University Of Nevada Las Vegas

NIH Research Projects · FY 2025 · 2023-08

Project Summary This proposal will test the hypothesis that chronic social jetlag attenuates adaptations to exercise training and increases susceptibility to cardiometabolic stress. Social jetlag (SJL) is a novel and pervasive form of circadian rhythm disruption caused by desynchrony between scholastic/professional clocks (i.e. - work or school schedules) and the endogenously driven circadian rhythm (weekend/free day schedules). Recent studies suggest that almost 80% of the population undergoes some degree of SJL (i.e. – ≥1:00 shift between weekday/weekend), with nearly 30% experiencing >2 hours of shifting. Social jetlag has been associated with cardiovascular risk factors and metabolic diseases including obesity, diabetes, and low cardiometabolic fitness (VO2max). However, it is currently unknown how SJL impacts the exercise training response. As exercise is a frontline intervention for the prevention and reversal of cardiovascular and metabolic diseases, it is essential to determine if, and when, exercise can be most effectively prescribed and most protective of the heart. We have previously shown that acute exercise differentially activates myocardial gene expression and signaling depending on the time of day it is performed in mice with intact circadian rhythms. However, it is unclear how exercise, and exercise timing, may be impacted during circadian rhythm disruption via SJL. As such, our overarching hypothesis is that SJL increases the susceptibility to cardiometabolic disease, and the time-of-day that exercise is performed will modulate its efficacy to elicit training adaptations and prevent cardiometabolic disease. To address this hypothesis, we will pursue the following three specific aims. 1) Determine the impact of social jetlag on molecular and physiologic exercise training-induced adaptations in mice, 2) Determine the effects of temporally prescribed exercise during chronic social jetlag on behavioral circadian rhythms, and 3) Determine the impact of chronic social jetlag on cardiometabolic health in mice, and potential reversal with TOD-dependent exercise prescription. Preliminary data presented in this application reveal temporal preference during time- restricted exercise training (i.e. – mice run further during the first half of the active phase compared to the second half), with little difference cardiorespiratory fitness, suggesting exercise training in the late active period may elicit comparable training adaptations with lower volume. How time-restricted voluntary exercise impacts metabolic perturbations during high fat feeding, as well as during SJL, is not currently known. Successful completion of these aims will expand upon these findings to include SJL-induced circadian rhythm disruption, and will increase our understanding on how exercise timing plays a critical role in cardiovascular disease prevention.

