Pennsylvania State University, The

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Levels of adolescent anxiety, depression, and suicidality have been steadily rising over the last decade and have reached record levels in the wake of the COVID pandemic, prompting declarations of a national emergency in youth mental health. These alarming trends are especially dramatic for youth living in poverty, and low-income youth who are members of minoritized racial or ethnic groups and those living in isolated rural areas, who experienced some of the most severe impacts from the pandemic. The COVID pandemic and its mitigation efforts exacerbated these disparities by increasing potent stressors such as social isolation, loss, and family disruptions. Mental health risks evident for diverse low-income adolescents are further compounded by limited access to culturally affirming services made even scarcer in the pandemic. Waitlists at many youth- serving clinics approach 12 months, and access to affordable services is even more limited. Equally important is the dearth of interventions designed specifically to meet the needs of low-income adolescents that are trauma-informed, and based on inclusive empowerment principles, contextual strength-based frameworks, and firm empirical evidence. The Building a Strong Identity and Coping Skills (BaSICS) program is a trauma- informed coping and empowerment intervention for early adolescents exposed to chronic stress that (1) teaches individual and collaborative skills for coping with stress and trauma, (2) develops positive social identity, and (3) culminates in group-based community action. By building supportive relationships with peers, improving active engagement coping, fostering identity development, and empowering youth to action, BaSICS gives adolescents tools with which to address the myriad stressors to which they are exposed. The proposed work aims to replicate and extend the findings from a smaller-scale trial of BaSICS where, relative to control group, youth randomized to BaSICS acquired targeted coping and self-regulation skills and demonstrated improved cortisol reactivity and reduced internalizing problems. The proposed study will examine treatment effects on depression, anxiety and suicidality in clinically referred youth from four sites across central Pennsylvania. The proposed project will also extend prior findings by integrating data across multiple biological stress response systems to further evaluate the potential for BaSICS to re-calibrate dysregulated stress physiology. Enrolling low-income youth from various racial and ethnic groups and from urban and rural areas, the trial will enable examination of potential moderators of BaSICS that can inform future dissemination efforts. The proposed study promises to further NIMH’s Strategic Framework on Youth Mental Health Disparities by improving our understanding of interventions with potential to reduce mental health disparities. Adding to our mental health arsenal a biologically potent, targeted intervention that balances the need for fundamental self-regulation and coping skills with the need for a culturally affirmative strength and resource building approach, could help move the needle on socioeconomic health disparities.

NIH Research Projects · FY 2025 · 2024-08

Project Summary The objective of this proposal is to develop a soft and stretchable tissue-like bioadhesive electronic device for the treatment of resistant hypertension. Hypertension is a major burden on healthcare systems and an important contributor to global morbidity and mortality. Although a number of medicines have been used for the treatment of hypertension, a large portion of patients (more than 10 million) are resistant to medications. Electrical activation of the carotid sinus baroreflex (CSB) has been proven to a promising strategy to reduce blood pressure (BP) in drug-resistant hypertension patients. Nevertheless, existing commercial devices for CSB activation have significant limitations that precludes their practical applications. They are stiff and unable to stretch in response to the carotid wall's periodic expansion and contraction, which causes tissue damage and inflammation. Besides, they also require to be sutured to the carotid wall and introduce further damage. Overall, these limitations of existing devices cause significant patient discomfort, illness, and failure of devices over time, which precludes their wide application in hypertension therapy. The development of a minimally invasive device for long-term CSB activation that does not cause harm is an urgent unmet need. Our goal is to develop a next- generation device for drug-resistant hypertension therapy that can enable long-term efficient, safe, and minimally invasive non-pharmacological neuromodulation therapies for hypertension. We adopt soft, stretchable, yet resilient hydrogel-based materials for the fabrication of the devices to match the mechanical properties of tissues and significantly reduce tissue damage and inflammation. Owing to its intrinsic stretchability, the whole device can deform with the contraction and expansion of carotid walls and thus minimize constraint and damage to the carotid. We will also adopt a bioadhesive component in the proposed system to eliminate the need for suturing of electrical devices on carotid walls, thus significantly decreasing the invasiveness of implanted devices and increasing the stability of the device-tissue interface. We propose the following Specific Aims to ensure successful completion of the project. Aim 1) to develop stretchable and printable bioadhesive materials for suture-free in vivo incorporation and characterization. We will fabricate 3D-printable stretchable bioadhesive materials to enable stable long-term interfacing between medical devices and in vivo tissue. Aim 2) to optimize soft and stretchable tissue-like bioelectronic device designs for optimal long-term tissue-response on dynamic tissue. By optimizing device designs and materials, we will improve the long-term tissue response of tissue-like bioelectronic devices implanted on the carotid sinus. Aim 3) to optimize the acute and long-term effectiveness of tissue-like bioelectronic device for electrical stimulation of carotid sinus baroreflex (CSB). We have an interdisciplinary team with expertise in tissue-like bioelectronics, soft materials, bioadhesives, additive manufacturing, resistant-hypertension, and carotid sinus baroreflex stimulation therapy for treatment of hypertension to guarantee the success of this project. The success of this work will provide a novel device for minimally invasive and long-term activation of the carotid sinus baroreflex for the treatment of resistant hypertension. This device will have an important positive impact because it introduces reduced tissue inflammation/damage and significantly increased stability and safety, which benefits millions of hypertension patients. 1

NIH Research Projects · FY 2025 · 2024-08

Aging is ubiquitous across the tree of life, impacting biology at all levels. Among the hallmarks of aging, the accumulation of somatic mutations over time has been implicated in many leading causes of death including cancer10-12, heart disease4, and dementia5. However, most risk factors governing somatic mutation rates and patterns with age remain unknown. It has recently become possible to study the relationship between somatic mutation rates and longevity using comparative genomics. Cagan et al. (2022) demonstrated a negative correlation between somatic mutation rates and longevity, and identified conserved, longevity-associated mutational spectra across mammals. Yet, this study lacked the power to explore further due to both sparce taxonomic sampling and low sample sizes per species. Thus, there is an outstanding gap in our knowledge of how somatic mutational spectra relate to changes in longevity, and the genes involved in longevity- associated mutational spectra. To properly study the mechanisms governing mutation rates and patterns, one must sample many individuals from a group of closely-related species spanning a wide range of lifespans. My central hypothesis is that somatic mutation spectra unique to long-lived mammals are signatures of enhanced DNA damage repair responses that contribute to their extraordinary longevity. In order to identify the genetic mechanisms underlying longevity-associated somatic mutational spectra, I have generated matched skin tissue and cell lines from over 200 individuals across 10 species of a closely related (14 million years) clade of bats spanning a 3-fold range in lifespans, including the longest-lived bat species in North America. In Aim 1, to explore how somatic mutation rates co-evolve with longevity and identify longevity-associated mutational spectra in bats, I will use the highly sensitive NanoSeq to sequence 60 individuals across a trio of species in skin tissue samples. In Aim 2, using matched cell lines from the same individuals I will identify both cis and trans regulators of somatic mutation rates and spectra by using the massively parallel CRISPRi screen Repair-seq. As I transition towards an independent researcher position, in Aim 3 I will expand my functional work to other tissues and developmental contexts by developing induced pluripotent stem cells (iPSCs) from my collection of bat cell lines, and combine the cell type diversity of embryoid bodies with the power of Repair-seq to assess DNA damage repair mechanisms across all cell types simultaneously. This project is the first to explore how somatic mutation rates and spectra co-evolve with longevity both mechanistically and at high resolution. The foundations of this project will be the cornerstone of my research program exploring the evolution of longevity-associated traits in extraordinarily long-lived species using functional genomics. Using iPSCs from non-lethal skin biopsies will enable us to study aging processes in internal tissues as a part of longitudinal studies, enabling new avenues of research in the comparative biology of aging.

