University Of Rochester

NIH Research Projects · FY 2026 · 2023-06

The choroid plexus (ChP) protrudes into the lumen of the four cerebral ventricles and is the principal source of cerebrospinal fluid (CSF), which together play an important role in neuronal patterning, brain physiology, buoyancy, and maintaining homeostasis by providing physical, enzymatic, and immunological barriers to the brain. Neuroimaging studies have observed ChP morphological changes with aging, neurodevelopmental and neuropsychiatric disorders, which suggests that the ChP may play a role in development and brain disorders. Despite this growing evidence, the ChP has not been the focus of commonly used neuroimaging tools, which causes it to be poorly segmented, mislabeled, and incorrectly quantified. Therefore, there is a critical need to more accurately segment the ChP. The overall obiectives for this proiect are to develop a novel, fast, reliable, generalizable, and dedicated open-source deep learning method for accurate ChP segmentation to understand how the ChP changes across the lifespan and differs among brain disorders. Samples for this study will come from high resolution [Human Connectome Project (HCP) and Connectome Related Human Disease (CRHD)] and conventional (inclusive of high risk for psychosis, first episode and chronic psychosis, bipolar disorder, and Alzheimer's disease) neuroimaging datasets totaling over 22,000 brains. The rationale for the proposed research is to provide an open-source segmentation tool that will allow for more robust analyses into the ChP's role in various brain disorders and a better foundational understanding of the how the ChP changes over time with age. To attain the overall objectives, the following three specific aims are proposed: (1) develop and validate a deeplearning method for the accurate segmentation of the ChP; (2) generate ChP volume data across the lifespan that can be used to characterize longitudinal changes and morphological differences across a variety of neuropsychiatric disorders; (3) establish reliability, generalizability, and fairness for broad distribution of FastPlex. To accomplish these aims, a total of 700 brains will be manually segmented - accounting for scanner type and image resolution that is balanced for age, sex, ethnicity/race, socioeconomic status, and brain disorder -to serve as training, validation, and testing labels for the deep-learning tool. Lasty, reliability and generalizability will be established to produce a tool that will be broadly distributed with the research community. The proposed research is innovative and significant because it will focus on an innovative comprehensive ChP segmentation tool (lateral, temporal horn, 3'd, and 4th ventricles) that also estimates partial volume effects and provides super resolution ChP labels, which together will enhance foundational knowledge on ChP neurodevelopmental and neuropsychiatric changes. The results of this research are expected to contribute meaningfully to the understanding of pathologic mechanisms underlying these disorders and to the development of novel strategies targeting specific disease processes.

NIH Research Projects · FY 2026 · 2023-06

Glaucoma is a very common age-related neurodegenerative disease characterized by the death of the retinal ganglion cells. Despite its prevalence, there are no neuroprotective treatments for glaucoma. The only current treatment is lowering intraocular pressure which unfortunately does not prevent or restore vision loss in many patients. Due to extensive research in both glaucoma patients and animal models of glaucoma, much is known about glaucomatous neurodegeneration, both at the physiological and molecular levels. However, despite this, we still lack a molecular understanding of the early pathological events that injure RGCs as a result of ocular hypertension. Microglia cells are a major component of the neuroinflammatory response in neurodegenerative diseases and after injury to the central nervous system. In fact, microglia cell response is thought to play key roles in many neurodegenerative diseases, including, Alzheimer’s disease, Parkinson’s disease, Huntingtin disease, and Amyotrophic Lateral Sclerosis. Work in other systems has shown that microglia can act be both protective and detrimental in the disease process, and possibly these two actions could take place sequentially in the same disease. Recent studies using modern sequencing technology has shown that microglia exist in different molecular states which correspond to their role in disease. A major, well-supported hypothesis in glaucoma research is that microglial cells are critical for maintaining retinal ganglion cell viability after a glaucomatous insult. However, the importance of microglia in an ocular hypertensive model of glaucoma has not been critically tested. In this application we propose to test the hypothesis that different activated states of microglia play distinct roles in glaucoma dependent upon stage of disease. Specifically, in two ocular hypertensive glaucoma mouse models, we will: (1) Determine if the role of microglia activation varies with disease stage, (2) define and test the importance of different molecular states, and (3) determine the role of microglial derived neurotoxic cytokines. Overall, this proposal we will define novel mechanisms by which microglia states modulate glaucoma onset and progression leading to novel candidates for therapeutic evaluation.

NIH Research Projects · FY 2026 · 2023-06

Project Summary This candidate is requesting support for a four-year program of training and research to use digital phenotyping to gain a novel understanding of how digital media influences like exposure to drug and alcohol- related content online can impact adolescent substance procurement and use. Addressing adolescent substance use is challenging due to the diverse social and environmental factors that can impact a youth’s decision to experiment with drugs or alcohol. Digital media use, including online exposure to substance-related content, is one such potential factor of growing daily influence in adolescent lives. However, little is currently known about how exposure to drug and alcohol-related content differs across media platforms (e.g. gaming, social media), nor whether exposure on one media platform may be more likely to facilitate drug procurement or precipitate an instance of substance use. This limitation in our understanding of these relationships is secondary to both recall bias and the cross-sectional survey methodology used in prior studies. This project will leverage novel digital phenotyping (DP) technology to collect smartphone sensor data in combination with active surveys about digital media exposures and substance use. In this manner, we plan to identify more accurately those digital media exposures and experiences that impact adolescent use of drugs and alcohol, and improve upon existing clinical guidance accordingly. In the proposed training plan, the candidate will build upon her previous experience in use of digital phenotyping to understand high-risk adolescent digital media use. Her training plan includes training in: 1) statistical methods for multivariate longitudinal analysis, 2) design and implementation of digital phenotyping tools that capture high-risk digital experiences/exposures in real time, 3) design and piloting of ecological momentary intervention protocols, and 4) responsible conduct of digital phenotyping research in adolescents with a history of substance use. In line with NIDA’s mission of identifying behavioral, environmental and social causes of substance use across the lifespan, this research plan will 1) determine which subtypes of digital media use are more frequently associated with exposure to drug and alcohol-related content and 2) assess which exposures are more frequently associated with instances of substance procurement and use. We will also explore the potential moderating effects of psychiatric symptoms and online victimization on the relationship between exposure to substance-related content and substance use. This study will be performed across 2 years in subjects between 15 and 18 years of age. A subsequent R01 proposal will then outline the design and pilot of an ecological momentary intervention protocol with the goal of intervening in real time upon digital exposures/experiences associated with adolescent substance use.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY Febrile infants are at risk for potentially fatal invasive bacterial infections, but clinical decisions vary widely and thousands of infants may experience harms from under-testing or over-treatment. Practice variation costs up to $700 billion each year and is associated with poor outcomes and low-quality care. However, there is a paucity of research examining the extent to which key sources contribute to practice variation, particularly for febrile infants. Addressing this gap in knowledge is an essential first step to improve the effectiveness, efficiency, and care for febrile infants. Dr. Yaeger is a board-certified pediatric hospitalist whose prior research has focused on understanding how clinical and social factors can improve child health outcomes. This K23 Mentored Patient-Oriented Research Career Development Award will allow him to learn new methods to investigate sources of practice variation, understand subsequent effects, and ultimately devise interventions to reduce practice variation, improve outcomes, and decrease costs, thereby improving care for all febrile infants. The proposed studies and career development plan will directly support the candidate’s goal of becoming an independent clinician-investigator and expert in clinical decision-making and advancing child health outcomes. To achieve this goal, he has assembled an inter-disciplinary mentoring team from the University of Rochester Departments of Family Medicine, Public Health Sciences, and Emergency Medicine. In addition to completing relevant coursework, workshops, longitudinal training programs, and individual didactic sessions, Dr. Yaeger will gain expertise from his team, who will guide him in achieving his Training and Career Goals. These goals include gaining expertise and skills in: 1) decision science; 2) multi-level modeling, and; 3) mixed methods. His research plan seeks to understand the extent to which disease rates, local supply of resources, clinical characteristics, parent/caregiver preferences, and local practice culture contribute to practice variation in febrile infants. The aims are: 1) To estimate practice variation and the extent to which disease rates and local resources explain practice variation; 2) To examine contextual factors associated with practice variation; 3) To investigate the effect of a national clinical practice guideline on practice variation. He will accomplish Aim 1 using a state-wide, population-based administrative dataset and small area variation analysis framework to estimate the extent to which key sources of practice variation contribute to differences in clinical decision-making. In Aim 2, he will use a mixed methods approach to identify contextual factors that may contribute to clinical decisions affecting practice variation. In Aim 3, he will investigate the extent to which a national clinical practice guideline reduces practice variation. These career development activities, mentorship, and results of these studies, provide a clear path for the candidate to secure independent funding to investigate pediatric clinical decision-making and advancing health outcomes for all children.

