University Of Rochester

NIH Research Projects · FY 2025 · 2022-07

PROJECT SUMMARY: The goal of this Chemistry-Biology Interface (CBI) training program is to prepare 10 predoctoral students to become next-generation scientists in the biomedical sciences. This goal will be achieved through recruiting top students and training them in cross-disciplinary research, critical thinking, writing and communication, rigorous experiment design and interpretation, and responsible conduct of research. Other distinctive components of the program are: a) a course on cutting-edge research at the CBI, b) workshops on entrepreneurship, intellectual property management, and networking, and c) participation in Peer-Led Team Learning (PLTL) experiences, which will further enrich the skillset and professional preparation of the trainees. The program will directly benefit from the close research relationship and physical proximity between Arts, Sciences, & Engineering (AS&E) and the School of Medicine and Dentistry (SMD) at the University of Rochester, and its established record in innovation and entrepreneurial translation of scientific discoveries into new businesses. The program includes 27 outstanding preceptors selected from six departments within AS&E and SMD, all of whom have a strong record of intra- and interdepartmental interactions in research and mentoring activities. A central theme of the program, as shared by the research interests of the preceptors, is the development of fundamental knowledge and strategies to support the generation, development, and delivery of new therapeutic agents and modalities for the prevention and treatment of human diseases. Trainees will conduct research in one of the four main areas around this unifying theme: Synthetic Chemistry, Drug Discovery & Delivery, Drug Target Identification and Sensing, and Structure and Function of Biomolecules & Biomaterials. The Program Director and two Deputy Directors will be aided by a Steering Committee comprising three additional faculty members. The CBI trainees will be drawn from the strongest students in the participating departments, with a particular emphasis on expanding trainee diversity through outreach activities, recruiting a diverse pool of applicants, and retaining and nurturing students in the program. New CBI trainees will start in Year 2 of their graduate studies and will participate in the core CBI courses, a course on responsible conduct of research, and a course on effective writing and communication. All trainees will participate and contribute to a host of CBI-sponsored enrichment and synergistic activities, including professional development workshops, an annual retreat, and monthly CBI lunches. In Year 4 of their PhD program, trainees will serve as PLTL workshop leaders for CBI courses, continue in professional development, and present a talk at the CBI retreat. Trainees also will complete and defend their theses supervised by one of the CBI preceptors. It is expected that students completing this program will be exceptionally well prepared to pursue a variety of careers in the life and biomedical sciences. Success in this program will also be determined by increased diversity of trainees and in the pool of applicants.

NIH Research Projects · FY 2025 · 2022-07

ABSTRACT- Aortic aneurysm (AA) is characterized by localized abnormal dilatation or bulging of aorta due to weakened vessel wall. AA occurs in different sections of aorta, such as thoracic AA (TAA) and abdominal AA (AAA). The rupture of aneurysm has high mortality and requires immediate surgical repair. Aortic smooth muscle cells (SMCs), by regulating aortic contractility and elasticity, are critical for reducing aortic wall stress in response to the pulsatile high-pressure blood flow from the heart. SMC loss and dysfunction can cause medial degeneration and contribute to AA development. cAMP and cGMP, are important regulators of SMC contractile function and vessel wall structural integrity. Cyclic nucleotide phosphodiesterases (PDEs), by catalyzing cAMP and/or cGMP degradation, play crucial roles in specific modulation of cyclic nucleotide signaling and have been proved to be promising drug targets in highly specific pharmacological interventions. Recently, a few sporadic lines of clinical and experimental evidence have suggested that stimulating cAMP and cGMP signaling may have different, even opposite, effects on AA and/or dissection. In this application, we will focus on two PDE1 family isozymes and AAA. Previous studies from our lab and others have shown that among three PDE1 members (1A, 1B, and 1C), PDE1A and 1C are two major PDE1 isozymes expressed in contractile and/or synthetic SMCs. PDE1A and 1C primarily hydrolyze cGMP and cAMP, respectively, in SMCs. We recently found that in the human and mouse aortic tissues, PDE1C is highly induced in synthetic SMC-like cells of AAA compared to normal controls. PDE1A is expressed in SMCs of both normal and AAA tissues. Interestingly, targeting PDE1A and 1C likely have opposing effects in AAA: PDE1A deficiency aggravates while PDE1C deficiency attenuates experimental AAA in mice. PDE1A regulates the contractility of contractile SMCs, and is important for synthetic SMC survival. However, PDE1C induction promotes SMC phenotype switching, senescence, and death. Interestingly, the protective effects from PDE1C inhibition overcome the detrimental effects from PDE1A inhibition in SMCs. These mechanistic differences may be responsible for their functional differences in AAA. Thus, we hypothesize that chronic PDE1C inactivation suppresses SMC phenotype switching, senescence, death, and ECM degeneration (e.g. MMPs), thus attenuating experimentally induced mouse AAA. In contrast, chronic PDE1A inactivation causes SMC contractile dysfunction and increases aortic wall stress, as well as promotes synthetic SMC death and ECM degeneration, thus exacerbating experimentally induced AAA. Inhibiting PDE1A/1C together produces a protective effect against AAA because the effect of PDE1C inhibition overrides the effect of PDE1A inhibition. We will study the regulation, function and mechanism of PDE1A or 1C in AAA and evaluate the pharmacological effects by targeting PDE1 in AAA. The translational significance of this study is highlighted by the fact that PDE1 pan inhibitors have been proposed for clinical trials to treat various diseases, suggesting an urgent need to investigate the potential outcomes of targeting PDE1 isozymes in AA.