NIH Research Projects · FY 2025 · 2023-08

Sexual minorities (SM), defined here as individuals whose sexual orientation differs from the heterosexual majority, continue to be underrepresented in Alzheimer’s disease and related dementia (ADRD) caregiving research. Estimates suggest at least 1 in 5 SM adults in the U.S. (nearly 1 million persons) are currently caregivers, with nearly half providing care to someone with ADRD. Our previous research has found that SM caregivers experience health disparities, including greater challenges to optimal health, depression, disability, and stress (e.g., physical, emotional, and financial strain). Given the critical contributions of informal caregivers to ADRD care and the changing nature of caregiver dynamics, roles, and needs, it is crucial that measures relating to caregiving accurately reflect all caregivers. This study proposes to enhance understanding of experiences, roles and dynamics for SM ADRD caregivers by identifying existing domains and developing new measures, testing and validating these measures, and ensuring measures accurately capture caregiving constructs and experiences of SM ADRD caregivers. Guided by a community based participatory approach, we will leverage expertise of advisory boards with knowledge of SM ADRD and caregiving research. This mixed method study has three specific aims. In Aim 1, we will identify and explore domains of ADRD caregiving for SM ADRD caregivers through focus groups (n=8) and in-depth interviews (n=40). These findings will inform Aim 2 and the identification of key domains and subdomains. In Aim 2, we will develop and refine new measures of ADRD caregiving for SM ADRD caregivers through the use of a modified online Delphi method that will garner input from advisory boards (community partners/researchers, n=40) with expertise in ADRD caregiving measures and the lived experiences of SM and non-SM ADRD caregivers. To ensure content validity of the new ADRD measures, they will be pretested and refined based on initial testing (n=40) and cognitive interviews (n=20) with SM and non-SM caregivers. In Aim 3, we will then test the new and existing measures of ADRD caregiving among a sample of SM (n=250) and non-SM ADRD caregivers (n=250). After evaluating the dimensionality structure of each item pool for a given domain and removing misfitting items, we will use item response theory (IRT) and an IRT-based model fit to further evaluate for item misfit. Finally, the resulting measures will be evaluated within an independent sample of SM (n=125) and non-SM (n=125) caregivers. This study’s iterative process will allow for the development of 6 to 8 new or modified caregiving measures that can help to improve access to supports and services of SM ADRD caregivers, and ensure that future studies and intervention efforts can meet the needs of all ADRD caregivers and their care recipients.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY/ABSTRACT Alzheimer’s Disease and Related Dementias (ADRD) are growing challenges to the public health and have unmet needs that can be addressed through: Specific Aim 1) innovation and entrepreneurship; Specific Aim 2) non-academic research-based careers; and Specific Aim 3) academic ADRD drug development. These three themes will be developed in seminars, internships, lived experiences, discussions, and supervised projects of the UNLV Brain Health Innovation Incubator (InnovaTor). The InnovaTor will be Co-Led by Principal Investigator (PI) Jeffrey Cummings, MD, ScD, an experienced ADRD investigator and trialist and PI Jamie Schwartz, MBA, Director of Industry and Business Engagement for the UNLV Office of Economic Development to create a science-business leadership team. The InnovaTor will be a platform to help students identify research products that have commercial value, protect intellectual property, initiate a start-up company, secure funding, promote commercialization, and advance a marketing campaign (Specific Aim 1). The curriculum will include an introduction to SBIR and STTR grant development. In addition to on-going seminars, a 1-week summer Entrepreneurship Immersion Experience engaging UNLV students and others in discussions, projects, and team exercises will be hosted by the InnovaTor. An annual Innovation Day will involve campus-wide activities to attract participants to the InnovaTor and provide insights into the opportunities for ADRD-related entrepreneurship. Discussions of non-academic career alternatives will be led by individuals with roles in government science administration, advocacy, non-profit organizations, science writing and editing, policy think tanks, and investment (Specific Aim 2). The InnovaTor has established a strategic alliance with Eli Lilly and Company to have industry- based faculty interact with participants and educate about research-based careers in biopharma. Drug development discussions will emphasize the academic-industry interface with associated start-up and entrepreneurial opportunities (Specific Aim 3). An Innovator Club will be comprised of current and past InnovaTor participants to encourage entrepreneurship and to support an evolving start-up community. An agile InnovaTor structure will be supported by a Steering Committee, External Advisory Board, and an assessment team. Defined milestones will guide the development of the InnovaTor. Outreach to UNLV programs as well as other educational institutions in Southern Nevada will be led by an Innovation NavigaTor including a program to attract undergraduate students (Pre-CubaTor). UNLV is both a Hispanic-Serving Institution and an Asian American and Native American Pacific Islander-Serving Institution providing an opportunity to build programs to attract minority students to InnovaTor activities. The InnovaTor will interact with NIH and NSF-funded programs at UNLV, UNLV innovation resources (Lee Business School, Boyd School of Law, Office of Economic Development), and local community biotechnology firms and organizations. The Brain Health InnovaTor will build a culture of innovation and entrepreneurship devoted to ADRD.