NIH Research Projects · FY 2026 · 2023-05

The COVID-19 pandemic has disrupted clinical research and highlighted the value of patient centered research methods that enable participation from the home and collection of data directly from participants. Such decentralized research studies that harness video visits, digital tools and participant reporting, can reach a large, geographically dispersed population of participants, increase the frequency and scope of evaluation, and reduce the burden of participation. Parkinson’s disease, a clinically heterogeneous neurodegenerative disorder that causes progressive disability, is well suited to such a model. Traditional assessments are typically subjective, insensitive to change, and limited to episodic administration and therefore fail to capture the complexity of Parkinson’s disease. AT-HOME PD, the largest on-going decentralized longitudinal observational Parkinson’s disease study with digital tools, is remotely characterizing ~225 participants with Parkinson’s disease from two NINDS-funded, phase 3 clinical trials, STEADY-PD III and SURE-PD3. These studies yielded cohorts with comprehensive clinical phenotyping, whole genome sequencing, and serial plasma collection. AT-HOME PD participants are being characterized through video visits, smartphone-based assessments, and an online survey platform. The cohort is now approaching mid-stage Parkinson’s disease, presenting an opportunity to advance our understanding of this under-studied population, improve the prediction of clinically relevant disease milestones like falls and cognitive impairment, quantify physical activity, and identify sensitive remote disease measures. This project will extend the follow-up of this cohort by 3 years and expand digital phenotyping of participants, using smartphone-based assessments and two wrist-worn sensors. The aims of this project are to 1) evaluate the extent to which digital tools and remote participant reporting can improve the prediction of clinically relevant disease milestones compared with traditional measures, 2) quantify longitudinal change in physical activity, steps taken, and gait in mid-stage Parkinson’s disease in the real-world, and 3) explore the relationship between physical activity and clinical outcomes in mid-stage Parkinson’s disease. We will generate a dataset with approximately 10 continuous years of data on PD progression that begins prior to use of dopaminergic medications and progresses to midstage Parkinson’s disease and beyond. This rich dataset will accelerate therapeutic development by filling knowledge gaps in the mid-stage Parkinson’s disease population, helping to optimize models for conducting patient-centered remote research, evaluating new methods for predicting disease outcomes, and evaluating remote outcome measures.

NIH Research Projects · FY 2026 · 2023-05

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a life-threatening condition which affects ~200,000 Americans each year with 10-15% of intensive care admissions and a mortality rate of ~ 25-40%. Sepsis is a prominent extrapulmonary cause of ALI in humans. Nearly 50% of patients with severe sepsis develop ALI/ARDS. All current therapies for ALI/ARDS still rely on supportive care; thus, there is an urgent need to develop new treatment strategies for ALI/ARDS that are safe and effective. Because endothelial cell (EC) barrier dysfunction is an early and critical component of ALI in sepsis, a better understanding of the mechanisms of EC permeability is key to developing effective therapy for ALI. The goal of this proposal is to understand how aberrant communication between endoplasmic reticulum (ER) and mitochondrion in sepsis, mediated by ER chaperone BiP/GRP78 and mitochondrial (MITO) chaperone Mortalin/GRP75, promotes EC barrier dysfunction to cause ALI. Our hypothesis is that a close interaction and functional cooperation between BiP/GRP78 and Mortalin/GRP75 at the MAMs (mitochondrial associated endoplasmic reticulum membranes) serves to increase cytosolic Ca2+ and ER-MITO contact sites to cause mitochondrial Ca2+ overload and inflammasome activation, leading to lung vascular injury in sepsis. We further hypothesize that targeting BiP/GRP78 and Mortalin/GRP75 in combination may prove a superior therapeutic approach against sepsis-induced ALI and mortality. The proposal is based on our novel findings that BiP/GRP78 and Mortalin/GRP75 are key regulators of Ca2+ signaling and ER-MITO contact sites in EC and silencing BiP/GRP78 or Mortalin/GRP75 each prevents EC barrier disruption caused by plasma from septic patients and other clinically relevant edemagenic agonists such as thrombin and LPS. BiP/GRP78 is induced in septic lung and overexpressing BiP/GRP78 in the resting lung endothelium is sufficient to cause lung injury in mice. Moreover, inhibiting BiP/GRP78 or Mortalin/GRP75 each mitigates ALI in mice. Importantly, combined inhibition of BiP/GRP78 or Mortalin/GRP75 is far more effective (requires ~5-fold less dose of BiP/GRP78 or Mortalin/GRP75 inhibitors) in improving survival in mice with sepsis. The proposal will address the following aims. Aim 1 will determine the role of BiP/GRP78 and Mortalin/GRP75 in regulating cytosolic Ca2+ to cause EC permeability. Aim 2 will determine the role of BiP/GRP78 and Mortalin/GRP75 in increasing ER-MITO contact sites and mitochondrial Ca2+ uptake to cause mitochondrial dysfunction and inflammasome activation leading to EC permeability. Aim 3 will determine (i) the contribution of endothelial BiP/GRP78 and Mortalin/GRP75 in causing lung injury, and (ii) assess the therapeutic potential of inhibiting BiP/GRP78 and Mortalin/GRP75 together against sepsis-induced ALI and mortality. These studies will provide valuable insight into the ER-MITO communication and its relevance in the pathogenesis of ALI and may lead to development of a safe and efficacious therapeutic strategy that relies on combined inhibition of BiP/GRP78 and Mortalin/GRP75 to control ALI and improve survival in sepsis.