NIH Research Projects · FY 2024 · 2022-07

Project Summary Fetal alcohol spectrum disorders (FASD) are the most common cause of non-heritable, preventable mental disability, occurring in almost 5% of births in the U.S. There is no known cure for FASD, and its mechanisms remain unclear. A wide range of cognitive, behavioral, and physical impairments have been reported in FASD, including deficits in behaviors related to the cerebellum. These changes in behavior may arise from ethanol's effects on the cellular level. The sole output of the cerebellum, Purkinje cells, as well as microglia, the immune cells of the Central Nervous System, are both impacted by developmental ethanol exposure. Reduced numbers of both neurons and microglia, as well as alterations in Purkinje cell excitability and firing have been reported. After developmental ethanol exposure, microglia display a phenotype associated with immune activation and release pro-inflammatory factors. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists can block this immune activation and have been shown to attenuate some of the inflammatory responses in microglia and reduce Purkinje cell loss in rodents. This suggests that microglia may be a therapeutic target in FASD. Microglia are known to shape neuronal circuit development and connectivity in the cerebellum, which is linked to microglial structural dynamics. How ethanol affects these dynamics and how that impacts microglia- Purkinje cell interactions is unknown. Additionally, it is not yet known when these changes occur and how they are maintained or progressively altered into adulthood. Elucidating how ethanol-induced changes in microglia mediate some of the pathological changes in cerebellar Purkinje cells may be critical for understanding the onset of FASD pathology. Furthermore, modulating microglial survival and activity during ethanol exposure through a PPAR-γ agonist may provide some answers and potential therapies for these diseases. Thus, I hypothesize that ethanol induces neuroimmune changes in cerebellar microglia that alter their dynamics and interactions with Purkinje cells, and reducing microglia-mediated inflammation through a PPAR-γ agonist mitigates the pathological effects of ethanol. To test this hypothesis, I will pursue two aims using a mouse model of FASD. The first will investigate how developmental ethanol and a PPAR-γ agonist affects microglial phenotype over time using in vivo two-photon imaging of microglial dynamics, immunohistochemistry, and quantitative real time PCR. The second will determine if Purkinje cell and microglia interactions are affected throughout life by developmental ethanol exposure and PPAR-γ agonist administration with two-photon imaging, immunohistochemistry, and electron microscopy. These experiments will elucidate the effects of cerebellar microglia on Purkinje cells in the cerebellum after developmental ethanol exposure and assess microglia as a potential target to mitigate disease pathology in a mouse model of FASD.

NIH Research Projects · FY 2025 · 2022-07

There is compelling evidence for a critical role of the maternal and infant gut microbiome in early infant brain neurodevelopment. Temporal milestones in postnatal infant gut microbiome development align with changes in early infant brain development, suggesting functional relationships between these two pivotal events. The premise of our proposal is based on a wealth of studies and new preliminary analyses reported below linking maternal prenatal anxiety (PNA), a prominent prenatal maternal risk factor, and child neurodevelopment. We hypothesize that the prenatal maternal microbiome and its influence on newborn neurodevelopment is shaped by PNA, and that early infant cognition is determined by mother-to-infant microbiome transfer, postnatal development and biosynthesis of microbiota-derived neuroactive metabolites (NAMs). Our study is framed by a proposed developmental model that includes two major components; prenatal anxiety and developmental phase trajectories of the infant gut microbiome. The proposed model has scientific as well as practical strengths, as it leverages a wealth of existing data collected as part of a large, prospective longitudinal and diverse pregnancy cohort that has been followed from the first trimester through the child’s 4th year, with extensive longitudinal characterization of prenatal exposures, child microbiome and other key biological samples, and child neurodevelopment assessed longitudinally that will enable important and previously neglected incorporation of potential confounds. We use these components to test the central hypothesis that neurodevelopment is dependent on age-driven biosynthesis of NAMs through the postnatal period of infant gut-microbiome (IGM) development. In Aim 1, we use metagenomic analysis of the prenatal maternal vaginal microbiome (MVM) to identify species and functional biosynthetic pathways for NAMs associated with PNA. We also assess the potential transfer of maternal anxiety through the initial colonization of the infant gut microbiome by an anxiety “imprinted” MVM. In Aim 2, we use metagenomic and metabolomic analyses to determine the association between key stages of IGM development and differential synthesis of NAMs over the first year, attending to confounds and competing exposures, most notably, maternal diet and infant feeding. In Aim 3, we apply this rich data to predict neurocognitive assessments from age 1 to 4 years to formally test the temporal relationship between microbiome phase and neurodevelopment in the first year of life and durability of the microbiota- neurodevelopment relationship through 4 years of age. The scientific impact of the study will be on advanced understanding of the role of prenatal exposures; documenting sources of between- and within-individual differences in the IGM through the first years of life; identifying NAMs with a possible mechanistic role in the MGB axis; documenting a potentially broad and persistent impact on neurodevelopment.