NIH Research Projects · FY 2025 · 2024-08

The long-term goal of the application is to understand how insertion sequences (IS) in bacterial genomes create heterogeneous subpopulations by amplifying chromosomal segments. IS are short, mobile DNA elements integrated into bacterial chromosomes and plasmids that encode a transpose flanked by inverted terminal repeats (ITR). IS activity plays a major role in shaping prokaryotic genomes, where they can destroy gene function through intragenic transposition, induce expression by juxtaposition of outward facing promoter elements, remove/rearrange large segments of genomes by recombination events, and tandem amplify DNA segments intervening between two IS elements. This proposal focuses on the latter process, as it is the least well understood despite arguably being the most common and effective mechanism for generating heterogeneous populations. Chromosomal tandem amplification catalyzed by IS elements generally occurs at much higher frequencies in comparison to point mutations, amplifies intervening segments of DNA that can be hundreds of kilobases long, and results in head-to-tail tandem copies of DNA segments separated by a third, hybrid IS element. In genomes with high IS content, amplification thus generates tremendous heterogeneity and transient single cell individuality that is revertible through subsequent recombination between the amplified segments. Heterogeneity in bacterial populations helps ensure survival in the event of environmental stress (including antibiotic treatment) by sampling a larger pool of cells with distinct phenotypes. The connection between IS element activity, genome amplification, and heterogeneity will be explored in this proposal using a model system with the non-pathogenic laboratory Escherichia coli B strain that harbors multiple, endogenous IS1 elements. In the first aim, how genomic IS1 element distribution impacts frequency of amplification and the requirements for amplification will explored. In the second aim, genetic and environmental factors will be identified by developing a Tn-seq assay to define IS1-flanked chromosomal amplification events. In the third aim, the contribution of IS1 to creating distinct lipopolysaccharide compositions and gene expression profiles at the single cell level will be explored using a paired IS1-less strain. All safety measures, procedures, and policies outlined for recombinant DNA and bacterial research will be adhered to according to the Office for Research Protections at Pennsylvania State University. By understanding IS1-induced heterogeneity in a model bacterial strain, the project will help formulate rationale strategies to mitigate the impact of heterogeneity on antimicrobial bacterial resistance.

NIH Research Projects · FY 2025 · 2024-07

Project Summary Data is the primary currency for all domains of today's biomedical research. However, data does not have some of the properties of a good currency: durability, portability, uniformity, convertibility, and acceptability. It is vast, heterogeneous, geographically distributed, and often protected by access control mechanisms. It requires hardware and software complex machinery to process. Skills needed for data interpretation are sparse across the entire biomedical domain. How does one make such a currency universally beneficial to all infectious disease researchers who study different organisms with disparate goals, motivations, and expertise? This brings us directly to the main point of this proposal: to implement a common data analysis medium—BRC.analytics—that would connect infectious disease researchers to data, tools, and workflows. The transformative tenets of the proposed system are: (1) giving access to an ensemble of data resources via a single workspace where data can be stored, combined, and analyzed; (2) enabling access to the majority of high quality open source tools and allow creation of complex workflows in the workspace; (3) ensuring that workspace in powered by powerful hardware capable of sustaining thousands of users analyzing large datasets; (4) providing several modes of access including a graphical user interface (GUI) as well as an Application Programming Interface (API). BRC.analytics is a unique knowledgebase that provides data, tools, and infrastructure as well as the know-how” on how to apply this power effectively.

NIH Research Projects · FY 2026 · 2024-07

PROJECT SUMMARY/ABSTRACT Three-dimensional (3D) bioprinting has been making a revolutionary impact on building living tissues and organs. Despite several attempts, vascularization is still an unmet problem for 3D bioprinting of scalable tissues and organs. In spite of significant efforts reported to generate vascular networks in 3D printed tissues, the gold standard is still the use of sacrificial inks, which has several shortcomings such as the need for extensive post- processing efforts to remove sacrificial inks, inability to remove these inks from low aspect-ratio features (i.e., highly thin, long vascular networks) and the residuals remaining from inks that usually interfere with biological function of cells inhibiting their adhesion and spread. In this project, we propose a highly novel technology through harnessing the power of compressibility of air in yield-stress gels and unveil 3D printing of air (3DAirP), which is an intangible ink. The process will induce open-channel network generation in yield-stress gels in a single step, which will overcome the outstanding limitations with the use of sacrificial inks. Moreover, the proposed 3DAirP technology will facilitate the generation of vascular channels (up to the minimum diameter of ~125 µm) at an unprecedented printing speed (i.e., >10-folds faster than 3D printing of sacrificial inks). In Specific Aim 1, we propose to develop 3DAirP technology, which has the capability of rapidly generating open stable channels in yield-stress gels. We will investigate the interplay among the viscoelastic properties of yield-stress gels and governing physical forces during 3DAirP, and how such interplay will enable us to dissect the knowledge for directly laying down the air channels to produce stable vascular networks in engineered tissues. To exemplify the technology, we will demonstrate two unique applications including (i) a scalable vascularized bone tissue and (ii) an atherosclerosis model on a chip, both in vitro. In Specific Aim 2, we will reconfigure the technology for 3DAirP intraoperatively that will facilitate air channel generation under surgical settings. To exemplify its utility, we will demonstrate two unique applications including (i) intraoperative 3DAirP within bioprinted bone constructs in critical-sized rat calvarial defects and (ii) coupling intraoperative 3DAirP with a new microsurgery technique to rapidly induce angiogenesis and orient vascular ingrowth in rat hindlimbs. In this regard, we have formed a complementary collaboration that merges essential domain knowledge in bioprinting, 3D printing process and instrument development, biomaterials, vascularization, microsurgery, craniofacial surgery, biomechanics and simulation, and bone and vascular tissue engineering with the depth necessary to propel the proposed work towards meaningful advances that would otherwise not be possible. Successful completion of the proposed work is anticipated to give rise to an advanced 3D printing technology for rapid generation of vascular networks towards fabrication of scalable tissues and organs.