NIH Research Projects · FY 2026 · 2023-05

The Genomic Intensive Data Science Research, Education and Mentorship (GIDS-REM) program at the University of Rochester aims to increase the number of researchers with strong quantitative skills in the genomics workforce. The focus is on training and retaining individuals with broad quantitative and analytical skill sets in biomedical fields. The proposal aims to 1) create a new track in genomics data science in the Goergen Institute for Data Science Master’s program (GIDS-MS) and recruit scholars into the track; 2) build core competencies in genomics data science through curricular training, workshops, and research experiences; and 3) retain GIDS-REM fellows in the genomics workforce through mentoring and cohort building. The innovative features of this proposal combine with existing strengths in research, academics, and efforts to ensure rigorous training opportunities at the University of Rochester. This proposal leverages the framework and resources for the existing GIDS-MS program and implements a new curriculum that trains students in theoretical and applied aspects of both data science and genomics. Through a partnership with the David T. Kearns Center, the recruitment strategies will bring in scholars with a broad skill set as GIDS-REM fellows. The proposal implements a team mentoring approach that will connect fellows to genomics research advisors throughout the University of Rochester and its Medical Center and industry. This proposal applies the University of Rochester’s strengths in cancer genomics at the Wilmot Cancer Institute and translational genomic research at the Clinical and Translational Science Institute. Key aspects of the proposal are in its mentor training and strong community-building to allow GIDS-REM fellows to thrive. These approaches will improve the retention of fellows in doctoral programs or in industry positions in the field of genomics. The effectiveness of the program will be assessed using quantitative and qualitative benchmarks, and instruments to evaluate mentor competency and student self-efficacy. The GIDS-REM program will not only have a direct impact on the fellows and their career directions, but will have a broad impact on the genomics community at the University of Rochester and beyond.

NIH Research Projects · FY 2026 · 2023-04

Project Summary/Abstract: Human chromosomes serve to compact the genomic DNA several thousand times its length to fit within the cell’s nucleus, while also allowing for processes such as and gene expression. To accomplish this, the genome is assembled into a complicated, multifaceted complex known as chromatin. The assembly of chromatin first involves wrapping short (~200 bp) segments around spools of protein comprised of core histone into structures known as nucleosomes. Immensely long, genome-sized strings of nucleosomes are assembled into large structures via to the self-interacting nature of nucleosomes. The key elements in formation of these large condensed structures are the ‘tail’ domains of the core histone proteins, which protrude out from the main body of nucleosomes to mediate inter-nucleosome interactions. However, despite their essential nature to the formation of chromosomes, little is actually known about how the histone tail domains contact neighboring nucleosomes. Moreover, these interactions represent critical points for regulation, and are modified by epigenetic posttranslational modifications, including acetylation, as well as other chromatin modifiers. This project will employ biochemical and biophysical techniques to define critical molecular aspects of the inter-nucleosome interactions mediated by the core histone tail domains in model systems, and elucidate how epigenetic modifications within the tail domains regulate these interactions. The specific goals of the work described in this proposal are to: 1) define inter- nucleosome interactions mediated by the core histone tail domains, and how posttranslational modifications transition inactive chromatin structures to those hospitable to active genes in a model chromatin system; 2) define aspects of how linker histones bind to nucleosomes, and oligonucleosome arrays, are affected by posttranslational modifications, and communicate the core histone tail domains; and 3) understand how the HMGN chromatin architectural factors influence H1 structure to destabilize chromatin condensates In addition, we will use lessons learned from the above work to understand the molecular basis a newly identified mutation in a linker histone that causes the genetic disorder known as Rahman’s disease. These results will fill in key knowledge gaps in our understanding of how chromosomes are assembled, and regulated to provide for transcription, replication, DNA repair, and other genome-related processes.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY/ABSTRACT – OVERALL Atopic dermatitis (AD) often precedes sensitization to food allergens and the development of clinical food allergy (FA) due to compromised skin barrier function allowing allergen sensitization through skin. A large body of data from Europe and North America suggest that living on farms is associated with a decreased risk of asthma and atopic diseases. Asthma has been a focus of farming lifestyle studies; however, little is known about the protective mechanisms of farming lifestyle on development of AD and FA which often precede respiratory allergies and asthma. The farm lifestyle protection against allergic diseases comprises likely three prerequisites: 1) innate immune training and a modified immune response upon re-exposure, 2) generation of suppressive regulatory T cells, and 3) preserved barrier function. Here, we propose to assess these preconditions in an extended longitudinal birth cohort study among the Old Order Mennonites (OOM), a population practicing traditional, single-family farming with a lower rate of asthma and allergic diseases, including atopic dermatitis and food allergies in early childhood. Biomarkers of Atopy Beginning Early (BABE) will test the overall hypothesis that perturbed skin barrier function, immune millieu and microbiome drive the development of atopic dermatitis, Th2 inflammation, allergic sensitization and FA, whereas a healthy gut microbiome modulates the protective metabolite pool such as short chain fatty acids and tryptophan metabolites and protective Treg immune development. Project 1 utilizes deep metagenomic sequencing to assess infant gut microbiome composition and corresponding metabolome to show that OOM infant gut microbiome is distinct from urban infants. Project 2 assesses markers of allergic sensitization and protective immune development utilizing multiparameter spectral flow, unbiased clustering analysis and transcriptomic studies to demonstrate that urban infants have a higher number of hyperinflammatory monocytes and Th2-skewed T cell subsets detected in early infancy, whereas OOM have gut-homing memory Tregs. Project 3 will characterize skin barrier function, microbiome and immune cell transcriptome. Our longitudinal birth cohort ZOOM1, funded by a U01 grant, is now 2-5 years old and is a shared foundation for the three projects (78 OOM and 79 urban). We will add another 120 infants as a ZOOM2 cohort (80 urban and 40 OOM). We will also replicate key T cell biomarkers in larger infant cohorts (Start Eating Early Diet ”SEED” and Microbiome and Allergic Asthma Precision Prevention “MAAP2”). The infrastructure to recruit, collect and share samples and data is provided by the Cohort Admin & Biorepository and Data Management & Bioinformatics Cores. The Admin Core will provide overall financial and administrative infrastructure. These studies aim to identify biomarkers, mechanisms, and protective strategies against atopic and food allergy.