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY/ABSTRACT Emergent Bilingual (EB) children of Spanish-dominant caregivers represent a large and growing proportion of the school-aged United States population. For EBs, developing proficiency in the language used by caregivers at home is foundational to supportive family relationships and later school outcomes, yet research has shown declines in EBs’ home language proficiency after school entry (Castilla-Earls et al., 2019; Jackson et al., 2014). A particularly vulnerable subset of EBs are those with Developmental Language Disorder (DLD), which is characterized by low language skills despite otherwise normal development and occurs in about 7% of children. Given the scarcity of bilingual service providers, caregiver-delivered language interventions are a practical and promising approach to preventing and treating DLD in the home language. Yet little is known about the specific caregiver behaviors that sustain home language development in EBs with or at-risk for DLD in preschool (age 3-5), a period when overall exposure to English increases. This project addresses this critical gap while supporting the candidate’s transition to independence through training in child language disorders, parenting interventions, and novel approaches to using bilingual daylong recordings. By leveraging observational language data from two large-scale randomized clinical trials (RCTs) of a parent-coaching program called Play and Learning Strategies (PALS; Landry et al., 2008) the current project will identify caregiver behaviors specific to bilingual contexts that contribute to preschool-aged EBs’ home language use and skills. During the mentored K99 phase, using existing data from a completed RCT, Aim 1 will determine the impact of PALS on targeted caregiver behaviors (e.g., contingent responsiveness) and child Spanish outcomes with the subset of parents who received coaching in Spanish (T=71, C=70). Aim 2 will recode video observations from this dataset to identify home-language supportive behaviors (e.g., caregivers Spanish use, responses to child English use) that predict children’s later Spanish proficiency (n=141). Next, new daylong recordings (n=160) will be collected alongside an ongoing PALS RCT tailored for Spanish-English EBs at risk for DLD (risk determined via Spanish and English language screeners at preschool entry). During the independent R00 phase, Aim 3 will determine 1) whether home-language supportive behaviors captured in daylong recordings predict child Spanish outcomes and 2) whether PALS coaching leads to changes in these behaviors, which in turn explain child Spanish outcomes. By capturing spontaneous language-rich interactions that occur throughout the day with different conversation partners in the context of a larger ongoing RCT, this project promises to generate new insights into the conditions and caregiver behaviors that support bilingual development in EBs with DLD and inform culturally and linguistically-sustaining interventions. This award also provides critical training that builds on the candidate’s background in bilingual language development and positions her to launch an independent research program focused on the intersection of bilingualism and language difficulties in preschool-aged children.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY The goal of this project is to find new neural substrates governing metabolic state in Drosophila melanogaster. Success of organisms through evolutionary time depends upon their ability to optimize utilization of resources. When environments become unfavorable, animals will preserve energy and attenuate reproduction. This strategy requires perception and assessment of a complex environment, which is an ancient role of the nervous system. Many metabolic disorders in humans, such as polycystic ovarian syndrome, remain incompletely understood, but probing an underlying role for the nervous system remains a monumental challenge. Here, we propose to exploit the genetic accessibility and cellular resolution experiments possible in the fly, Drosophila melanogaster, to explore how the brain sets metabolic and reproductive state. Given the importance of environmental adaptation, we expect the biological principles underlying these strategies to be highly conserved among motile animals with nervous systems, including flies and humans. The Meiselman lab seeks to establish a network map for the nervous system components that permit the fly brain to change metabolic state, thereby laying groundwork for investigations in organisms with brains of higher complexity. During my postdoc I showed that DN3 circadian neurons and expression of their operant neuropeptide, Allatostatin-C (AstC), are temperature-sensitive and terminate cold-induced reproductive arrest when warm temperatures return. In this proposal, we will find the minimal neural subset that depends on temperature information from DN3s and adjusts reproductive output, then examine how their innate activity responds to temperature change with calcium imaging (Aim 1.1). Next, we will determine if the minimal subset controlling reproduction causes changes to rhythmicity, feeding, and metabolic rate (Aim 1.2). We will then investigate a second subset of neurons that depress reproduction when activated, heart-innervating LkAC neurons. We will assess their role in modulation of metabolism (Aim 2.1) and examine if their activity affects heartbeat (Aim 2.2). Finally, we will find the molecular (Aim 3.1) and neural (Aim 3.2) substrates that attenuate reproduction in response to noxious percepts (hunger, thirst, and high heat). In sum, this work will offer comprehensive insight into how the nervous system integrates sensory information to control metabolic state and reproduction. This project will present opportunities for diverse students at a minority-serving institution (UNLV) to engage in research which utilizes cutting-edge techniques. My co-mentors Dr. Mariana Wolfner and Dr. Frank van Breukelen, and collaborators Drs. Allen Gibbs and Nilay Yapici collectively have world-leading expertise in fly genetics, metabolism, and neurobiology. Their support will allow me to foster a successful laboratory environment wherein I can offer top notch mentorship to my students and reach my career goals. In addition to critical technical skills, my mentors will offer me guidance that will allow me to establish a successful extramurally funded research program, and to unveil new insights into the interface between brain and metabolic state.