NIH Research Projects · FY 2025 · 2024-07

Abstract. Obesity is a predictor of multiple negative health outcomes, including type 2 diabetes, coronary heart disease, hypertension, various cancers, and premature death. Today, nearly two-thirds of US adults are overweight or obese, and one out of three is obese or morbidly obese. Obesity disproportionally affects African Americans, who have the highest age-adjusted prevalence of obesity (49.9%). Obesity disparities by race and geolocation result from complicated interactions between individual behaviors (e.g., physical activities, healthy food choices) and socioeconomic and environmental context (income, public infrastructure, neighborhood green lands). Individuals’ obesity-related behaviors are embedded in their communities and shaped by structural factors (e.g., racial segregation) and built environments (infrastructure and resources). The obesogenic environment produces conditions that encourage the overconsumption of calories and sedentary behaviors. For instance, distribution of different food resources (e.g., healthy food grocery stores, fast-food restaurants) within a residence area may influence people’s food choice and consumption. Likewise, neighborhoods with few walking or bike trails, poor street lighting, limited public transportation, and a lack of recreational spaces such as parks hinder physical activity and thus increase obesity risk. Traditional obesogenic environment indices are limited by a lack of timely monitoring the dynamic utilization of the infrastructures, challenges in integrating with behavioral data, and the potential bias due to self-report survey. To address these limitations and better assess and explore racial disparities of obesity, we propose to develop and test a novel measurement tool to assess obesity-related behaviors at multiple geographic levels (i.e., census blockgroup, tract, and county) in the US. First, a novel visitation-based obesogenic environment measurement (VOEM) will be developed using cellphone-based place visitation data to measure three types of obesity-related behaviors: physical activity (visitation to the exercise facilities such as parks and gyms), healthy food choices (visitation to healthy food outlets such as supermarkets and organic groceries), and less healthy food choices (visitation to fast-food restaurants and convenience stores). Second, the validity and performance of the VOEM will be assessed in terms of predicting adult obesity rates and explaining associated racial disparities at multiple geographic levels in the US by controlling for population-level social determinants of health and other sociodemographic factors based on public available datasets. This comprehensive, valid, and near real-time measurement instrument can be used as a surveillance tool to monitor population-level patterns and changes of proxy obesity-related behaviors over space and time (e.g., seasonal trends), map obesogenic environments at various geographic levels, and thus inform tailored and evidence-based policy decision making and public health strategies for reducing racial disparities of obesity in terms of resource allocation, development of prevention efforts, and efficacy evaluation of relevant health behavior interventions.

NIH Research Projects · FY 2025 · 2024-07

PROJECT ABSTRACT/SUMMARY Reading is a developmental process and a core component of education that depends on the acquisition, integrity, and processing efficiency of fundamental text-based, linguistic, and neurocognitive processes refined over time. The recent declines in reading proficiency among fourth and eighth grade students nationwide underscore the pressing concern related to the developmental challenges posed by adverse childhood experiences (ACEs) as ACEs are well-recognized ecological determinants of many negative educational and health outcomes. ACEs are prevalent in over 50% of the United States population and are known to disrupt crucial neurocognitive processes essential for reading development; however, whether the effect of ACE- related changes to neurocognitive processes can impact reading outcomes has not been formally studied. Complicating our collective understanding of these connections is evidence of outcome variability observed across different reading domains depending on how researchers choose to model ACEs. To bridge these gaps, data from the Environmental influences on Child Health Outcomes (ECHO) dataset will be used to address three research aims: 1) examine the path relationships between four neurocognitive processes (working memory, inhibition, cognitive flexibility, metacognition) and three benchmarks of reading proficiency (receptive vocabulary, word identification, and standardized reading assessments) as they pertain to high- and low-cumulative risk groups, 2) examine variability among pathway relationships between adversity and reading through neurocognitive processes using different modeling approaches of adversity (i.e., cumulative risk, threat/deprivation dimensions, latent classes), and 3) develop an integrated reading framework that considers the developmental sequelae of adversity for future research. Longitudinal, multi-group structural equation modeling will be used to examine the group-specific relationships between neurocognitive processes, including a latent factor of metacognition, in middle childhood and reading outcomes measured during early adolescence. Variability among pathway relationships between groups for each ACE modeling approach, in addition to comparisons across each approach using global fit indices, will be evaluated to assess how operationalization of ACEs can differentially influence longitudinal models of reading. This study’s impact lies in its comprehensive examination of ACEs effects on neurocognitive processes and its subsequent impact on reading outcomes to develop a conceptual reading framework to inform future work and translational practices.

NIH Research Projects · FY 2025 · 2024-07

More than 71% of individuals with developmental disorders are being cared for by familial caregivers, and this caregiving often extends beyond childhood. It is estimated that 5.5 million people aged 18 and older in the United States are diagnosed with autism, a number that is expected to increase with rising prevalence rates. Individuals with autism and very substantial support needs (level 3), also known as profound autism, often have co-occurring severe cognitive impairment , little to no functional communication, and require 24 hour-a-day care. It is estimated that those with high support needs encompass up to 48% of the spectrum. Many caregivers are family members, often an aging parent. Parents face many challenges in raising children with autism, such as lack of resources, lack of support, and financial strain. It is not well known how these challenges continue or change as the child becomes an adult, and the caregiving needs continue and often increase. With an economic value estimated at 600 billion dollars, informal familial caregiving is a crucial component to the healthcare system in the United States. The purpose of this mixed methods study is to better understand how predictors of health, caregiving factors, and care-recipient factors impact parental caregiver quality of life and explore the context and relationship of these factors in-depth to create a better understanding of the caregivers’ experiences. The proposed research seeks to utilize an explanatory sequential mixed methods design to better understand the caregiver’s experience. Previous research highlights the need for increased and improved research into the quality of life of parental caregivers as improved caregiver quality of life can lead to improved outcomes for the adult-child with profound autism. To successfully accomplish this research and my future career goals, a training plan with three key areas has been developed: 1) expand my knowledge of mixed methods study design, data collection, and analysis, 2) deepen my understanding of caregiving science and how it can be used to understand the needs of those caring for adults living with autism, 3) strengthen my scientific writing and presenting skills. An interdisciplinary mentorship team and the strong research infrastructure at Penn State will support the project and my career development.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY The primary goal of this training program entitled “Research Training in Physiological Adaptations to Stress” (PAS) is to provide a new generation of future scientists with authentic interdisciplinary training and educational experiences that emphasize a translational approach to understanding the physiological mechanisms which mediate organismal stress adaptation. Key aspects of the new PAS program include using the One Health interdisciplinary public health framework as a lens for solving human health and disease problems, better integration of entrepreneurial principles to develop a discovery mindset, and applying with fidelity principles of rigor and reproducibility. Familiarity with opportunities and challenges posed by generative artificial intelligence is another key innovation, which we view as a training imperative to prepare our trainees for the 21st century workforce. Value added training in entrepreneurship using a boot camp approach, and team process through the Penn State MBA program will facilitate discovery. Graduate students presently encounter little formal training in regulatory science, and the inter-disciplinary curriculum we propose will better prepare our students for emerging academic and nonacademic biomedical careers. An understanding of the business, legal and regulatory issues which shape key milestones in the biomedical science pathway, and the ability to work in diverse teams will allow our trainees to be leaders of innovation. Here, rigorous research design and core competencies necessary for effective communication are also emphasized. The training program takes advantage of existing faculty biomedical expertise in four academic colleges who have amassed an impressive training record while maintaining research excellence, with an overall time to the PhD of 5 years with little attrition. We propose selection of 5 students per year for a period of two years (total of 24 trainees). Additional institutional matching funds will allow for the training of 7.5 additional trainees. The institutional commitment to our training program is outstanding. A foundational course entitled “Physiological Adaptations to Stress” has been designed specifically for the training program, and will serve as a capstone experience to emphasize program goals using multiple levels of scientific inquiry (cells to human). Defining a new conceptual framework for hypothesis-driven research to inform mechanisms of stress adaptation within a rich academic environment with dedicated mentoring, strong research support and institutional commitment is proposed. We envision trainees will continue to participate in program activities at the conclusion of their tenure as a T32 Fellow.