NIH Research Projects · FY 2026 · 2022-07

Opioid use disorder (OUD) is a national crisis that affects public health and economic stability. Recent years have witnessed the highest overdose death toll since 2017, with a 50% increase in overdose mortality rate and limited understanding of underlying contributing factors. Economic disruption from 2020-2022 fundamentally altered employment patterns, healthcare access, and amplified pre-existing economic conditions in communities. Widespread business and school closures persisted through mid-2021 and created substantial unemployment challenges. In response, multiple economic stabilization policies were implemented to offset economic disruption including stimulus payments, child tax credit, more generous unemployment and food assistance, and eviction moratoria. Healthcare policies such as continuous Medicaid coverage and medication for OUD (MOUD) policies aimed to increase access to care and treatment. While economic and social disruption can influence OUD trajectories, it remains unclear which components of these policy responses and resulting economic and healthcare changes differentially affected individuals with existing or elevated risk of OUD. Additionally, the uneven distribution of impacts across communities requires further investigation. The goal of this study is to leverage comprehensive claims and electronic health data, capturing nearly half of the U.S. population from 2018 through 2025, to test our hypothesis that economic and employment disruption escalate the prevalence of OUD and related adverse outcomes. We further hypothesize that policies enacted in recent years (e.g., take-home methadone, telemedicine buprenorphine, the MAT Act, continuous Medicaid) increased access to treatment and reduced related harms. Building on our extensive existing work, we use quasi-experimental methods to measure adverse OUD-related outcomes using existing records capturing longitudinal OUD at the individual patient and community levels. In Aim 1, we evaluate whether the increase in OUD mortality during 2020 was worse in communities with higher pre-existing opioid-related challenges or greater employment disruption. In Aim 2, we evaluate longer-run OUD trajectories for communities that experienced greater degrees of economic loss and differing degrees of policy response over five years. We further examine OUD outcomes and leverage individual longitudinal data for important subpopulations (e.g., adolescents, older adults). At the successful completion of the proposed research, the expected outcomes are evidence-based insights into economic, clinical, and policy factors that influenced OUD diagnoses, treatment initiation and adherence, healthcare utilization, and mortality outcomes. This research will support NIH NIDA's goals by identifying economic and clinical factors that impact OUD and populations experiencing barriers to care access.

NIH Research Projects · FY 2025 · 2022-07

PROJECT SUMMARY Sepsis is a life-threatening systemic inflammatory condition with dysregulated host responses to an infection. Although key hyperinflammation-based organ dysfunctions that drive disease pathology have been discovered, the syndrome is often difficult to recognize, and current published prognostic criteria poorly identify those destined to die with the condition. Continued failure of our efforts in improving disease prognosis in sepsis is mainly due to substantial heterogeneity in the patient response. Even with similar age, sex, and medical comorbidities, there is a substantial heterogeneity in the patient mortality despite excellent supportive efforts. Here, (1) we discovered that a subpopulation of CD49c+ neutrophil arising in critically ill patients independently predicts mortality from sepsis. (2) We further found that the neutrophil subpopulation associated with septic fatality dramatically upregulated gene expression of the complement component C1q. (3) Importantly, neutrophils from septic survivors expressed higher levels of C1q protein, while deceased patients failed to maintain C1q expression in their neutrophils. (4) In mouse sepsis models, blocking C1q with neutralizing antibodies or conditionally knocking out C1q in neutrophils led to a significant increase in septic mortality. (5) Treatment of septic mice with C1q drastically increased the survival. Based on these preliminary observations, our overarching hypothesis is that neutrophil C1q is a reliable prognostic biomarker of septic mortality. It is hypothesized further that apoptotic neutrophils release C1q to control their own clearance in critically injured organs during sepsis. Thus, C1q is a druggable target for attenuation of inflammatory damage to septic patients with resulting improvement in survival. In Aim 1, we will determine the correlation between C1q expression in peripheral blood neutrophils and sepsis mortality in ICU patients. Aim 2 will investigate the mechanisms by which C1q regulates the resolution of sepsis, including C1q-dependent phagocytosis of apoptotic neutrophils and differentiation of macrophages. Aim 3 will investigate mechanisms underlying the heterogenous C1q expression. Aim 4 will determine the effects of recombinant C1q and its mutant variants on the survival of septic mice. Taken together, this proposal addresses mechanisms regarding how the dysregulated host response threatens patient survival and offers a molecular target for dampening the destructive arms of the hyperinflammatory response while promoting disease resolution and tissue recovery.