NIH Research Projects · FY 2026 · 2023-06

Project Summary Alternative splicing generates transcripts that vary between tissues and cell types, and contributes to cell differentiation and organ development. Despite its importance in development and cell identity, alternative splicing is usually neglected in single cell RNA sequencing (scRNA-seq) analysis. This is due to the challenge in identifying confident alternative splicing events from scRNA- seq data, which are limited in read-depth, and comes with large amount of noise due to variation in molecule capture efficiency, amplification bias, and excessive zero-counts or dropouts. We propose a novel approach to infer differential splicing based on short-read full-length scRNA-seq data, utilizing read counts mapping to adjacent exons. In addition, we plan to systematically evaluate existing approaches to answer questions on the strategy regarding the variable, pooling and dispersion estimates. Finally, we will assess the accuracy of short read based methods by comparing against scRNA-seq generated with new types of protocols. The work proposed will increase our understanding on the utility and limitations of short read scRNA-seq data, and provide a better pipeline for alternative splicing analysis in scRNA-seq.

NIH Research Projects · FY 2025 · 2023-06

Abstract Clostridium difficile infection (CDI) is the main identifiable cause of antibiotic assoicated diarreah. The incidence of CDI is approximately 677/100,000 patients resulting in close to 500,000 cases annually in the US alone. CDI causes approximately 25,000 deaths a year and costs the health care system an estimated $6.3 billion/year. The main CDI risk factor is aggressive broad-spectrum antibiotic use. Similarly, older populations are more susceptible to CDI than younger cohorts. Conditions that reduce immunity (e.g. organ transplant, chemotherapy, AIDS) are also strongly correlated with CDI severity. Importantly, studies have shown that women have higher risk of CDI than men. CDI symptoms range from asymptomatic colonization to mild diarrhea to deathly colitis. All studies that delineate risk factors associated with CDI have been conducted with infected populations. Hence, the determinants of individual predisposition to contracting CDI are not well understood. Similarly, it is not clear why CDI symptoms severity vary among individual patients. Mice have been used successfully as a model to test novel approaches to treat for C. difficile infections. The murine CDI model present symptoms progression reminiscent of human CDI and respond to the same treatments. During our screening for CDI prophylactics, we observed that female mice developed more severe CDI signs compared to their male counterpart. In this application, we will test the hypothesis that sex hormone levels correlate with CDI symptom onset and severity. We will also determine whether sex-related variables affect CDI prevention and treatment. The data obtained in this project will allow determining the contribution of steroidal sex hormones and/or sexual status to murine CDI susceptibility. This information will then be used in a follow-up R01 application to determine the mechanisms underlying the differences between male and female CDI susceptibility.

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY/ABSTRACT 683,000 women are sexually assaulted annually in the US, half of whom develop chronic posttraumatic stress disorder (PTSD). Women with sexual assault-related PTSD are at markedly increased risk for cannabis use disorder (CUD), a public health problem affecting 13 million Americans and contributing to the >$200 billion US annual costs of substance use. Indeed, in an observational study of 706 women sexual assault survivors, half had clinically significant PTSD and reported cannabis use. Those with comorbid PTSD-CUD have more severe presentations and worse treatment outcomes than either condition alone, underscoring the need for preventive interventions for PTSD-CUD. 100,000 women annually seek emergency care after sexual assault and are offered preventive interventions for pregnancy and sexually transmitted infections, but not the more common sequelae of PTSD-CUD. Addressing the critical unmet need for preventive interventions for PTSD-CUD after sexual assault would reduce the public health burden and personal suffering associated with these conditions. Anxiety sensitivity (AS; fear of anxious arousal) is a malleable risk factor that prospectively predicts PTSD among sexual assault survivors in pilot data, may underlie the PTSD-CUD comorbidity, and can be reduced with brief digital therapeutics that lead to reductions in PTSD and CUD. Theoretically, and in our pilot data, AS causes PTSD symptoms to be interpreted as threatening and to be avoided, leading to substance cravings and use to dampen physiological arousal measured via electrodermal activity (EDA). Specifically, cannabis is commonly used as an anxiolytic after sexual assault among those with high AS, but unfortunately can lead to the adverse effects of comorbid PTSD-CUD on symptoms and outcomes. The proposed K23 will leverage smartphones and an established research network of emergency care sites for sexual assault to provide a digital therapeutic targeting AS (based on a validated cognitive behavioral treatment) and conduct biobehavioral assessments of mechanisms underlying targeting AS to reduce PTSD-CUD. Aims are to test acceptability, initial efficacy, and mechanisms of an AS digital therapeutic to reduce PTSD-CUD compared to a relaxation control. Women presenting for emergency care after sexual assault (total N=78) will complete assessments at the emergency visit and 1 week, then will be randomized and complete their assigned interventions. Outcomes and mechanisms will be assessed by ecological momentary assessment and intervention (EMA/EMI), a wearable assessing EDA over 6 weeks, and via 6 week and 6 month self-report follow-ups. In this context, the applicant will receive training in the design and conduct of preventive multi-site emergency care-based RCTs, advanced statistical analysis for RCTs incorporating EMA, and biobehavioral assessments of mechanisms underlying PTSD-CUD prevention, setting the stage for an R01 definitive mechanistic clinical trial and launching her independent research career focused on reducing the public health burden of PTSD-CUD after sexual assault using digital therapeutics.