NIH Research Projects · FY 2025 · 2024-07

ABSTRACT College drinking continues to be a major public health concern in the United States and a priority area within NIAAA. About 1 in 3 students report heavy episodic drinking (HED; 4+/5+ females/males) and 1 in 10 engage in high-intensity drinking (HID; 8+/10+ females/males). Students who engage in risky drinking behaviors (HED or HID) are at risk for experiencing alcohol-induced blackouts (AIBs; i.e., absence of memory for all or part of a drinking episode). AIBs are critical to reducing harm because they are associated with experiencing higher numbers of consequences and more severe consequences, even after controlling for drinking. A secondary data analysis of ~800 student drinkers over 18 weekends showed that on nights when AIBs occurred, students experienced ~3.5 more consequences than on non-AIB nights. At least one of these additional consequences were considered to be severe. AIBs also occur at a high frequency to warrant their examination. Our pilot data showed risky drinking students experienced AIBs on 1 out of every 3 drinking days. Although AIBs are associated with risky drinking, there are many unanswered questions about why and when AIBs occur (which events result in an AIB). The overall goal of the proposed research is to extend the field by using objective transdermal alcohol concentration (TAC) sensors to increase our understanding of why and when AIBs occur. The proposed study will utilize a comprehensive theoretical model which includes psychosocial variables (e.g., willingness to drink and experience AIBs, drinking/AIB attitudes/subjective evaluations, expectancies, and norms), behavioral constructs (e.g., self-report drink counts, protective behaviors), and a novel biometric assessment (i.e., TAC sensors) to examine the associations between risky drinking and AIBs. TAC sensors assess alcohol use in near real time measuring features of intoxication repeatedly to provide a curve of biological alcohol intoxication for every drinking day. Prior research suggests that the manner individuals consume drinks (via TAC sensors) may differ when reporting the same number of drinks (e.g., speed of drinking, time spent drinking). I served as a Co-I on a small pilot study (n=33) using similar methods to support the proposed research. Students wore TAC sensors and completed 12 event-level drinking surveys over 4 weekends (Thurs, Fri, Sat). The preliminary findings included: 1) high compliance to study protocols (91% retention/TAC use/event survey completion); and 2) 70% reported at least 1 AIB during the 12-weekend day period, and 55% reported multiple AIBs at a rate of 1 out of every 3 drinking days. These findings are encouraging and demonstrate my ability to carry out the proposed study. The aims are as follows: Aim 1 utilizes a comprehensive theoretical model to examine why and when AIBs occur (which events result in an AIB); and Aim 2 examines trait constructs (self-regulation and sensation-seeking) and sex as moderators for the associations between psychosocial constructs, TAC drink features, and AIBs.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY Gene regulation is the foundation of nearly all aspects of biology and human disease. The Eukaryotic Gene Regulation (EGR) Predoctoral Training Program will train a future generation of scientists in experimental, molecular and computational sciences to understanding the mechanisms of eukaryotic gene regulation. EGR connects and further develops trainees and faculty from five established graduate programs: Biochemistry, Microbiology and Molecular Biology (BMMB), Chemistry (CHEM), Biology (BIOL), Molecular Cellular and Integrative Biosciences (MCIBS), and Bioinformatics and Genomics (BGEN). The EGR training program builds upon a successful 5-year period of prior support and is led by a close-knit group of 22 highly productive faculty. We seek funding for 4 new trainees/yr, supported for two years each in the 2nd and 3rd years. A generous institutional match will fund 1-2 additional trainees/yr, strengthening recruitment efforts to diversify the trainee pool and allow for a strong cohort of 8-10 predoctoral students/yr. Students will be prepared for laboratory training in gene regulation through a carefully crafted curriculum, including foundational courses in molecular sciences and specialty courses in gene regulation, computation, statistics, and ethical and rigorous research methods. Students will be trained by faculty and interact with peers using structural biology, computation and genomics, molecular and cellular biology and biophysical techniques in their research, preparing them to perform outstanding cross-disciplinary research. Activities include weekly meetings to build presentation and data analysis skills, monthly trainee-run meetings, a yearly retreat, and cohort-strengthening activities. Comprehensive and continuous RCR and rigor and reproducibility instruction are provided by the faculty and are incorporated into activities throughout the training program. Exemplary institutional match supports enhancements and innovations to the current EGR, including internship opportunities through an industry-academic partnership and a new Alumni Mentor Program for career development. Trainee leadership skills will be built through student-organized monthly meetings, and a new peer mentoring program, which we predict will contribute to increased retention through improved trainee satisfaction and feeling of belonging. An evidence-based assessment plan has been developed to track program effectiveness and guide future improvements. Mentor training and close attention to student progress and tracking will improve the overall experience for students and help recruit future cohorts. Trainees will obtain a thorough understanding of the scientific process, learn to conduct research responsibly and rigorously, gain fluency in innovative research methodologies, learn to utilize bioinformatics and statistical tools in advancing genome-wide experimental approaches. The impact of EGR will extend well beyond those supported by this grant by allowing unfunded students to participate in the training activities and by modeling best practices in training, RCR and rigor and reproducibility instruction and preparing a diverse cohort for careers in the biomedical sciences.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY By 2050, roughly 83.7 million individuals in the U.S. alone will be over the age of 65. Within this population, memory declines are at the forefront of age-related cognitive complaints. Associative memory, or the ability to link together multiple pieces of information, is especially vulnerable to aging. Associative memory is central to everyday memory function, supporting everything from our ability to remember face-name associations to links between medicines and their daily dosages. As such, there is an urgent need to identify methods that can improve associative memory in older adults. Our long-term goal is to identify effective, theory-driven, evidence- based approaches for enhancing associative memory in older adults. The objective of this application is to elucidate the mechanism underlying the cognitive and neural benefits of environmental support, in the form of schematic and perceptual grouping. Such support promotes unitization of information without requiring older adults to self-initiate cognitively demanding encoding strategies. This project integrates theories of perceptual and semantic processing with theories of unitization to advance our understanding of associative memory. Specifically, we will examine how schematic and perceptual processing induces unitization and how unitization can be strengthened with exposure-based repetition. Our overarching hypothesis is that grouping principles enhance associative memory by creating representations of item pairs that parallel how single items are processed in memory. This will be tested using high-resolution neuroimaging alongside univariate, multivariate and network connectivity analyses characterizing unitized, non-unitized, and item memory at encoding and retrieval in long-term memory. The approach is innovative because it directly applies well-established theories of information processing and perception to ameliorate the burden of binding in associative memory processing, with the goal of enhancing associative memory in aging. It is also amongst the first set of studies to apply high resolution fMRI and cutting-edge multivariate and network connectivity analyses to test the neurocognitive mechanism underlying memory processing in aging. The proposed research is significant because it tests multiple methods for enhancing associative memory in aging that can be employed across a range of applications absent of subject-generated strategy deployment. In doing so, the work is a critical step in elucidating the flexibility of neural processing across the lifespan to the betterment of memory function. By identifying ways to improve memory function in young and older adults, this work has the potential to 1) enhance other cognitive processes, 2) improve the quality of life in aging, and 3) help dissociate normal aging from early signs of dementia.