NIH Research Projects · FY 2025 · 2022-07

His-Bundle Corrective Pacing in Heart Failure PI: Valentina Kutyifa, MD, PhD, Roderick Tung, MD University of Rochester Medical Center, Rochester, NY, and University of Chicago, Chicago, IL Heart failure (HF) is a significant chronic health issue with the most prevalent cause of preventable hospitalizations, linked to insurmountable health care costs. Cardiac resynchronization therapy with a defibrillator (BIV-CRT) has been shown to improve outcomes of HF patients with severely reduced left ventricular function, however it was shown to be less beneficial in a subset of patients with right bundle branch block (RBBB) ECG morphology. His-bundle corrective pacing for cardiac resynchronization (His-BIV) is an emerging technology that could be especially helpful in patients with RBBB ECG pattern in whom BIV-CRT is less optimal. However, data are limited on the efficacy and on the mechanism of action of His-CRT as compared to BIV-CRT. Therefore, we propose a randomized mechanistic clinical trial to prospectively evaluate the efficacy and mechanisms of His-CRT vs. BIV-CRT on electrical and mechanical resynchronization in 120 HF patients with severely reduced left ventricular function, wide QRS, and RBBB ECG morphology. The primary aim of this trial is to prospectively evaluate whether His-CRT is more effective improving LV ejection fraction (LVEF) at 6 months than BIV-CRT in HF patients with RBBB. Our secondary aim includes assessing the mechanism of benefit with His-CRT vs. BIV-CRT by evaluating changes in ECG biomarkers, serum biomarkers, and echocardiography biomarkers. Our tertiary aim is to evaluate the temporal development of the biological processes of electrical and mechanical resynchronization with His-CRT vs. BIV-CRT, including temporal changes of ECG biomarkers, NT-proBNP levels, and improvement in functional status and quality of life at 6, 12, and 24 months following device implantation with His-CRT as compared to BIV-CRT. Safety assessment will include serious adverse events, implant procedure-related complications, and evaluation of device and implanted lead parameters during follow-up. Study population will include 120 HF patients with RBBB randomized to His-CRT vs. BIV-CRT in a 1:1 ratio. We will be collecting echocardiography data at baseline and 6-month, and serial ECG data at 6, 12, and 24 months, analyzed by central core laboratories. High-volume, experienced centers with implanted device track records and research infrastructure will participate, with implantation of His-CRT and BIV-CRT performed according to standard of care.