NIH Research Projects · FY 2025 · 2023-04

During aging, tendons demonstrate substantial disruptions in homeostasis, leading to impairments in structure and function. Given the central role of tendon in appropriate skeletal locomotion and ambulation, impaired tendon function contributes to substantial declines in overall function and quality of life during aging. Moreover, aged tendons are more likely to undergo spontaneous rupture, and the healing response following injury is drastically impaired in aged tendons. Thus, there is a clear need to develop strategies to maintain tendon homeostasis and healing capacity through the lifespan. Tendon cell density sharply declines by about 12 months of age in mice, and this low cell density is retained even in geriatric tendons. Our preliminary data suggests that this decline in cellularity initiates a degenerative cascade due to insufficient production of the extracellular matrix components needed to maintain tendon homeostasis. Thus, preventing this decline in tendon cellularity has great potential for maintaining tendon health. In addition, the tenocytes that remain in aged tendon demonstrate substantial alterations in their molecular programs, relative to young tendon cells. Surprisingly, this programmatic skewing does not seem to drive additional homeostatic disruptions, but we hypothesize that it is a key driver of age-related impairments in tendon healing. Thus, reversing this programmatic skewing may restore physiological healing function to aged tendons. While the pathways that drive aging-induced tendon cell death vs. programmatic skewing are likely distinct, epigenetic modifications underly nearly every aspect of cell function. Indeed, partial epigenetic reprogramming has demonstrated tremendous potential in addressing a range of age-related pathologies. In this proposal we will test the central hypothesis that age-related tenocyte apoptosis driving tendon degeneration, and intrinsic programming shifts leading to impaired healing capacity can be prevented via partial epigenetic reprogramming. In Aim 1 we will define the multi-scale mechanisms of age-related tendon degeneration using a combination of genomics, histological, and mechanical analyses. We will then determine the efficacy of partial reprogramming to maintain tendon structure-function through the lifespan. In Aim 2 we will define how aging alters the cellular response to tendon injury using a well-established model of healing in the flexor digitorum longus tendon. We will then demonstrate that partial reprogramming can successfully restore the tenocyte functional plasticity that is required for physiological healing. Successful completion of these studies will define the tendon aging signature and establish partial reprogramming as a novel approach to maintain tendon health and healing capacity through the lifespan.

NIH Research Projects · FY 2026 · 2023-04

ABSTRACT Articular cartilage in load-bearing joints is a resilient tissue, yet 32 million Americans suffer from osteoarthritis (OA), characterized by the progressive degeneration of cartilage. Disease-modifying therapies to prevent carti- lage degeneration are unavailable and urgently needed. Mechanical factors heavily influence chondrocyte met- abolic activities and play a critical role in cartilage homeostasis and degeneration. Chondrocytes are the unique post-mitotic cells expressing both Piezo1 and Piezo2 mechanosensitive channels robustly. Since the discovery of Piezo1 and Piezo2 in 2010, it has been identified that Piezo1 and Piezo2 exhibit distinct gating properties, expression patterns, and mechanotransduction signaling mechanisms in human physiology and pathology. We and others reported that Piezo1 and Piezo2 in chondrocytes sense injurious loading, and pre- treatment with GsMTx4, a pan Piezo1/Piezo2 blocking peptide, significantly reduced the injury-induced chon- drocyte death in vitro. Ironically, our preliminary data reveal the augmented Piezo1 in arthritic conditions and the up-regulated Piezo2 by exercise. Also, our preliminary data show that chondrocytes in injured knees are more susceptible to mechanical injury, but exercised cartilage are less vulnerable to mechanical injury than controls. Thus, our central hypothesis is differential roles of Piezo1 and Piezo2 in chondrocyte mechanosensi- tivity and cartilage homeostasis. A significant knowledge gap exists in understanding Piezo1- and Piezo2-me- diated mechanotransduction mechanisms of chondrocytes in the context of joint health and disease. In this program, we will take advantage of mouse models to delineate the role of Piezo1 and Piezo2 in chondrocyte mechanotransduction, metabolism, and cartilage homeostasis. Our custom-built platforms, a mechano-micro- scope and impact loading devices, will be employed to quantify cellular mechanosensitivity in a culture system or in situ. A successful outcome will provide insights into OA pathology and therapeutic strategies targeting Pi- ezo1- and Piezo2-mediated mechanotransduction for cartilage degeneration and regeneration.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY Chronic pain is a highly prevalent problem in our society, is associated with significant personal suffering, and disability, and incurs billions of dollars in cost annually. Despite its highly negative impact this medical problem remains a clinical diagnosis relying on patients’ reports of pain intensity and the clinician’s physical exam. The availability of reliable biomarkers for chronic pain, which do not rely on clinical diagnosis and subjective pain reports, will increase our understanding of the pathophysiology of different chronic pain conditions, improve care by providing clinicians with tools to classify and follow patients, and help greatly in clinical trials developing novel analgesics where subjective pain reports remain the primary tool. Neuroimaging results from our lab as well as others are starting to reveal reproducible brain signatures of chronic pain involving changes in specific aspects of structural and functional cortico-striatal plasticity. As such, we and others have shown that altered activity in, and functional connectivity between the nucleus accumbens and medial prefrontal cortex, and loss of accumbens and dorso-lateral prefrontal cortex volume are reproducible across laboratories and can potentially constitute an objective neural signature of chronic low back- pain. However, it remains unknown whether this neural signature is generalizable to other musculoskeletal chronic pain conditions like arthritis and/or chronic neuropathic pain like trigeminal neuralgia and/or chronic affective conditions like major depression or is specific to CLBP. In addition, the effects of patients’ age and sex on the neural signature of CLBP, which are major determinants of the clinical experience of chronic pain, remain unknown. The overall aim of this application is to determine these two unknowns. In Aim 1 we will test the specificity of the neural signature to musculoskeletal CLBP by testing its predictive accuracy in chronic knee pain from osteoarthritis (KOA), which is a different musculoskeletal pain condition, in chronic pain from trigeminal neuralgia (TN), which is a neuropathic pain condition, and in major depressive disorder (MDD), which is a chronic negative affective condition. To that end, we will use machine learning techniques to train a predictive model and classify CLBP patients from healthy controls (i.e., training set) using a priori defined brain features drawn from reproducible findings based on our work and on the CLBP neuroimaging literature. Next, this model will be validated on a new sample of CLBP patients and healthy controls (i.e., test set) and tested in KOA, TN, and MDD patients to assess generalizability to other chronic pain or affective conditions or specificity to CLBP. In Aim 2 we will study how age affects the predictive power of the neural signature of CLBP and test how robust are the group differences between CLBP patients and healthy controls in the brain features making up the neural signature across young (18-30 years old) and older (> 50 years) age groups. In Aim 3 we will explore the effects of sex on the neural signature of CLBP following a similar approach to the one used in Aim 2 but using instead a grouping based on sex.