NIH Research Projects · FY 2024 · 2024-06

PROJECT SUMMARY/ABSTRACT Obesity is a key risk factor for several types of cancer. Development of healthy weight and eating behaviors during childhood has the potential to reduce cancer risk in adulthood. Preadolescence is a key risk period, as children become more independent in their food choices and eating behaviors. Non-homeostatic eating, i.e., eating that occurs in response to external cues rather than physiological need, increases in preadolescence and is a risk factor for obesity. Individual differences in interoception, the process by which internal bodily states, like hunger and fullness, are sensed, integrated, interpreted, and regulated, may contribute to propensity for non-homeostatic eating. A number of studies have found that children with obesity have poorer interoceptive awareness than children without obesity, but studies examining the relationship between interoception and eating behavior are lacking. Furthermore, it is unknown if obesity-related impairments in interoception are due to inadequate physiological signaling of internal states (‘bottom up’ processes) and/or impaired cognitive interpretation of these signals (‘top down’ regulation). Levels of ghrelin, a hunger hormone produced by the stomach, typically peak just before a meal and decline following food intake; however, this response to food intake is blunted in individuals with obesity. Altered ghrelin secretion in response to a meal may result in incorrect interoceptive signaling to the brain. The primary goals of this R21 are to better understand how individual differences in multiple features of interoception contribute to objectively-measured non-homeostatic eating in children. To do this, children age 7-10 years with or without obesity (n=60) will complete a series of questionnaire and laboratory-based behavioral measures of interoception. On a separate occasion, children will consume an ad libitum meal followed by a non-homeostatic eating task (Eating in the Absence of Hunger [EAH]), providing saliva samples for measurement of ghrelin and leptin before, during, and after these tasks. For Aim 1, we will determine if interoception is associated with kcal intake in the EAH task; we hypothesize interoception will be inversely associated with intake. For Aim 2, we will examine salivary ghrelin and leptin as interoceptive signals of hunger/satiety; we hypothesize that children with greater postprandial ghrelin suppression will have better interoceptive awareness and will eat less in the EAH task, and that elevated leptin will attenuate the relationship between ghrelin suppression and interoception. For Aim 3 (Exploratory) we will use cluster analysis identify profiles of interoception based on global and system- specific (e.g., cardiac, gastric) interoception, and then examine differences in eating behavior, executive function, and weight between clusters. This project will extend our understanding of the drivers of non- homeostatic eating and reveal how interoceptive awareness impacts food intake, setting the foundation for intervention strategies tailored for children based on individual differences in interoceptive function.

NIH Research Projects · FY 2025 · 2024-05

Project Summary Malaria parasites quickly amplify their numbers in both the human host and mosquito vector, with a single parasite capable of creating dozens, hundreds, or thousands of daughter parasites. The formation of merozoites (asexual blood stage, liver stage) or sporozoites (mosquito stage) involves the segmentation of these daughter parasites within the bounds of the initial parasite. This segmentation process has best been defined during schizogony in the asexual blood stage, during which the basal complex is assembled to direct the appropriate partitioning of subcellular contents to each daughter cell. Several stable, core members of the basal complex have been defined in both asexual and sexual stage development through complementary experiments, but nothing is known about the composition or functions of the basal complex during the even more complicated segmentation process involved in sporozoite budding. Therefore, in this proposed work, we will investigate the process of sporozoite segmentation that occurs within the Plasmodium yoelii oocyst using ultrastructural expansion microscopy, focused ion beam-scanning electron microscopy (FIB-SEM), and proximity proteomics. This will enable three-dimensional microscopy-based assessments across the process of sporogony that will focus on the involvement of the basal complex. Proximity proteomics approaches will allow a cross-stage and cross-species comparison of the composition of the basal complex, and provide a first view of how it changes over the lengthy process of sporozoite segmentation, which takes up to 10 days in Anopheles mosquitoes. In accomplishing this proposed work, we will advance our understanding of the cell biological processes that underlie sporozoite budding with these complementary microscopy and proteomic approaches. Our focus on the essential basal complex will provide the molecular landscape that is used for effective sporozoite segmentation required to promote parasite transmission.