NIH Research Projects · FY 2025 · 2022-07

ABSTRACT Interactions of stem cells with their surrounding microenvironment are known to be essential for both normal development, and for sustaining self-renewing adult stem cells, such as the hematopoietic stem cells (HSCs). Since cancers often hijack developmental signals for their progression, it is likely that niche-driven signals that sustain HSCs also influence the growth of leukemias arising from mutations in HSCs and early hematopoietic progenitors, such as acute myeloid leukemia (AML) and blast crisis chronic myeloid leukemia (bcCML). Despite recent advances in treatment, ~75% of AML patients still succumb to the disease, highlighting the need to better understand mechanisms of disease progression. While much work has focused on leukemia cell-intrinsic regulators, the role of the microenvironment in disease establishment and propagation is poorly understood. Our overall goal is to define the role of leukemia-niche interactions on myeloid leukemogenesis. In support of a functional role of the niche in disease progression, our work has shown that adhesive interaction of AML with endothelial cells is critical to maintain the therapy-resistant leukemia stem cells (LSCs). Since osteoprogenitors expand in the leukemic bone marrow, it is possible that these osteoprogenitors also create a cancer-supporting microenvironment. As an alternate to identifying niche-driven signals promoting leukemogenesis, we determined cell surface antigens expressed on LSCs that can act as receptors for these signals using our recent in vivo genome-wide CRISPR screen. The 140 cell surface genes identified by our screen included those known to promote leukemia growth (e.g., Cd47, Cd157) and novel regulators of leukemia progression. To focus on signals likely to be cancer-specific, we selected a subset of novel cell-surface regulators with 2-fold higher expression in human bcCML LSCs compared to normal HSCs in our new RNA-seq dataset. Of these, the taurine transporter SLC6A6 (TauT) is of particular interest since its high expression is associated with poor prognosis in AML (TCGA). Using TauT-/- mice, we find that genetic loss of TauT significantly impairs leukemia growth in vivo as compared to TauT+/+. Our key preliminary data show that enzymes for synthesis of the non-essential amino acid taurine are upregulated with osteolineage differentiation of bone marrow stromal cells, and taurine is secreted in the environment. Based on our pilot studies showing taurine synthesis by osteoprogenitors, a requirement for LSC TauT expression for cancer growth, and expansion of osteoprogenitors in AML, we hypothesize that osteoprogenitors sustain LSCs and support leukemia progression by secreting taurine. We will now test if TauT expression is essential for disease progression in mouse models of disease, as well as for the propagation of primary human leukemias. We will also determine if osteoprogenitors form a supportive microenvironment for leukemia progression by secreting taurine. Collectively, these studies will establish the role of taurine from the bone marrow osteolineage niche in myeloid leukemia progression. In the long term this work may lead to development of new therapies targeting microenvironmental signals supporting cancer cells.

NIH Research Projects · FY 2025 · 2022-07

Several reports have highlighted the presence of cognitive and psychiatric manifestation associated with severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) infection. Autopsy and CSF studies suggest that COVID-19 associated injury of the central nervous system derives from a combination of coagulopathy, endothelial injury with subsequent alteration of the blood brain barrier, infection and activation of microglia and macrophages followed by release of cytokines. The neurocognitive symptoms may persist in the subacute phase of the recovery while it remains to be determined what the long-term effects will be. The documented involvement of the brain microcirculation by SARS-CoV-2 infection, is likely to contribute to cerebral small vessel disease (CSVD). CSVD pathogenesis is not fully understood and is likely multifactorial. Among the factors that may link COVID-19 to CSVD are direct injury to endothelial cells, platelets and leukocyte activation. These processes can then lead to an altered blood brain barrier (BBB) with increased crossing of activated monocytes into the brain parenchyma. CSVD is clinically quite relevant since it is a leading cause of cognitive impairment and dementia. There are several unknowns that justify the implementation of this proposal. We do not know whether there is an increased burden of CSVD in those older adults who have been infected by SARS-CoV-2 and whether there will be an accelerated progression of CSVD in this population. It is also unclear whether the initial endothelial dysfunction induced by the infection may persist in a milder form that is sufficient to maintain a chronically altered cerebral microcirculation. If this occurs, it will contribute to several neurodegenerative disorders including vascular dementia and Alzheimer disease. In this proposal, we will focus on older individuals aged between ≥65 and 80, who were infected with SARS- CoV-2 at least six months prior to study enrolment, who were hospitalized but not admitted to a critical care unit and did not have a significant neurological history prior to SARS-CoV-2 infection. We will match by age and sex, 150 COVID-19 patients with 150 controls who will be followed for two years. CSVD will be assessed via state- of the-art magnetic resonance multimodality imaging. We will address the specific aims listed below. AIM 1: To assess the severity and progression of CSVD in individuals previously infected by SARS-CoV-2 compared to age and sex matched controls. Sub-AIM 1: To assess the impact of SARS-CoV-2 on brain microstructure integrity. AIM 2: To assess in individuals previously infected by SARS-CoV-2, compared to controls, changes in cerebrovascular function and its association to peripheral makers of endothelial function and altered blood brain barrier. AIM 3: To assess changes in cognitive performance and its relation to imaging metrics in individuals previously infected by SARS-CoV-2 compared to controls.