NIH Research Projects · FY 2026 · 2023-04

Short peptide-encoding sequences in the 5' untranslated region of messenger ribonucleic acids (mRNA), called upstream open reading frames (uORFs), are widespread in ~50% of human mRNAs. Translating these uORF sequences reduces the protein output of an mRNA main open reading frame (mORF). Our bioinformatic analysis of human and mouse ribosome profiling databases uncovered a group of cardiac mRNA transcripts containing translated uORFs, such as transcription factors, including GATA4. Biochemical analysis suggests that stabilizing the double-stranded RNA (dsRNA) structure downstream of the start codons of these peptide-encoding sequences enhances their translation, thereby inhibiting the translation of mORFs. This translational inhibitory mechanism is mitigated by DEAD-box RNA helicase DDX3X that unwinds dsRNA and inactivates uORF. Genetic depletion of GATA4 uORF activity using CRISPR-Cas9 mediated genomic editing of the start codon in human embryonic stem cells (ESC) provides evidence of uORF-mediated regulation of mORF translation and cardiomyocyte (CM) hypertrophy. In addition, an established CRISPR-Cas9-derived uORF start codon mutant knock-in mouse model shows spontaneous cardiac hypertrophy and will be used to characterize CM hypertrophy at baseline and under stress conditions. Based on our discovered molecular mechanism of DDX3X-regulated, dsRNA-dependent, uORF-mediated translational inhibition of mORF, we have developed two types of antisense oligonucleotides (ASOs) that can either enhance or reduce uORF translation by strengthening or disrupting dsRNA structures. The uORF-enhancing ASO locks the dsRNA structure and activates translation of the uORF, thereby reducing GATA4 mORF protein expression in human CMs. Treatment of mouse cardiomyopathy models with uORF-enhancing ASO reduces GATA4 protein expression, antagonizes cardiac hypertrophy, and restores cardiac function. Based on our findings, we hypothesize that cardiac transcription factor mRNA uORF-dsRNA element acts as a switch for translational control of mORF, regulating cardiac hypertrophy, and can be targeted by ASOs to modulate mORF protein translation and cardiac hypertrophy. We will focus on 3 Specific Aims. Aim 1. Elucidate mRNA structural elements and their interplay with the GATA4 uORF for regulating mORF translation. Aim 2. Determine the biological role of the GATA4 uORF in genetic knock-in mouse models and primary CM cell culture systems. Aim 3. Develop proof-of-concept translation-manipulating ASOs targeting the GATA4 uORF for short-term anti- hypertrophy intervention. These studies will provide novel insights into translational control mechanisms in cardiac biology. This project will promote novel therapeutic approaches (targeting uORF-dsRNA elements) to regulate cardiac hypertrophy. Our mechanism-based design of translation-manipulating ASOs can serve as a proof-of-concept model to apply to different pathogenic mRNA targets.

NIH Research Projects · FY 2026 · 2023-03

Reversible phosphorylation is a critical regulatory mechanism for spine morphogenesis, synaptic transmission, long-term potentiation (LTP) and memory formation. Protein phosphatase 1 (PP1) contributes to almost half of the serine/threonine phosphorylation in the mammalian cells, however, the role of three different PP1 isoforms (PP1α, β, γ) in these processes is ill defined. PP1β is not believed to play a role in CNS function. On the other hand, whether PP1α and PP1γ play a role in synaptic functions have never been determined directly. By using conditional knockout mouse models, we found that PP1β inhibits synaptic transmission and spine maturation while promotes LTP induction and memory formation. On the other hand, we found that PP1γ increases synaptic transmission, with PP1α compensating PP1γ. The overarching hypothesis of this application is that myosin phosphatase targeting 1 (MYPT1) and neurabin (Nrb) mediate the distinct effects of PP1β and PP1γ/α on synaptic function, respectively. In detail, we will test our hypothesis in Aim 1 that PP1β-MYPT1 holoenzyme inhibits non-muscle myosin IIB-mediated F-actin contraction in inhibiting spine maturation and synaptic transmission. We will determine in Aim 2 that PP1γ, in combination with PP1α, promotes spine maturation, synaptic transmission by interaction with Nrb, a major synaptic scaffolding protein. We will also test our prediction that PP1γ/α achieves these via dephosphorylating Nrb at Ser200. In Aim 3 we will test our prediction that PP1β inhibits LTD induction, promotes LTP induction and memory formation while PP1γ/α plays an opposite role. We will determine the structure-synaptic function relationship in the roles of PP1β in synaptic transmission and plasticity, with an emphasis on PP1β C-termini in which one of the human PP1β de novo mutations resides. These studies will provide signaling mechanisms of, and structure determinants on, PP1 isoforms in regulating their distinct roles on synaptic functions.

NIH Research Projects · FY 2026 · 2023-03

PROJECT ABSTRACT Acinetobacter baumannii has emerged as a major healthcare concern due, in part, to the organism’s propensity to develop resistance to front-line antibiotics. The A. baumannii resistome includes aminoglycoside and β-lactam modifying factors, but is primarily comprised of at least 40 drug efflux systems belonging to 6 distinct pump families. Intrinsic multidrug resistance occurs via mutations that lead to overexpression of one or more efflux systems, thereby allowing the organism to extrude antibiotics from the cell. Recently we discovered efflux systems also modulate adaptive A. baumannii antibiotic resistance. Meaning, transfer of antibiotic susceptible strains to physiologically relevant growth conditions, such as human serum, leads to the upregulation of at least 18 annotated efflux pump components, which in turn allows for efflux mediated resistance to antibiotic levels that are achievable within a patient. This phenomenon, which has been termed adaptive efflux mediated resistance (AEMR) by Handcock and colleagues, has been hypothesized to be one means by which otherwise antibiotic susceptible strains fail to respond to antibiotic treatment within the clinic. We hypothesized that the hyper-efflux phenotype of AEMR conditions would provide a unique and innovative screening platform to identify broad- spectrum efflux pump inhibitors that inhibit multiple A. baumannii efflux pumps. Indeed, a pilot high throughput screen led to the identification of the benzenesulfonamide class of efflux pump inhibitors that eliminate AEMR and antibiotic resistance within strains that overexpress efflux pumps that are notorious causes of multidrug resistance among clinical isolates. Our goals herein are to 1. Expand our screening approach to include a larger, chemically diverse compound library to arrive at additional chemical series of A. baumannii efflux pump inhibitors (EPIs), 2. Use medicinal chemistry to optimize the benzenesulfonamide and as many as two additional chemical series of EPIs, 3. Define the cellular target of the benzenesulfonamides and new chemical classes of EPIs, and 4. Test the in vivo efficacy of front runner compounds against A. baumannii strains that exhibit efflux mediated multidrug resistance.

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY: Imagine Times Square in New York City: tall buildings, flashing lights, a swarm of people. This visual scene represents a potential overload of sensory information. To guide behavior, the brain uses a collection of filtering mechanisms that either boosts the processing of behaviorally relevant information or suppresses the processing of distracting information. Impairments in this selective processing of sensory information can have critical consequences for human health. Such consequences are apparent, for example, in visuo-hemineglect associated with stroke, and in some neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). The present proposal specifically focuses on the selective processing of locations in visual space, referred to as spatial attention. A large-scale network of brain regions directs spatial attention, but the specific contributions of each network node to attention-related enhancement and suppression remain largely unknown. Here, we will test whether distinct circuits within the attention network are driving these complementary processes in a well-characterized region of visual cortex, i.e., visual area 4 (i.e., V4). We will specifically investigate functional contributions from two cortical nodes of the attention network in macaques: the frontal eye fields (FEF) in frontal cortex and the lateral intraparietal area (LIP) in parietal cortex. FEF and LIP both contribute to top-down attentional control, based on behavioral goals. To determine whether there are distinct or redundant neural circuits underlying the effects of attention-related enhancement and suppression on visual processing, we will record layer-specific neural activity from V4, while simultaneously using optogenetics (i.e., the use of genetically coded, light-driven ion channels or pumps) to inactivate known corticocortical pathways, either from FEF to V4 or from LIP to V4. The use of optogenetics, in comparison to other causal manipulations (e.g., electrical microstimulation or pharmacological inactivations), will allow us (i) to isolate contributions from specific between-region, corticocortical pathways and (ii) to compare the effects of inactivating these pathways, from either FEF or LIP, on different trials within the same experimental session. The present proposal has three specific aims: (i) to establish the retrograde-only expression of virus in FEF and LIP after optogenetic injections in V4, (ii) to test whether corticocortical pathways from FEF and LIP make distinct contributions to attention-related neural effects in V4, and (iii) to test whether the complementary processes of attention-related enhancement and suppression interact in V4. We will test the Central Hypothesis that FEF primarily contributes to the goal- directed enhancement of behaviorally relevant information in V4 through connectivity in supragranular layers, while (ii) LIP primarily contributes to the goal-directed suppression of distracting information in V4 through connectivity in infragranular layers. The present proposal will advance our overarching objective of understanding how the attention network shapes visual processing of our complex and dynamic environment.