NIH Research Projects · FY 2026 · 2024-05

Project Summary Sensitive and accurate measurement of change in cognitive performance is necessary for the detection of subtle cognitive decline in the preclinical phase of Alzheimer’s disease and related dementias (ADRD). It is also required to evaluate outcomes of early interventions aimed at mitigating advanced cognitive decline. However, this is a difficult task as these changes are subtle; not only in terms of magnitude, but also in terms of the latent processes through which they manifest. Although researchers and clinicians are often interested in detecting long-timescale patterns of change (i.e., normative aging vs. disease progression), learning processes on short and long-timescales confound such effects. To address these challenges, we will develop a modern statistical toolset designed for use with data from high- frequency repeated assessments. For this, we will combine longitudinal measurement “burst” designs with a novel Bayesian computational toolkit to simultaneously capture multi-timescale learning processes together with cognitive change and decline. These tools will provide interpretable features (e.g., change in peak performance, probability of decline, caution in decision making, etc.) that can then be deployed as digital markers of subtle cognitive decline. The Bayesian approach will also provide for a principled framework to communicate individual-specific dementia risks towards clinicians. Our specific aims are to: 1. Separate multi-timescale learning processes from cognitive changes related to aging and neurodegeneration and extract key digital cognitive markers to identify digital computational phenotypes of ADRD risk. 2. Disentangle cognitive processes in task performance by developing novel statistical tools that quantify latent processes to enrich our set of novel digital cognitive markers. 3. Identify which combination of digital cognitive markers and test interval between measurement bursts carries the most power for predicting ADRD risk. For Aim 1 we will analyze two measurement burst design data sets. To further refine the framework in Aims 2 and 3, we develop novel statistical tools and collect data with fine-tuned, novel feature binding tasks known to be sensitive for preclinical AD. We will evaluate the predictive power of the identified novel digital cognitive markers by linking them to AD biomarkers levels and ADRD risk scores.

NIH Research Projects · FY 2026 · 2024-05

Project Summary Local delivery of growth factors has been applied to treat various human diseases. However, many growth factor delivery systems cannot stably sequester bioactive growth factors for sustained delivery, primarily due to a lack of high-affinity and high-specificity molecular recognition. This deficiency leads to the rapid release of growth factors, thereby requiring supraphysiological levels of drug loading and delivery to achieve therapeutic efficacy. Unfortunately, such a delivery approach has been found to cause high toxicity and even cancer in patients. Therefore, the objective of this project is to study a novel transformative drug delivery platform based on non- covalent functionalization with bispecific aptamers. Different from traditional methods requiring co-valent functionalization, this innovative method does not require alterations to the manufacturing procedures or properties of existing biomaterials. Furthermore, growth factors can be loaded into off-the-shelf biomaterials when needed. To achieve the goal, we will: 1) design and evaluate bispecific aptamers; 2) evaluate growth factor loading and release; and 3) evaluate in vivo growth factor delivery. It is anticipated that bispecific aptamers can stably attach to delivery systems and sequester growth factors due to high binding affinities and specifities, allowing for local, sustained growth factor delivery. The success of this project will not only lead to the development of a technological platform for growth factor delivery, but also transform the way of functionalizing various materials at different scales in applications such as bioimaging, biosensing, cell engineering, etc.

NIH Research Projects · FY 2026 · 2024-05

Project Summary: Wolbachia are a genus of endosymbiotic bacteria that comprise a promising, cost-effective tool to curb arboviral transmission based on two key facets. First, Wolbachia block pathogenic RNA viruses by inhibiting their replication in arthropods. Second, Wolbachia selfishly alter sperm and egg via a process termed cytoplasmic incompatibility (CI) that can drive the bacteria into host populations. CI is expressed as embryonic lethality in crosses between infected males and uninfected females, but this lethality is rescued in crosses between infected males and infected females, which are the transmitting sex of Wolbachia. Consequently, CI is deployed in field trials to either suppress mosquito population sizes or replace uninfected populations with infected individuals resistant to arboviral infection. We recently discovered pre-fertilization impairments to sperm genome integrity that underpin the CI drive. The CI-causing Cif proteins CifA and CifB from a prophage region in wMel interact with developing spermatid nuclei to alter the epigenetically-controlled, histone-to-protamine transition, namely by increasing histone retention in developing spermatids and decreasing protamine levels in the mature sperm. The Cif proteins do not paternally transfer to the fertilized embryos, instead the modified sperm in testes with impaired chromatin integrity transfers to bestow CI. Despite decades of intense research and current applications to vector control, the mechanistic details of these pre-fertilization impairments remain a central enigma and are only now subject to investigation. Here, we propose the first, in-depth examination of CI-defining histone marks and protamine types to test the central hypothesis that the Cif proteins alter epigenetic events during gametogenesis to cause CI and rescue. In Aim 1, we will use CUT&Tag chromatin profiling to determine CI- defining, pre-fertilization changes in sperm histone modifications causing histone retention in wMel-infected Drosophila melanogaster and Aedes aegypti. We will also test the essentiality of these epigenetic changes to CI by chemically inhibiting histone modifier enzymes. In Aim 2, we will investigate the type and abundance of CI- defining protamines that are depleted in mature sperm. Knockout and knockdown transgenic experiments will link CI-defining embryonic death with the necessity of specific sperm protamine genes. Finally in Aim 3, we will evaluate rescue-defining changes in the gametic chromatin by first characterizing maternal changes in histone transcripts and protein abundance during oogenesis. We will then determine post-fertilization epigenetic changes in sperm DNA that orchestrate paternal chromatin decondensation for embryonic viability. We will also validate the essentiality of epigenetic modifiers to rescue by inhibiting their enzymatic activity. Despite the rising interest in deploying Wolbachia to curb arbovirus transmission, studies have not yet yielded a refined, molecular breakthrough uncovering the host epigenetics driving Wolbachia. If successful, the proposed research will (i) reveal the incipient, host epigenetic events underlying the CI drive system at the heart of vector control strategies and (ii) provide a significant gateway to eventually engineer CI and rescue via the host arthropod itself.