NIH Research Projects · FY 2024 · 2022-07

Electrical stimulation has been shown to be a useful technique for delivering information to the brain from brain-machine interfacing technology. The brain is remarkably capable of learning to interpret such information, most notably demonstrated by the success of cochlear implants. Learning to translate stimulation into useful information can be attributed to neural plasticity, yet little is known about the relationship between localized electrical stimulation and subsequent effects on brain regions distant from the simulation site. In the specific context of stimulating cortical gray matter, or intracortical microstimulation (ICMS), a common assumption is that post-stimulation effects remain localized to a small volume of neurons near the stimulating electrode. However, there is evidence that suggests the effects can spread substantial distances. Prior work in my lab has shown that subjects can learn to interpret ICMS delivered to four different electrodes in the primary somatosensory cortex (S1) as instructions to perform four different arbitrarily- assigned movements. My preliminary studies using that dataset suggest that ICMS delivered in S1 can have two types of effects on neurons in distant cortical areas: 1) ICMS pulses can directly elicit spikes in neurons from both ventral premotor cortex (PMv) and primary motor cortex (M1) – either antidromically, monosynaptically, or oligosynaptically – which I term “direct driving”. 2) Other neurons not directly driven by the ICMS pulses may nevertheless fire differently between trials instructing the same movements with only trains of ICMS pulses versus with only visual cues, which I term “instruction-modality dependent modulation”. Thus, the effects of ICMS may extend to parts of the cortical network more distant than previously appreciated. I propose to investigate the effects of ICMS instructions for arbitrarily-associated movements delivered in S1 on several distant cortical areas involved in motor control. Specifically, I will study effects in seven frontal and parietal regions: pre-supplementary motor area, dorsal premotor cortex, ventral premotor cortex, rostral primary motor cortex, caudal primary motor cortex, anterior intraparietal area, and dorsal posterior parietal cortex. Aim I will examine which of those cortical areas contain neurons that are directly driven by ICMS pulses delivered in S1. Aim II will examine which of those cortical areas contain neurons that show instruction- modality dependent modulation. The proposed studies will show the extent to which ICMS in S1 modulates distant parts of the cortical network, and how such modulation develops over time as subjects learn to use the ICMS as instructions to perform arbitrarily-associated movements. That information can be used to design inputs to cortex from brain-machine interfacing technology that is clearer to the subject and encourages healthy plasticity to reduce cognitive demand during the training process. Those improvements serve to benefit patients with diseases of the nervous system that can be treated with brain-machine interfacing technology including stroke, sensory neuropathies, or head trauma.

NIH Research Projects · FY 2025 · 2022-06

Background Cancer cachexia (CC) is a systemic, metabolic wasting syndrome featuring body weight loss due to skeletal muscle and adipose tissue wasting. CC is suffered by ~80% of cancer patients that causes reduced performance status, intolerance to chemotherapy, and increased mortality. This debilitating condition is poorly understood and has no effective treatment. If CC therapy existed, it would improve treatment responses, increase quality of life, and prolong survival. With 50 years of study, the field has focused on defining pathways that promote atrophy in the end-organs most affected by cachexia. While this work has been fruitful, it has not led to identification of the upstream mediators of CC, nor has it generated effective therapies. There is an urgent need for high-quality discovery science and more detailed clinical phenotyping. We have created a virtual institute comprised of diverse, international, multidisciplinary scientists and clinicians with expertise in cancer, metabolism, neuroendocrine function, immunology, human metabolic diseases, preclinical models, and clinical phenotyping. We hypothesize that CC is driven by tumor-intrinsic factors that activate neurohormonal sickness pathways, which then induce anorexia, metabolic dysfunction, and tissue atrophy. Methods Our approach involves sophisticated measures of host-tumor interactions including innovative investigation of (1) systemic metabolic flux in mice using isotope tracing, imaging mass spectroscopy, dynamic nuclear imaging, and dietary and pharmacologic interventions; (2) cellular components and secreted factors from the tumor microenvironment using imaging mass cytometry, patient-derived organoid xenografts, microbial toxins, and CRISPR-based manipulations; (3) central pathways regulating appetite, behavior, and peripheral organ metabolism using human metabolic phenotyping, optogenetic, and pharmacological methods. We will perform the largest, most comprehensive observational study in CC subjects to thoroughly define CC subtypes and their clinical biomarkers using epidemiologic tools, novel image segmentation algorithms, and cluster analyses. Project Goals Our vision is to develop mechanistically informed treatments for cancer cachexia (CC) to improve quality of life and life expectancy for patients. Working as a multidisciplinary team with expertise in basic science, clinical research, and epidemiology, we will establish a therapeutically relevant classification of molecular and clinical subtypes of CC. We will build therapies to normalize metabolism and neuroendocrine dysregulation in CC to enable successful anti-cancer treatment and systemic recovery for patients. In 5 years, we will have laid the foundation for a new generation of CC treatment trials and strategies that will, for the first time, deliver practice-changing evidence for improved outcomes for patients with cancer who are at risk of or suffer from CC.