NIH Research Projects · FY 2026 · 2023-03

Frailty is a significant problem for older (age 65+) survivors of cancer. Older survivors of cancer are at 46% greater risk of being physically frail compared to those without a history of cancer. No standard treatments for physical frailty in older survivors of cancer exist. Tumor necrosis factor-α (TNF-α) and related immune markers are associated with physical frailty in older survivors of cancer. Epigallocatechin-3-gallate (EGCG) is a potent anti-inflammatory nutraceutical that reduces TNF-α and related immune markers and risk of functional decline. EGCG is a promising intervention to reduce physical frailty in older survivors of cancer. This proposal builds upon my previous work demonstrating a relationship between cancer treatments, physical frailty, DNAmage, and TNF-α and related immune markers. My work also shows that an EGCG intervention (capsules with 800mg EGCG + 250mg Vitamin C) is safe and feasible in older survivors of cancer. This proposal presents a five-year complimentary research and career development plan. For this proposal I will conduct a Phase II, multicenter, 2-arm placebo controlled randomized clinical trial in 118 older survivors of cancer (aged 65+), who have completed cancer treatment (≤12 months) and are at least pre-frail (Fried Frailty Score ≥2) and randomized to the EGCG intervention or placebo for 12 weeks. The aims of the proposed study are: 1) To evaluate the preliminary efficacy of the EGCG intervention on physical frailty; 2) To evaluate the preliminary efficacy of the EGCG intervention on TNF-α and related immune markers; 3) To explore if baseline TNF-α and related immune markers and DNAmage are associated with baseline and post-intervention physical frailty; and 4) To explore the efficacy of the EGCG intervention on physical frailty and TNF-α and related immune markers across different population subgroups of older survivors of cancer. I will also complete the following new training goals: 1) To develop expertise to design, conduct, analyze and lead multicenter randomized clinical trials focused on nutraceuticals as interventions for frailty in older survivors of cancer; 2) To obtain training in epigenetics as a biomarker of frailty; 3) To gain expertise in strategies that improve the recruitment and retention of clinical trial participants, with the goal of enhancing representation to better reflect the general population. My mentorship committee includes national and international experts in nutraceutical and behavioral interventions, geriatric oncology, translational science, biostatistics, and recruitment and retention strategies. Under the guidance of Drs. Michelle Janelsins and Luke Peppone (primary mentors), Dr. Supriya Mohile (co-mentor), and Drs. Charles Kamen, Paula Vertino, Michael Sohn and Ms. Canin (advisors) I will obtain essential skills that I currently do not possess. The training and research plan will position me to achieve my long-term goal to become an independently R01-funded translational scientist in geriatric oncology who develops, and tests mechanistically driven, cancer control interventions.

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY/ABSTRACT Suicide is the fifth leading cause of death among U.S. children 5 to 12 years, yet limited research on childhood suicide and suicidal behavior (SB) exists. The National Institute of Mental Health (NIMH) has acknowledged this critical gap as a high research priority. A significant risk factor for the early onset of a first suicide attempt (SA) is a parental history of SB. Although the familial transmission of SB is well documented, research examining the specific mechanisms associated with familial risk is limited. Our ongoing NIMH-R21 study (Cohort 1) is investigating factors related to the familial risk of SB in children, 6-9 years, with (PH+; n=100) and without (PH-; n=100) a parental history of SA. This proposed R01 study will continue annual follow-ups for Cohort 1 and add an additional 300 newly enrolled families (Cohort 2; ages 9-11 years; 150 per PH group) for a total sample of 500 parent-child dyads. Youth will be followed for four years from mid/late-childhood through early/mid-adolescence. Using the Research Domain Criteria (RDoC) framework, we will examine the trajectories of neurocognitive function (NF), emotional reactivity/regulation (ERR), non-suicidal self-injury (NSSI), suicidal ideation (SI), and SA in PH+ and PH- youth along with contributions by sex and race. Study participants at first assessment include youth 7-12 years. At last assessment, youth ages will range from 10-15 years. Both groups, PH+ and PH-, will be balanced by sex and race. Two main research aims and one exploratory aim will be tested. Aim 1: Examine longitudinally how PH status is associated with trajectories of NF and ERR constructs measured during mid/late-childhood through early/mid-adolescence. Aim 2: Investigate the potential mediating role of NF and ERR constructs on the association between PH status and offspring NSSI, SI, and SA. Exploratory Aim: Test sex and race as potential moderators of ERR and NF trajectories, and on the association between PH status and offspring NSSI, SI, and SA. This proposal’s central hypotheses are that (1) PH+ status increases vulnerability for developmental trajectories characterized by NF deficits and emotional dysfunction/dysregulation; (2) these trajectories will mediate the association between PH status and youth NSSI, SI, and SA; and (3) these associations between trajectories and SB/NSSI will be moderated by both sex and race. The hypotheses are informed by preliminary findings from the ongoing NIMH- R21 study, where group differences were found for ERR, SB, and NF. The proposed R01 study aligns well with the NIMH 2020 Strategic Plan for Research with emphasis on Goal 2-investigating mental health trajectories and inclusion of diverse samples. Completing the proposed study will assist with the identification of specific mechanisms associated with the familial risk of SB, determine if sex and race moderate the associations between risks and youth SB, and provide direction for targeted prevention strategies for high-risk youth.

NIH Research Projects · FY 2026 · 2023-02

Poxviruses are a large family of DNA viruses with several members capable of infecting and causing disease in humans. Whereas the most notorious member, variola virus, is the causative agent of smallpox and was eradicated from natural infection, there are still concerns about a clandestine release during a biological attack. In addition, other members of the family, such as monkeypox virus, have raised concern about epizootic infections that are capable of causing epidemics. For these reasons several poxviruses are listed as Category A priority pathogens by NIH/NIAID. Poxviruses produce two infectious forms, intracellular mature virus (IMV) and extracellular virus (EV). EV are formed by the intracellular envelopment of IMV and are critical for cell-to-cell spread, systemic infection, and pathogenesis. The long-term goal of our research is to understand the molecular mechanisms employed by orthopoxviruses to envelope, transport, and release infectious EV. Only 9 viral proteins are known to be unique to the EV form. Whereas some functions have be assigned to these 9 proteins, none of them have been shown to be a matrix- like protein and make a direct connection with the IMV form of the virus to coordinate envelopment. The immediate goal of this application is to better define the role of the putative matrix protein F13 in intracellular envelopment of EV and its relationship with the other EV glycoproteins. We propose 3 aims to better understand the function of F13: 1) Interrogate interactions between F13 and IMV surface proteins. We hypothesize that F13 acts as a matrix protein and provides a link between the outer EV membrane and the inner IMV particle and facilitates interactions with IMV at the site of intracellular envelopment, the TGN. In this aim we will further characterize interactions between F13 and IMV surface proteins. 2) Uncover cellular and viral proteins that interact with the putative matrix protein F13. We will use BioID to identify viral and cellular proteins that interact with F13 during specific stages of envelopment. 3). Determine the relationship between F13, glycoprotein content, EV cell binding, and non fusogenic dissolution for virus entry. We will utilize a panel of recombinant viruses to determine how F13 controls glycoprotein content and how this effects cell binding and entry of EV. The results obtained from these studies will provide greater insight into the molecular mechanism poxviruses use to produce infectious EV, spread cell-to-cell, and cause disease in their hosts. This information will in turn inform intelligent decisions in designing recombinant poxvirus vectors for both vaccines and oncolytic platforms.