NIH Research Projects · FY 2026 · 2024-05

Project Summary/Abstract Numerous cellular signaling pathways of critical importance to organism health rely on heterotrimeric G protein signaling. Heterotrimeric G proteins are composed of Gα, Gβ, and Gγ subunits. Classically, ligand binding to transmembrane G-protein-coupled-receptors (GPCRs) elicits conformational changes that lead to exchange of GDP for GTP on the Gα subunit, and resultant separation of Gα from the Gβγ dimer, either or both of which then signal to downstream effector proteins until intrinsic GTPase activity of Gα restores the heterotrimeric state. G proteins participate in numerous signaling cascades in both metazoan and plant systems and many aspects of G protein signaling are remarkably conserved across this evolutionary divide. The overarching goal of my research is to harness the simpler G protein complement of the model plant, Arabidopsis thaliana, to reveal how heterotrimeric G protein genotypes and molecular phenotypes control cellular signaling cascades, and thus whole organism consequences. Our laboratory has been a leader in plant heterotrimeric G protein signaling for >25 years; we have elucidated G protein signaling via methods ranging from single cell electrophysiology to imaging to -omics approaches, to sophisticated whole organism phenotyping and genome-phenome analyses. This proposal focuses on two types of molecular phenotypes – phosphorylation and natural variation -- and their attendant consequences on G protein biochemistry, cellular signaling, and whole organism vitality. We have ascertained that Gα phosphorylation at sites conserved across mammalian and plant Gαs can dramatically impact the G protein cycle. In Theme 1, we plan to utilize >60 Gα phosphomimic and phosphonull lines we have created to determine the phenotypic consequences of Gα phosphostatus. We will assess how phosphorylation changes Gα molecular partners (i.e. how phosphorylation biases signaling), and phenotypic consequences. We propose that phosphorylation “diversifies” the number of functionally distinct Gα proteins, resolving an apparent mismatch between the number of G protein subunits vs. the much greater numbers of GPCRs and phenotypes. Some G protein mutations are known to cause disease. Many more are statistically “associated’ with disease outcomes, but whether they actually cause disease is difficult to ascertain due to the high heterozygosity of humans, low phenotypic penetrance, and inaccessibility of humans to experimentation. Arabidopsis is naturally inbred and can be genetically manipulated with ease. In Theme 2 research, we plan to determine the impact of natural missense single nucleotide variants (SNVs) on Gα biochemistry. We will next experimentally reveal in Arabidopsis the phenotypic consequences of these mutations. Then we will ask whether, in nature, deleterious SNVs are accompanied by other SNVs in Gα that forestall the negative consequences of the missense mutations, in positive “intrageneic epistasis”. Next, we will assess intergenic epistasis between Gα variants and regulatory proteins. Demonstration of such phenomena is both mechanistically revealing and will allow medical science to better ascertain whether or not an individual with a given Gα SNV is actually predisposed to disease.

NIH Research Projects · FY 2025 · 2024-05

Appalachian women are at high risk for lung cancer, which is the leading cause of cancer-related death for women in the region. Although lung cancer rates have declined steadily among men, such decreases have not been seen among women, including alarming mortality rates in Appalachia. Interventions to reduce lung cancer risk among Appalachian women need to consider social and environmental contexts. The K99 phase research has identified few existing interventions to reduce lung cancer risk in this population. The majority of existing studies focus on individual behavior change (e.g., tobacco cessation) during pregnancy with few studies on multi-level factors, those for non-smokers, or those during other phases of the life course. This project, titled Reducing Lung Cancer Risk among Appalachian Women Using Community-Engaged Intervention Research, relies on community perspectives to guide the adaptation and pilot testing of an intervention to reduce lung cancer risk among Appalachian women. We will continue community-engaged research from the K99 phase using the NIH model for creating behavioral intervention trials, including refining an intervention through direct community input (Phase 1a; Aim 1) and pilot testing the adapted intervention protocol using a 2-armed randomized controlled trial (Phase 1b; Aim 2). In the pilot, we will demonstrate the feasibility of the adapted intervention protocol, including demand, acceptability, and implementation. The adapted intervention will seek to increase knowledge, self-efficacy, and targeted behaviors among Appalachian women thereby reducing their future lung cancer risk. This R00 proposal will provide evidence for a future R01 to test the efficacy of the community-informed lung cancer risk reduction intervention among Appalachian women.

NIH Research Projects · FY 2026 · 2024-05

Project Abstract/Summary Outmigration profoundly impacts the health and well-being of older adults who remain in communities of origin – the so- called “left behind”. Evidence suggests that left-behind older adults are predisposed to increased levels of depression4, cardiovascular disease, diabetes, and poor physical health due to familial separation, changes in social network structures, increased social isolation, and absence of instrumental support. As in many migrant-sending societies, Puerto Rico faces substantial challenges owing to rapid population aging and pressures on its family networks because of outmigration. Most outmigrants from Puerto Rico are young adults, which means that ever-larger cohorts of people will enter older adulthood without the dense family networks that have traditionally been a mainstay of social support in this and many other contexts. At the onset of the current migration wave, approximately 33% of Puerto Rican older adults report living alone, and 48% of older adults have at least one adult-child residing in another country. Likewise, even as other Caribbean and Central American societies face similar issues stemming from high rates of out-migration, Puerto Rico presents a particular case, given its relationship with the United States and the possibility that its migrants can more easily return for short visits, resettle, or engage in circular migration patterns. Though an increasing number of studies have demonstrated important links between smaller local social networks and well-being in various global contexts, no prior study has assessed the prevalence, predictors, or consequences of this phenomenon in Puerto Rico, nor how it compares against other contexts. This research project will examine social network typologies, their association with health, and how Puerto Rico compares to other relevant contexts. We will use data from a NIA-funded studies in Puerto Rico, Mexico, Costa Rica, and the United States. We will 1) Characterize and compare contemporary social network structures of older adults in Puerto Rico and comparator contexts, 2) Examine within-person changes of social network composition and its association with health among older adults in Puerto Rico and comparator contexts. 3) Estimate and project the kinship networks of older adults in Puerto Rico, and Mexico. This research project will provide a better understanding on social networks in late life in the Caribbean, Latin America and the United States and potentially provide evidence for strategic interventions aimed at buffering the effect of migration and transnational family ties. We will examine social network trajectories, its association with health, and project kinship networks; this has the potential to inform more specialized interventions geared towards higher risk older adults, with the goal of reducing health disparities and promoting healthy aging.

NIH Research Projects · FY 2026 · 2024-03

Abstract Functional communication in a typical conversation involves complex adjustments by conversation partners (interlocutors) at multiple levels of language structure. Current accounts of this center on typical interlocutors and do not provide an adequate framework for understanding how functional communication emerges in interactions involving those with communication disorders. The current proposal aims to expand existing accounts through the systematic study of communicative interaction involving persons with ALS (PALS). ALS is a degenerative neurological condition that negatively affects verbal communication. This decline in verbal ability significantly diminishes quality of life of PALS and their family. Current interventions to enhance verbal communication focus mainly on improving a speaker’s productions, but this approach is less effective in degenerative conditions such as ALS in which speakers’ abilities continue to decline in spite of intervention. In the current proposal, we aim to (a) extend current theoretical accounts to involve those with communication disorders by studying PALS and (b) explore the feasibility of clinical interventions that leverage interactions to support verbal communication in degenerative diseases like ALS. We will do so through a set of three concordant, independent aims. In Aim 1, we will study highly structured interactions involving PALS and unfamiliar interlocutors that will focus on the phonetic level. In Aim 2, we will study more naturalistic interactions to study the flexibility PALS have at other levels of language structure (e.g., syntax and pragmatics). In Aim 3, we will incorporate caregivers into structured interactions with PALS and assess the clinical feasibility of interventions based on interactions. Upon the successful completion of this project, we will obtain an improved understanding of communicative interactions involving interlocutors with communication disorders. Specifically, our findings will elucidate patterns of change that support communication success for PALS and their interlocutors. These findings will also provide an evidence base for novel interventions to support verbal communication for people with degenerative conditions.