NIH Research Projects · FY 2024 · 2022-09

PROJECT SUMMARY The dramatic increase in the prevalence of childhood obesity in recent decades has made obesity one of the greatest public health challenges of the modern world. It is estimated that by 2030, 33% and 50% of US children ages 6-11 and 12-19 years, respectively, will be overweight or obese. Environmental exposures in utero and during postnatal periods of heightened susceptibility may increase risk of obesity and adversely impact cardiometabolic health. Organophosphate esters (OPEs) are additive flame retardants and plasticizers that are extensively used worldwide after the phase-out of polybrominated diphenyl ethers (PBDEs). The ubiquitous use of OPEs has resulted in almost all pregnant women having OPE exposures and children having a higher body burden compared to adults. OPEs interfere with well-recognized biological pathways contributing to the development of obesity and cardiometabolic health, including disruption of: 1) thyroid hormones; 2) sex steroid hormones; and 3) peroxisome proliferator-activated receptors as well as inducing 4) chronic low-grade inflammation. Toxicological studies indicate OPEs increase lipid accumulation, disrupt metabolic function, and impair glucose tolerance, supporting their role as potential obesogenic and metabolism-disrupting chemicals. Epidemiological studies report increased odds of being overweight and obese as well as higher waist circumference, body mass index (BMI), total cholesterol, and triglycerides. However, no longitudinal study in humans has examined repeated OPE measures in early life and their association with adiposity and cardiometabolic health in adolescence, which is a significant data gap. This proposed application will capitalize on resources of the Health Outcomes and Measures of the Environment (HOME) Study to be among the very first to examine whether early life OPEs are associated with adiposity and cardiometabolic health measures in adolescence, including BMI and waist circumference z-scores, fat-mass index, body fat %, blood pressure, fasting glucose, serum lipids, adiponectin, and leptin, using a prospective study design. We will additionally measure novel cardiometabolic intermediates, including high molecular weight adiponectin, glycoprotein acetyls (GlycA), irisin, vaspin, and lipoprotein particles, as well as biomarkers of inflammation. We will use Quantile g-computation (Q-gcomp) and Bayesian Kernel Machine Regression (BKMR) to examine complex OPE mixtures to determine the individual and joint effects of OPEs on adiposity and cardiometabolic profiles in adolescence. We will use data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a pan-Canadian cohort, to validate findings from the HOME Study. We will generate novel findings on whether early life OPEs are obesogenic and metabolism-disrupting chemicals during adolescence and identify potential windows of susceptibility. Given the ubiquity of OPEs and the global burden of obesity and type 2 diabetes, the findings will be highly valuable for environmental policy making and exposure reduction.

NIH Research Projects · FY 2025 · 2022-07

PROJECT SUMMARY A main challenge in the regeneration field has been to identify the signaling pathways and suitable cell types needed to enable productive tissue repair. For the eye, the successful generation and maintenance of eye-specific stem cells is a key goal. Although the process of vertebrate eye development is well-studied and characterized, the mechanisms that can induce eye stem cell proliferation following injury or disease remain difficult to identify. This is partly because natural stem cell proliferation typically occurs during embryo development whereas studies of retinal regeneration have largely utilized adult (or mature) models – a very different environment. The highly regenerative clawed frog, Xenopus laevis, is an established model for both development and organ regeneration. It is also closely related to humans. We found that Xenopus embryos successfully regrew functional eyes within 5 days. Our studies also showed that successful eye regrowth required increased and extended retinal stem cell proliferation while delaying new eye formation. One candidate pathway to regulate eye regrowth is bioelectrical signaling. Bioelectrical signaling is well-characterized for its role in limb regeneration but its role in eye development and regrowth is unclear. Our data showed that inhibition of bioelectrical signaling blocked eye regrowth, indicating that its function is required. We seek to understand and define the roles of bioelectrical signaling during eye regrowth, as a first step towards establishing a protocol for effectively dissecting the similarities and distinctions between development and repair. This project will: 1) define the expression patterns and key function of bioelectrical signaling components during eye regrowth and development; 2) assess the role of bioelectrical signaling in activating regenerative retinal progenitor cell proliferation and expansion, and 3) identify potential downstream targets. Together, this proposal will leverage the unique biology of Xenopus to establish an efficient strategy to rapidly define key mechanisms that regulate regrowth-induced retinal progenitor cell proliferation in vivo. This protocol will set the foundation for eventually building a blueprint for productive eye repair strategies.