NIH Research Projects · FY 2026 · 2023-02

Children’s neurodevelopmental disorders (NDDs), such as Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorders (ASDs), have tremendous societal, economic, and personal consequences. The incidence rates and behavioral presentation of these disorders vary by genetic sex, with a male bias. While multifactorial risks have been reported for this male bias, the mechanistic origins remain unresolved. Increasingly, epidemiological and animal studies identify a role for endocrine disrupting chemical (EDCs) exposures in the etiology of children’s NDDs. However, translating risk is difficult because early childhood exposures are increasingly characterized by low dose exposures to mixtures of EDCs, as exemplified by a recent study that found 90% of newborn children had measurable serum levels of both bisphenol-a (BPA) and perfluorooctanoic acid (PFOA) at birth. Our previous data utilizing a curated mixture (MIX) of EDCs, representative of these infant exposures, found that a low dose EDC mixture altered testosterone (T) levels in male mice at birth and resulted in male-specific behavioral changes, including reduced attention, impulsivity, and reduced sociability, phenotypes seen in ADHD and ASDs. Occurring in both rodents and humans, males experience a surge of T shortly before and after birth that is essential for nervous system development. Our data indicate that T at birth may be a sensitive target of multiple EDC mixtures. MIX exposure also marginally reduced DNA methyltransferase (DNMT1) levels and hypomethylated sensitive imprinted genes in male striatum, a region essential for these behavioral domains. DNA methylation profiles are influenced by various EDCs and suggested as a potential mechanism by which EDCs confer risk. Consequently, this proposal will investigate a hypothesized mechanistic pathway linking EDC-induced elevated T levels at birth with DNA hypomethylation in striatum as a mechanism of sex-dependent behavioral deficits. This hypothesis will be examined in a series of 3 Aims that systematically manipulate endocrine and epigenetic signals and track brain and behavioral function into adulthood. First, it will test the ability of neonatal T administration to phenocopy both the epigenetic and behavioral consequences of MIX EDC exposure. In addition, the role of EDC-induced DNA hypomethylation via DNMT inhibition will be tested using a genetically modified strain of mice with reduced DNMT1 activity. Because epigenetic mechanisms of brain development are highly region and cell-type specific, and our prior assessments used whole striatum, the proposed aims will investigate genome-wide DNA methylation profiles in neurons from ventral striatum. As an essential step forward, this proposal will integrate translational behavioral assays and advanced epigenetic techniques to inform our understanding of male vulnerability. The perinatal T surge is an understudied target of EDC neurotoxicity. The proposed studies will significantly expand our limited knowledge of how EDC mixtures alter CNS development in a sex-dependent fashion and will provide new data that are essential for risk assessment and public health protection.

NIH Research Projects · FY 2026 · 2023-02

ABSTRACT Biological sex, a nearly universal feature of metazoan species, modulates many aspects of animal development and physiology. It can also bring about resistance or susceptibility to numerous neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. Nevertheless, the extent to which biological sex influences the development and function of the nervous system, the mechanisms by which this occurs, and the functional consequences of these effects, remain largely unknown. The nematode C. elegans, with its extraordinarily well characterized nervous system, powerful experimental tractability, and conserved genetic mechanisms, provides outstanding opportunities to address these questions. C. elegans adults of both sexes share a core group of 294 neurons; superimposed on this, each sex has a complement of sex-specific neurons that implement sex-specific behavior. Recent research from our group and others has found that the influence of biological sex on the C. elegans nervous system goes far beyond these overt neuroanatomical dimorphisms. We have found not only that neurons and circuits shared by both sexes are modulated by biological sex, but also that this is a consequence of the sexual state of the nervous system itself, rather than signals from other tissues. Chemosensory function is an important target of this modulation, but multiple lines of evidence indicate that the effects of sex on shared circuits are not limited to this. These findings reveal a previously unappreciated aspect of C. elegans neurobiology and raise many interesting new questions, particularly regarding the role of biological sex in sensory integration, behavioral state, and decision-making, that these studies will address. Further, recent results have indicated that, at a molecular level, the internal representation of biological sex is surprisingly flexible, such that the sexual state of individual neurons may be responsive to both developmental and environmental signals. We will study the functional significance of this flexibility as well as the regulatory programs that underlie it, which involve a novel long non-coding RNA that may be part of a conserved, cell-autonomous developmental timing mechanism. Together, these studies will provide new insight into the ways in which biological sex interacts with developmental and physiological programs to bring about sex-specific cellular, circuit, and behavioral features. As such, they will provide an important framework for understanding how these poorly understood mechanisms operate in more complex animals, including humans. In turn, this will help provide insight into how sex-typical features of the human brain could confer protection or susceptibility to a variety of nervous system disorders.

NIH Research Projects · FY 2026 · 2023-01

Promoting Social Connection to Prevent Late-Life Suicide Older adults have high rates of suicide and projections indicate subsequent cohorts will usher in even higher rates. We can expect an increase in suicide deaths among older adults in coming decades. However, there are no evidence-based interventions to prevent suicide deaths in later life, and scant data support strategies to prevent suicide deaths at any age. Social disconnection is a promising intervention target for late-life suicide prevention, but it is not known whether targeting social connection is an effective strategy to prevent suicide in later life. The objective of this R61/R33 proposal, in line with NIMH priorities of reducing suicide and understanding mechanisms, is to test whether a behavioral intervention—Social Engage Coaching (S-ENG)—reduces suicide risk in later life (clinical outcome) via social connection (target mechanism). We propose a two-phase experimental therapeutics project with multimodal assessment of objective and subjective indicators of social connection (via smartphone assessments). The R61 is a single-arm trial of S-ENG (n=30) with 1 week of smartphone-based target assessment at baseline, 8-weeks, and 16-weeks. The R33 is an RCT (S-ENG vs. eCAU; n=120) with longer duration follow-up to test clinical impact (20-weeks). Subjects are lonely older adults in Senior Living Communities (SLCs) who endorse suicide ideation. Study conditions are S-ENG (10 individual coaching sessions) and enhanced usual-care in SLCs (eCAU; exposure to SLC milieu with geriatrician medical directors). Our first aim for the R61 phase is to test target engagement (social connection). We hypothesize that S-ENG will be associated with increases in four indices of social connection. Our go/no-go criteria will determine if we move to the R33 phase: At least two indices of social connection must evidence clinically meaningful improvement—one objective and one subjective. If go/no-go criteria are met, we will address two aims for the R33 phase. First, to confirm target engagement in a randomized trial. We hypothesize that S-ENG (vs. eCAU) will be associated with greater increases in social connection. Second, to examine clinical and functional indices of reduced suicide risk. We hypothesize that S-ENG (vs. eCAU) will be associated with greater improvement in suicide ideation and quality of life at 20-week follow-up and improvement in social connection at 16-weeks will be associated with reduction in indices of suicide risk. A confirmatory efficacy trial will follow this study. Promoting social connection to prevent suicide is an under- studied but promising strategy to address mental health and well-being in later life.