NIH Research Projects · FY 2025 · 2022-06

While fewer older adults are dying from heart disease and cancer, deaths from Alzheimer’s disease and related dementia’s (ADRD) have risen 145% in the last two decades. Progress to find a solution to this public health crisis has been slow. To help accelerate progress in the understanding, treatment, and prevention of ADRD, this application is for establishment of an NIA Institutional National Research Service Award (T32) titled, “University of Rochester Aging and Alzheimer’s Disease Training Program (UR-AADTP)”. Consistent with longstanding and established strengths at the University of Rochester in foundational and translational research on aging and ADRD, our goal is to accelerate the development and application of strategies to reduce the morbidity and mortality associated with ADRD. We seek support for six predoctoral fellows (3 slots in year 1) in basic and translational research programs who will undergo an innovative curriculum that emphasizes interdisciplinary science and informs their training through interactions with people affected by dementia and their health care providers. The UR-AADTP’s primary objective is to develop a cadre of early-stage scientists with the depth and breadth of knowledge, skills, appreciation, and experience necessary to establish careers as independent investigators in the area of dementia research; to work in an interdisciplinary environment designed to aggressively translate research to practice; and to reduce the toll of cognitive disorders in later life. The URAADTP T32 has these specific aims: Aim 1: We will recruit a group of highly qualified predoctoral trainees who are committed to careers in aging research, retain them until their training is complete, and support their successful transitions to postgraduate academic positions. Aim 2: Through courses, seminars and workshops, and mentored research experiences, we will provide URAADTP T32 trainees with a firm foundation in the theories and methods of basic and early translational aging research that are necessary for study of dementia pathogenesis and treatment development. Aim 3: By fostering interactions between trainees and faculty members trained in different theoretical and methodological approaches to aging and dementia research, we will stimulate interdisciplinary collaborations in aging research that accelerate the progress of dementia research, treatment and prevention. Aim 4: Through structured exposure to clinical settings, people affected by dementia, and the providers that care for them, trainees will appreciate the connections between research and practice necessary to accelerate the development of effective approaches to illness prevention and mitigation. Aim 5: We will rigorously evaluate the program and its participants (faculty and trainees).

NIH Research Projects · FY 2026 · 2022-06

Efferocytosis by bone marrow stromal cells and bone aging Pre-clinical studies show that senescent bone marrow-derived mesenchymal stromal (a.k.a. stem) cells (MSCs) and osteolineage cells contribute to age-dependent bone loss and bone marrow failure. Therefore, the identification of novel mechanisms that accelerate MSC dysfunction could enable mechanistic approaches to degenerative processes that impact the skeleton. While a handful of in vitro studies previously demonstrated MSCs’ ability to phagocytose apoptotic cells (efferocytosis), matrix, pathogens and metal particles, whether efferocytosis by MSCs impacts their function and bone maintenance is not known. We found that bone marrow MSCs indeed efferocytose apoptotic neutrophils in vivo. Preliminary data from adult mice with transgenic overexpression of the direct phosphatidyl serine receptor BAI1 in MSCs suggest that chronic low dose enhancement of efferocytosis by MSCs may be beneficial to skeletal health. We also found that, in aged mice, efferocytosis by MSCs is significantly increased. Moreover, transcriptional and functional preliminary data in vitro suggest that excessive efferocytosis by MSCs decreases osteoblastic differentiation and promotes senescence. Since efferocytosis is accompanied by oxidative stress and mitochondrial changes, which we previously found to modulate osteoblastic differentiation, mitochondrial disruption may mediate functional changes in MSCs that clear high numbers of apoptotic cells. Based on these data, we hypothesize that phagocytosis by MSCs is an important component of osteoimmunology; however when pathologically increased in aging, it causes MSC oxidative stress, mitochondrial dysfunction and senescence, thus contributing to bone loss. To test this, using aging and genetic models, we will 1) determine the mechanism of MSC efferocytosis; 2) define the pathogenic mechanisms induced by efferocytosis in MSCs; and 3) establish the role of efferocytosis by MSCs in normal osteoimmunology and in aged bone. Defining the role of facultative phagocytosis/efferocytosis in metabolic changes and senescence in MSC and their relevance to human aging and disease will provide innovative, actionable strategies impacting degenerative disorders that target the skeleton.