NIH Research Projects · FY 2026 · 2022-01

PROJECT SUMMARY Stroke is the leading cause of adult disability and one of the most common causes of death in the US. To date, no clinical trials have succeeded in alleviating patients' neurological impairment. The clinical and economical burden of this disease urges the need for a medical solution outside the confines of conventional practices in neurology. While the overwhelming majority of research on brain repair is centered on neurons, an increasing body of evidence suggests that angiogenesis and immunomodulation in the injured brain play a fundamental role in guiding post-stroke neuroplasticity and functional recovery. Recent advances in tissue engineering have led to the development of hydrogel materials that can be injected directly into the stroke lesion site to form cell- instructive scaffolds for tissue repair. However, these biomaterials have not been actively designed to promote angiogenesis and reduce inflammation in the lesion site, which significantly limits their reparative capability. We have recently shown that injection of hydrogels that are actively designed to promote angiogenesis or reduce inflammation enhance brain tissue repair, but do not lead to complete tissue regeneration or functional recovery. The studies in this grant investigate the development of a novel injectable material that is specifically designed to mimic the mechanical, structural, and biological properties of the brain extracellular matrix (ECM), while simultaneously inducing the formation of a mature and functional vascular network with a restored blood brain barrier, and modulating the immune response of reactive astrocytes and microglia in the injured brain. We propose to design, fabricate, characterize, and optimize the development of a “biomimetic regenerative angiogenic immunomodulating nanocomposite” (BRAIN) material that combines the synergic reparative potential of two distinct engineered systems previously developed by our team: 1) a microporous scaffold made of annealable microgel building blocks to target the post-stroke immune response, and 2) highly clustered vascular endothelial growth factor (hcV) immobilized onto heparin nanoparticles, to promote angiogenesis in the lesion site. We will follow a systematic multifactorial mathematical approach to simultaneously alter the mechanical, structural and biological hydrogel properties and screen for the optimal formulations that result in the highest degree of brain tissue regeneration and functional recovery. Successful completion of this proposal will pave the way for pioneering nanotechnology-based medical solutions to repair the injured brain and regain lost function after stroke.

NIH Research Projects · FY 2025 · 2021-09

Maternal and child health is critical to achieving the Healthy People 2030 Goals. Investing in integrated nurturing care interventions from preconception through childhood and adolescence defines one’s developmental trajectory with benefits that accumulate across the life course and promote the health of generations to come. The 2019 global pandemic disrupted essential nurturing care services such as prenatal, perinatal, and pediatric services. As a result, over a million preventable child and maternal deaths globally are estimated to have occurred due to extreme poverty and food insecurity (i.e., lack of consistent access to enough healthful food for an active, healthy life due to limited financial resources). Amid the pandemic, food insecurity in the US tripled among households with children (~19.5%), disproportionately burdening low-income families and those in vulnerable communities. Food insecurity is strongly linked with social determinants of health and adverse maternal-child health and nutrition outcomes. Integrating effective food security interventions within nurturing care services post pandemic is an achievable strategy to promote the health of economically vulnerable populations. The West Las Vegas Promise Neighborhood (WLVPN) is an intervention addressing social determinants to improve population health in economically vulnerable communities in the Southwest US. The WLVPN has been implemented by over 50 multi-sector partners in key life domains (health, education, employment, housing, and civic participation) and is coordinated by Nevada Partners, Inc., with whom we have a solid and long-term collaboration. While the WLVPN social intervention is a unique opportunity and platform to address maternal-child mortality and food insecurity in the community’s vulnerable population, it lacks a focus on maternal-child health and nutrition. Therefore, our partnership with Nevada Partners, Inc. is well-placed for carrying out the maternal-child component within WLVPN and advancing implementation and health promotion research. Using a community-based participatory approach we will co-create with the community an intervention to integrate maternal-child health and nutrition consisting of a bundle of effective food security interventions retrieved from the literature (e.g., universal screening, community referral, monitoring system, and nutrition-focused counseling strategies) and then adapted and integrated into the nurturing care services within WLVPN communities. A Hybrid Type III quasi-experimental within-site trial will be designed to 1) develop and implement a community-engaged system-level intervention to integrate maternal-child health and nutrition and 2) assess the effectiveness of this intervention in decreasing levels of food insecurity and/or improve health outcomes of pregnant women and their young children under the age of 3, which will nurture their potential, enabling them to thrive. This project is designed to inform how the best multi-sectoral maternal-child health and food security interventions can be integrated to transform maternal-child health and nutrition in economically vulnerable communities.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY Though a number of studies have been reported regarding how aging-associated mutations lead to the higher incidence of cancer development and more aggressive cancer progression in elderly patients, few studies, if any, address that how altered mechanical characteristics of the microenvironment in aging tissues affect the course of cancer pathology. Mounting evidence strongly supports that mechanical properties of the tissues, including elastic modulus and relaxation time, significantly contribute to the pace of tumor progression. The reported results so far agree with the notion that the mechanical properties of aging tissues and cells are different from those of young tissues and cells. Given that tissues are, in general, stiffer in older individuals and tissue stiffness is known to promote tumor progression, we hypothesize that aging skin tissue, exhibiting distinct mechanical characteristics, promotes the progression of skin cancer in elderly patients via p53-mediated pathways. To prove this hypothesis, first, we plan to overcome the knowledge gap in the systematic quantification of the different mechanical properties between young and aging tissues. We will measure the elastic modulus and relaxation time of human skin tissues of different ages using a custom-built indentation-based mechanical analyzer. Second, to systematically investigate how the altered mechanical property promotes tumor progression, we will establish an in vitro model system in the mimicry of young and aging tissues. Third, we will use the in vitro model system to evaluate the rate of tumor progression, p53 abundance, stability and activity in skin cells growing in the varied mechanical/viscoelastic microenvironment.