NIH Research Projects · FY 2026 · 2022-12

Post-traumatic stress disorder (PTSD) is a highly prevalent and debilitating disorder. Despite efforts to characterize PTSD pathophysiology, no biomarkers have been established to aid in diagnosis, treatment development, and prediction of treatment response. New evidence poses that PTSD is mediated by dysfunctional discrimination of context/cues in both threat and reward processing, involving the hippocampus, nucleus accumbens, amygdala, and prefrontal cortex. Still, the contextual component, or the formation of mental boundaries of the environment (mental representations) that delineate threat/safety and reward/non-reward cues/signals within a single environment, and the neural circuits of these processes are yet to be studied in PTSD where contextual processing is often impaired. I have developed two virtual reality (VR) tasks to examine threat and reward discrimination, to assess the underlying mechanisms of learning valence discrimination within an environment using location-specific information. Briefly, the task used for this study consists of neutral (CS-) and threat or reward (CS+) areas, within a single environment, and participants must use spatial information to learn to discriminate between both areas. The task is designed to reveal brain regions involved in learning locations predictive of environmental reward. This research proposal aims to investigate brain activity differences between patients with PTSD (n=80), trauma-exposed controls without PTSD (TE; n=80), and healthy controls (HC; n=80). Functional magnetic resonance imaging (fMRI) during the VR paradigm will be used to clarify the neural mechanisms underlying threat and reward learning and discrimination processing across groups. Multiple levels of assessment will include multimodal MRI, coupled with peripheral measures of arousal (e.g., Skin Conductance Response), eye-tracking, and subjective ratings of learning. This is a first step to clarify the process of threat and reward discrimination learning within an environment, particularly to elucidate if the neural signatures are specific to valence signaling or to PTSD psychopathology in general. In the long term, this research will shed light on the specific role of brain areas needed for discrimination learning within an environment which will advance the development of effective diagnostics and treatments for PTSD and other psychopathologies.

NIH Research Projects · FY 2026 · 2022-12

Each year in the U.S., ≥20,000 women and 14,000 men are affected by HPV-related cancers, including cervical and oropharyngeal cancer. However, in 2020, only 59% of U.S. adolescents aged 13-17 were up-to-date with guideline recommended HPV cancer prevention, with even lower rates for 11–12-year-olds, the recommended age group for HPV cancer prevention. Workflow enhancements that enable nurses to deliver cancer prevention strategies to families seeking such measures, with parent/patient consent, have proven effective in inpatient settings for other preventive interventions. However, they have not yet been evaluated for the prevention of HPV-related cancers in primary care settings. Also, the ways in which organizational readiness for change (resources, motivation, staff attributes, leadership support) moderate the effect of these workflow enhancements has not been studied. We have developed a successful online, interactive, communication education program that will be adapted to train nurses and staff alongside physicians on HPV cancer prevention. We propose testing workflow enhancements for guideline recommended HPV cancer prevention in Western New York and assessing which provider and practice factors moderate the effect of these enhancements. This setting includes a diverse group of rural, urban, and suburban practices, and data infrastructure and analytics that allow practices to evaluate HPV cancer prevention in real time. Our aims are: Aim 1: Apply mixed methods (in-depth interviews and practice surveys) to identify provider- and practice-level barriers and facilitators to implementing workflow enhancements for guideline recommended HPV cancer prevention; Aim 2: Using a 2-arm cluster randomized trial, we will assess the effectiveness of workflow enhancements + HPV communication education (intervention arm) relative to HPV communication education alone (control arm) on guideline recommended HPV cancer prevention for 11-17 year-olds. A secondary aim is to measure the implementation of workflow enhancements using surveys; Aim 3: Measure costs and cost-effectiveness of the interventions. If successful, this study will add a deep understanding of how to make workflow enhancements effective in primary care to reduce HPV-related cancers.

NIH Research Projects · FY 2026 · 2022-12

PROJECT SUMMARY Chronic pain is highly prevalent and costly to individuals and society. Once chronic, pain is very hard to treat or reverse making early identification key for prevention and early treatment to improve long-term outcomes. Recent brain imaging data from our lab as well as others have provided evidence that the structural properties of the limbic brain, such as the volume and/or shape of nucleus accumbens (NAc), amygdala, and hippocampus can predict the likelihood of “chronification” of low-back pain after an episode of sub-acute low back pain (SBP) (duration 6-12 weeks). The role of the limbic brain in predicting vulnerability or resilience to chronic pain fits with the general understanding that chronic pain is partly due to an interaction between peripheral nociceptive input and vulnerable limbic brain circuitries, which are known to mediate the negative affective and aversive learning associated with chronic pain. Hence, understanding how the structural properties of the limbic brain circuitries predict risk or resilience to chronic pain in humans is innovative and has high translational significance. However, the brain imaging studies of the transition to chronic pain remain very limited in number and scope and, hence, we still have a poor understanding of the exact limbic circuitry and structural connectivity underlying risk of or resilience to chronic pain. To date, only one small study reported that local white matter properties can predict resilience to pain chronification. Furthermore, no brain imaging study of pain chronification investigated the role of important biological variables like sex or established clinical phenotypes like the presence or absence of a neuropathic component of the low back pain. Therefore, the overarching aim of this proposal is to use state of the art structural mapping techniques to study local anatomical properties (e.g. volume, shape, neurite orientation) and white matter connectivity to identify biomarkers for pain chronification. We will use 2 different approaches, one based on biologically plausible hypotheses, and one based on data driven hypotheses identified in our preliminary data. In addition, the proposal will explore the effect of sex and clinical low-back pain phenotypes on theses biomarkers. We will recruit SBP patients and obtain brain anatomical and multi-shell diffusion weighted imaging data at baseline and at 6 months follow-up. Patients will be classified as recovered or persistent after the follow-up visit. Aim 1 will test baseline local and global gray, white matter differences between recovered and persistent patients in areas of the limbic brains like NAc, amygdala, hippocampus, anterior cingulate cortex, and white matter pathways known for their role in chronic pain (e.g., the cingulum bundle and internal capsule) and assess whether these measures change at follow-up. Aim 2 will use a data- driven approach to examine global and local gray, white matter properties predicting risk or resilience to chronic pain. Finally, aim 3 will explore the effect of sex and presence or absence of radiculopathy symptoms on the biomarkers identified in Aims 1 and 2.