NIH Research Projects · FY 2026 · 2024-03

ABSTRACT Adolescent alcohol use is a national health problem. It is associated with negative health outcomes, such as addiction and cognitive dysfunction, but relatively little is known about the mechanisms underlying sex differences in adolescent binge drinking and changes in cortical circuits involved in brain health and psychiatric conditions. In our mouse model of adolescent alcohol consumption (Drinking in the Dark, or DID), we have observed sex-dependent changes in exploratory behaviors that are associated with dysregulation of somatostatin (SST) neuronal signaling in the prelimbic cortex. Here I propose to investigate 1) the contributions of L-type calcium channels (LTCCs) as a mechanism through which SST cells are altered due to drinking and 2) the temporal relationship between altered SST cell activity and observed behavioral deficits. Male and female transgenic mice with fluorescently tagged SST cells with undergo DID prior to brain collection. Functional changes in LTCCs on SST cells will be assessed using patch-clamp electrophysiology, and LTCCs as a druggable targets will be explored with behavioral pharmacology. I will then use freely moving single-photon neuroimaging during homecage and behavioral test conditions following DID. Using this technique, we will observe the precise temporal relationship between SST cell activity and the expression of exploratory behaviors in vivo. This research will be guided by my mentorship team, which has extensive experience in electrophysiology and in vivo imaging techniques, as well as experience in postdoctoral mentorship. Thus, conducting the proposed research will simultaneously advance our understanding of the neurobiology impacted by adolescent alcohol exposure and provide me with valuable training by qualified mentors, preparing me for an academic career in alcohol research.

NIH Research Projects · FY 2026 · 2024-02

PROJECT SUMMARY Tuberculosis (TB) in humans results from infection with members of the Mycobacterium tuberculosis complex (MTBC). The disease is endemic in many parts of the world. So is bovine tuberculosis (bTB) - a well-recognized zoonotic disease of bovine species (cattle and buffalo) also caused by infection with members of the MTBC. India has the world’s highest TB burden in humans, with more than 2M new cases and 400,000 TB-related deaths each year. India also hosts the largest bovine herd on the planet (~300M animals), and our recent studies suggest that more than 22M of those animals may suffer from bTB. Yet the risk of zoonotic TB (zTB) resulting from transmission of MTBC from bovines to humans in India and other high-TB burden settings is unknown. This is a major knowledge gap, and elimination of TB will be considerably more difficult if there is spillover from a domestic livestock reservoir to humans. This is of particular concern in countries such as India where the frequent consumption of unpasteurized milk and close contact with infected animals likely present additional elevated risks for zoonotic transmission. Because of this, the World Health Organization (WHO) and other supranational organizations have developed a "Roadmap for zoonotic TB" that calls for the establishment of a stronger evidence base to improve understanding of the burden and risk pathways of zTB to guide an effective response. To fill these knowledge gaps, we propose studies with the overall objective of estimating the risk associated with zTB in a high-TB-burden setting. We will accomplish this by applying rigorous quantitative risk assessment augmented by state-of-the-art whole-genome sequence (WGS)-based molecular epidemiology and multi-host transmission modeling. Performed at well-established study sites in Vellore and Tiruvallur districts in Tamil Nadu, India, our Specific Aims are to: 1) Estimate the risk of human TB associated with exposure to cattle, buffalo, or the consumption of raw milk in ~1,750 human cases and ~3,500 controls; 2) Apply WGS-based approaches to define the genetic diversity and molecular epidemiology and perform phylodynamic and phylogeographic analysis of MTBC lineages circulating in human TB cases, sympatric cattle and buffalo, and locally sourced raw milk; and 3) Perform multi-host transmission modeling to quantitatively assess zTB risk to humans and the potential benefits of control. These studies involve the application of innovative and powerful nested case-control epidemiological surveys with WGS-based genotyping and mathematical modeling. The results of our studies will inform and refine estimates of zTB risk, enable identification of transmission chains at a local scale, and transform our understanding of spillover and circulation of MTBC strains between human and bovine hosts. In the long-term, our findings will provide sustained positive impact through the development of evidence-based approaches to quantify and reduce risk of zTB in support of the global efforts to end TB.

NIH Research Projects · FY 2025 · 2024-02

Metasurface based chromatic confocal endoscope Endoscopy is an indispensable diagnostic tool for imaging hard-to-reach regions inside the body. Confocal endo- microscopy, with its capability of cellular imaging resolution, optical sectioning, and three-dimensional imaging, has proved to be a valuable tool in health diagnosis, including cancer screening. However, the traditional design approach used in current confocal endo-microscopes, which involves using multiple discrete optical elements such as objective lenses and prisms, leads to bulky size and high cost. Moreover, the lateral mechanical scanning in the distal end presents a significant challenge, limiting the imaging speed and hindering its broader applicability. To overcome these challenges, we propose a meta-photonic design approach that empolys a metasurface, an artificial ultrathin metamaterial consisting of subwavelength nanostructures, to realize spectral encoding for wavelength division multiplexed confocal imaging and to integrate all necessary functionalities, including high-numerical-aperture focusing, into a single ultracompact device. This new type of metasurface- based chromatic confocal endo-microscope will have a miniature distal end that can be integrated with a conventional endoscope, and it will have a low cost potential for mass production. Importantly, the proposed confocal endo-microscope has high imaging speed by eliminating one lateral scanning (Aim 1) or both lateral scannings (Aim 2). We will develop a metasurface that integrates the dual functions of an objective lens and a grating. The metasurface will be directly fabricated on a silica coreless fiber spacer that is epoxied to a cantilevered single-mode fiber, resulting in a miniature confocal endo-microscope probe of just 400 μm in diameter. Different wavelengths of broadband illumination light delivered through the single-mode fiber (which also behaves as a confocal pinhole) will be focused by the metasurface linearly along a selected lateral direction, enabling parallel confocal imaging of multiple lateral points simultaneously. The other lateral direction will be scanned by using a piezotube to achieve real-time imaging speed (30 frames per second). We will also design a spatial-spectral encoding metasurface that focuses each wavelength to form a random array of focal spots across a two-dimensional (2D) area. Different wavelengths sample the 2D image with different random sampling focal spots. The proposed strategy is thus an analogue of the compressive single-pixel camera, in which each wavelength is an effective single-pixel detector, and a spectrum represents a series of multiplexed measurements. The proposed metasurface will enable 2D compressive confocal imaging and eliminate lateral scanning, leading to a detector-limited imaging speed (up to KHz). The proposed metasurfaces will be fabricated and characterized. Lateral and axial resolutions of the proposed confocal endo-microscope will be quantified. Imaging speed and field of view will also be characterized. We will also demonstrate and validate the proposed systems by imaging tissue phantoms.