NIH Research Projects · FY 2025 · 2021-04

Abstract The National Institute on Aging Alzheimer's Disease and Related Dementias Research Implementation Milestones articulate the goals of the Institute for advancing Alzheimer's disease (AD) research. The Leadership Award for AD and Related Disorders requires that the applicant address objectives of the Milestones and provide mentorship to new and early stage investigators. The research proposed must be groundbreaking and paradigm changing. Among the eight focus areas within the Implementation Milestones' framework are Trial Innovation and Translation and Clinical Research – Pharmacological. The Alzheimer's Clinical Trial InnOvationN (ACTION) Initiative proposed here embraces both the research and mentoring aspects of the Leadership Award. The ACTION Initiative will include development of a Clinical Trials Observatory (CTO) and an embedded mentorship program. The CTO builds on the principal investigator's prior analyses of clinicaltrials.gov. This federal registry contains all trials conducted in the US and many trials conducted ex-US. It includes Phase 1, 2 and 3 clinical trials of preclinical, prodromal, and AD dementia trials. The PI has conducted and published research on the trial design, biomarker, and clinical outcomes data from the registry. In 2016, Congress passed a law requiring that trial outcomes be posted on the site within 1 year of completion of the trial. The PI proposes to build a multi-disciplinary team of engineers, computer scientists, statisticians, and bioinformatic experts to interrogate the range of data now available using artificial intelligence techniques including machine learning and deep learning. An external advisory committee will ensure quality and dissemination. The Alzheimer's Association will collaborate on results dissemination. An accessible web portal for the database will make reviewed data readily available for analyses and prediction/modeling of planned clinical trials. The growing database of real-world AD trial data will allow increasingly precise prediction of trial outcomes based on complex relationships among baseline features, trajectories of decline, drug mechanisms, and clinical and biomarker characteristics across all stages of AD. The data will be used by the PI, mentees, academic trial leaders, and industry trial sponsors. Three initial mentees are identified from neuropsychology, psychiatry, and engineering; more will be added with growth of the program. The ACTION Initiative has the potential to transform clinical trial planning and outcomes, leading to substantial impact on the Implementation Milestones of the NIA and accelerating development of new therapies for patients with AD and those at risk. Mentees will power the future of AD drug development and clinical trial planning.

