction between obesogenic diet and the epigenetic reprogramming of hypothalamus, where leptin elicits its action, remains largely unknown. Jumonji D3 (JMJD3; KDM6B) is a histone lysine demethylase that epigenetically activates genes by demethylating the repressive histone mark H3K27me3. While JMJD3's involvement in various biological processes, such as development, immunity, and autophagy, has been demonstrated, its metabolic roles in the hypothalamus remain unexplored. In our preliminary study using mice, we observed that a high-fat diet (HFD) leads to the specific downregulation of JMJD3 expression in the ventromedial hypothalamic nucleus (VMH), a region characterized by high leptin signaling activity. shRNA-mediated VMH-specific downregulation of JMJD3 disrupts hypothalamic leptin signaling, contributing to the development of obesity. Conversely, lentivirus-mediated VMH-specific overexpression of JMJD3 enhances leptin signaling, offering protection against obesity and metabolic syndrome induced by HFD. The present study aims to demonstrate the crucial role of JMJD3 as an epigenetic modifier in regulating hypothalamic leptin signaling and energy homeostasis. Aim 1 aims to examine whether hypothalamic JMJD3 protects against obesity through an epigenetic mechanism. We will create Jmjd3 knockout mouse models that are specific to the ventromedial hypothalamus (VMH) region and leptin receptor-expressing cells to investigate the anatomical and functional role of JMJD3 in hypothalamic leptin signaling and obesity development. Aim 2 will explore the molecular mechanism by which JMJD3 influences leptin signaling. We will investigate whether JMJD3 induces epigenetic modifications in known regulators of leptin signaling, such as the leptin receptor. Additionally, we will use ChIP-seq and RNA- seq to identify other targets of JMJD3 in an unbiased manner. Aim 3 will explore nonpharmacological strategies to enhance hypothalamic JMJD3 expression, aiming to alleviate leptin resistance. This proposal will establish the significance of hypothalamic JMJD3 in the leptin signaling pathway, potentially identifying JMJD3 activation as a therapeutic target for combating obesity by enhancing leptin sensitivity.

NIH Research Projects · FY 2025 · 2024-07

Project Summary/Abstract. Hypertension (high blood pressure) affects 1 in 3 of the over 90 million people currently enrolled in Medicaid, and is a leading cause of cardiovascular disease and stroke in the U.S. While multiple effective anti-hypertensive (AH) drugs are widely available in the U.S., they require high (≥80%) life- long medication adherence to successfully counter cardiovascular morbidity and mortality. Unfortunately, AH medication adherence is lowest among Medicaid enrollees compared to other insured populations, and nonadherence is a major barrier to controlled blood pressure. The mechanisms of present bias and habit strength have been shown to maintain behavior change in several settings, but have not been tested for maintaining high AH medication adherence. Incentives are effective for improving medication adherence in the short term, and may reduce present bias by helping people better internalize the future benefits of their actions, which in turn could maintain AH medication adherence. Therefore, we propose to partner with the widely-used, commercial Wellth smartphone app, where app users can earn incentives for sending photographic evidence of their daily pill taking. After withdrawing the Wellth-delivered incentives, we will measure adherence maintenance. Habitual pill-taking is another key strategy for maintaining behavior change, since habits performed in response to the same contextual cue for roughly four months are executed with high habit strength, i.e., are performed with little or no cognitive effort. Existing habit formation interventions have had difficulty effectively supporting participants, but behavioral economics suggests that providing small incentives for cueing the new behavior can effectively support habit formation. Thus, this study proposes to also adapt the Wellth app to reward cued AH pill taking. In a Stage III, 24-month 3-arm real-world efficacy trial, hypertensive adults with low (<80%) adherence from Arizona Complete Health’s Medicaid plan (n=600; 200 per group) will be randomly assigned to: 1) ‘Control’ group; 2) ‘Wellth Only’ that will receive daily incentives for submitting a picture of their AH pill taking; or 3) ‘Wellth+Cue’ that will be asked to describe the cue that will trigger their AH pill taking and send a second picture of the contextual cue, such as a coffee mug. A 4-month intervention will be followed by a 20-month post-intervention period to measure maintenance. The Primary Outcomes are mean AH medication adherence (days covered measured via Medicaid claims) and blood pressure (via at-home readings at baseline and months 4, 8, 12, and 24). Secondary Outcomes are healthcare utilization (emergency and inpatient visits) and the costs incurred by Medicaid (via claims data). After the study ends, interviews with stakeholders and participants (using a positive/negative deviance approach) will ask about potential implementation barriers to inform intervention refinements and cultural adaptation to prepare for Stage V implementation research in a future study. If found effective, the study has the potential for immediate scale-up for maintaining treatment adherence for hypertension and a range of other chronic conditions.

NIH Research Projects · FY 2026 · 2024-07

Project Summary / Abstract Protein interactions are the fundamental basis of all cellular processes. Proteins interact with each other to form complexes that carry out a wide range of functions, from signal transduction, and gene regulation, to DNA re- pair. Disruptions in protein interactions are implicated in a wide range of human diseases. While wet-lab assays to study protein interactions are indispensable, with advancements in algorithms and machine learning, com- putational methods for predicting protein interactions have the potential to revolutionize our understanding of cellular processes, identify new drug targets, and develop more effective therapies. Our research applies domain knowledge from biological sequence analysis, structural biology, and machine learning to computationally predict whether given protein complexes will interact or generate novel protein receptors that may recognize target lig- ands. These computational algorithms and machine learning models can be used to 1) develop new therapeutic molecules to treat infectious diseases or cancer, and 2) produce new diagnostic tools to detect abnormality in cells. To provide biological sequences (such as protein sequences) as input to these computational methods, one must first express them as a fixed-size numeric vector, often referred to as an embedding of the input sequence. However, the mainstream embedding techniques for biological sequences are simple adaptations of embedding techniques from the field of natural language processing. Biological sequences are highly complex and struc- tured, where the unit of information is less noticeable when compared to natural languages. Two primary goals of the proposed research in this project are: 1) pinpointing the determinant of an effective embedding of biological sequences to have generalized principles to design protein language models for a given specific family of pro- teins, and 2) applying these embedding techniques to better generate immune receptors such as T cell receptors (TCRs) and B cell receptors (BCRs) that interact with a target epitope. Both research goals build on our previous TCR embedding model that boosts downstream model performance by a wide margin on TCR-epitope binding prediction and clustering of TCR repertoire. The outcome of this project will be a unified computational frame- work for predicting protein interactions and designing novel TCRs and BCRs, which will have a profound impact on human health.