NIH Research Projects · FY 2025 · 2014-12

Abstract Clostridium difficile infection (CDI) is the main identifiable cause of antibiotic assoicated diarreah. in the US alone, there are close to 500,000 cases annually causing approximately 25,000 deaths and costs the health care system an estimated $6.3 billion. C. difficile spores do not cause disease but can revert to toxin-producing bacteria (a process called germination) in the microbiota-depleted gut of hospitalized patients. We found that synthetic cholan-24-amides inhibit C. difficile spore germination and, more importantly, protects rodents from CDI without toxic effects. While amide-linked bile salts have many attractive properties, their hydrolysis can release toxic byproducts. To address this liability, we developed heterobicyclic non-hydrolysable bile salts (NHBS) as anti- germinants. Importantly, two analogs protect mice from CDI and are stable to the gut microbiome. This R01 renewal is based on five foundational discoveries obtained during the last funding period: (I) Optimized pipeline for CDI prophylactic development, (ii) synthetic bile salt analogs can be uptaked by the host’s enterohepatic circulation (EHC), (iii) bile salt analogs can be modified by the gut microbiota, Bile salt side chain integrity and hydroxylation state influence anti-germination activity and/or CDI prophylaxis, and (v) NHBS analogs are stable towards the gut microbiome, have anti-germination activity against hypervirulent C. difficile spores, and can protect mice from CDI. Based on the sum of these discoveries, we hypothesize that the anti-germination and CDI prophylaxis activities of new NHBS analogs can be modulated by the combined metabolic action of the EHC and the gut microbiota. To achieve these goal, we will: (1) Synthesize libraries of NHBS analogs, (2) characterize the binding sites of anti-germinant binding proteins, (3) determine in vitro efficacy, permeability, stability, and toxicity of NHBS analogs, (4) assess pharmacokinetic parameters of selected NHBS analogs, and (5) determine the pharmacodynamics of CDI prophylactics on bile salt homeostasis At the start of this project, we will finish characterizing our lead NHBS. This data will provide benchmarks for new analogs. Our medicinal chemistry efforts will be initially guided by germination activity, but subsequent identification of NHBS binding sites could aid this effort. As in vitro and in vivo data is obtained, GO/NO GO criteria will eliminate sub-optimal analogs and inform the rational synthesis of more potent and stable anti-germinants. This iterative process will be continued until at least one optimized CDI prophylactic is obtained. As a secondary goal, we will develop CDI prophylactic dosages that can match the heterogenicity of human CDI risk and variable antibiotic regimes.

NIH Research Projects · FY 2024 · 2010-05

Project Summary Nucleoid structuring proteins (NSPs), like the histone-like nucleoid structuring protein H-NS, bind to DNA and transcriptionally silence genes in bacteria. DNA-binding proteins, known as anti-silencers, counter NSP- mediated silencing leading to gene expression. These opposing processes govern DNA management and control transcription in all bacterial cells, impacting many aspects of bacterial physiology, including virulence. In the bacterial pathogen Shigella flexneri, genes on the 230 kb virulence plasmid are silenced by H-NS and, at 37°C, are anti-silenced by VirB, a required regulator of Shigella virulence. The overarching goal of this project is to fully understand transcriptional silencing and anti-silencing mechanisms of virulence genes in the bacterial pathogen Shigella. Over the last project period, a three-step model of anti-silencing has been developed, in which VirB i/ binds to its site, ii/ spreads along DNA, and iii/ causes a localized change in DNA supercoiling that evicts or remodels proximal H-NS:DNA complexes, allowing transcription to proceed. Here, our model will be explored further, based on our new finding that VirB specifically binds an unusual ligand, the nucleoside triphosphate CTP, like distant relatives in the ParB superfamily. We hypothesize that “The CTP ligand of VirB is essential for its role as an anti-silencing protein that controls Shigella virulence.” This hypothesis will be tested using three independent aims. In Aim 1, the role of CTP in VirB:DNA interactions, that underpin VirB-dependent anti-silencing, will be characterized using biochemical and genetic approaches with innovative elements. Based on preliminary data, this work will likely identify which of the three mechanistic steps of anti-silencing requires the CTP ligand. In Aim 2, CTP hydrolysis by VirB will be measured and the effect this has on VirB:DNA interactions and anti-silencing will be characterized. While the ParB/Spo0J literature, suggests that hydrolysis of CTP by VirB may cause a conformational change that impacts VirB:DNA interactions, structural differences highlighted by a new VirB model (collaborator A. Iyer, NIH) make it uncertain if hydrolysis of CTP by VirB has been retained. Finally, in Aim 3, VirB mutants with intermediate CTP binding activity will be examined to determine the effects on Shigella virulence. Here, a novel genetic screen allowing the identification of VirB derivatives with intermediate CTP binding activity will be used so that these VirB derivatives can then be characterized in assays that measure Shigella virulence. This aim is likely to i/ strengthen the link between CTP binding by VirB and Shigella virulence and may ii/ provide the first evidence that CTP pools regulate virulence gene expression. In sum, the proposed work will bring us closer to achieving our stated long-term goal (above) by specifically examining the role of CTP in the anti-silencing of Shigella virulence genes by VirB. Furthermore, since the anti-silencer, VirB, is a fast-evolving member of the ParB superfamily that does not participate in DNA segregation, this work will broaden our understanding of this superfamily; an important group of proteins that play critical roles in many different bacteria, including those that cause human disease.