NIH Research Projects · FY 2026 · 2022-05

Project Summary: The overarching goal of this proposal, submitted in response to RFA-AG-22-020, is to adapt an existing communication tool developed by our team for use in patients with Alzheimer’s Disease or Related Dementias (ADRD) and their care partners, and to evaluate if this tool can enhance communication about cognition in the context of a cancer management decision. This proposal is important because approximately 7% of older adults diagnosed with cancer have pre-existing dementia. For older adults with ADRD and cancer, medical decision making is more complex, and integrates information about the risks and benefits of potential interventions in the context of the dual diagnoses. Limited data are available to guide the “best” approach and thus, relies on discussions about the risks and benefits of options in the context of patient and care partner goals and preferences. Unfortunately, there is no standard approach among oncology clinicians as to how to discuss cognition in the context of a cancer management decision for patients with pre- existing ADRD and their care partners. Preliminary research by the PI (Magnuson) and team suggest that cognitive impairment is prevalent in older patients with cancer and that a geriatric assessment-based communication tool can facilitate conversations about aging-related conditions, such as cognition, with older patients and their care partners. However, the intervention was not tested in patients with ADRD and did not address patient and care partner concerns about cognition in the context of cancer. Adapting this tool for patients with ADRD (adapted tool called “COACH-Cog”) may improve both care partner and patient outcomes through greater acknowledgement and support of cognitive concerns and cognitive-related goals, thereby improving goal concordant care. COACH-Cog adaptations will include: 1) brief, focused training for oncology clinicians about ADRD in the context of cancer and communication training to navigate the triadic nature of these conversations, thereby enhancing oncology clinician knowledge and supporting their decision processes; and 2) care partner and patient Communication Coaching and Question Prompt List providing knowledge, skills, and behavioral cueing for discussing their cognitive concerns and cognitive-related goals with oncology clinicians. Focus groups with key stakeholders will guide the adaptation. Subsequently, we propose to conduct a pilot, Stage I RCT (cluster randomized at physician) with older adults with a clinical diagnosis of ADRD and their care partners (N=130 dyads) to evaluate the preliminary efficacy of COACH-Cog on care partner and patient autonomy support, care partner well-being, and goal concordance in outcomes at 3 months. Our uniquely qualified, multidisciplinary team includes expertise in geriatric oncology, cognition, behavioral neurology, intervention development, communication science, biostatistics, palliative care, and care partner research. This innovative proposal will develop a pragmatic tool for improving communication about cognition in the context of cancer treatment decision making for patients with ADRD and their care partners.

NIH Research Projects · FY 2026 · 2022-05

Project Summary/Abstract T helper cells (Th1 and Th17) play an important role in bone homeostasis through regulating osteoclast (OC) formation in autoimmune diseases and OVX-induced osteoporosis. However, how these T cells interactions with bone cells disrupt bone homeostasis during aging to cause bone loss in age-related osteoporosis (AROP) remains poorly understood. We reported that TGFβ1 (Tβ1) is a major bone loss-causing cytokine in AROP. It induces lysosomal degradation of TRAF3, a receptor adaptor protein that negatively regulates NF-κB activation, in mesenchymal progenitor cells (MPCs) to directly inhibit bone formation. However, the release of active Tβ1 from resorbing bone is limited because of low bone turnover in AROP. We have identified a novel subset of CD11b+F4/80+Ly6ChiLy6G- macrophages expressing membrane-bound Tβ1 (mbTβ1), which we call MbTβ1Macs, whose numbers are increased in the bone marrow (BM) of aged mice. MbTβ1Macs also express ITGB8 which can directly activate mTβ1. MbTβ1Macs have less potential to form OCs, but significantly inhibit osteoblast (OB) differentiation. Th1 cells expressing IFN-γ and senescent/immune checkpoint PD-1 are also increased in the BM of aged mice. IFN-γ induces Ly6Chi macrophages to express mbTβ1, which in turn stimulates Th1 cells producing IFN-γ and PD-1 in vitro, associated with reduced levels of TRAF3. These effects are blocked by the FDA approved lysosomal inhibitor, hydroxychloroquine (HCQ). Our proposed studies will 1) determine if ITGB8 activates mbTβ1 in MbTβ1Macs to inhibit bone formation during aging; 2) determine if IFN- γ polarizes MbTβ1Macs, which in turn promote Th1 cell senescence with enhanced production of inflammatory factors via Tβ1 induction of TRAF3 lysosomal degradation in aged mice; and 3) evaluate if our recently patented bone-targeted HCQ, with dual anti-resorptive and anabolic effects in an OVX-induced osteoporotic model, can prevent and treat AROP and low level chronic inflammation during age by blocking the reciprocal interactions between macrophages and Th1 cells. Completion of the proposed studies will identify novel mechanisms to explain the disruption of bone homeostasis during aging through reciprocal interactions between macrophages and Th1 cells, in which this novel subset of macrophages inhibits bone formation and causes BM low-level chronic inflammation by stimulating Th1 cells to produce inflammatory factors. Importantly, it will provide proof of principle that a bone-targeted HCQ may be a novel treatment for AROP.

NIH Research Projects · FY 2026 · 2022-05

SUMMARY Early childhood caries (ECC) is the most common chronic childhood disease. Although largely preventable, ECC affects one third of socioeconomically disadvantaged and racial/ethnic minority preschool children in the US. Effectively reducing ECC disparity requires a better understanding of its biological factors from birth to early childhood including identifying differential exposure to risk factors by race and socioeconomic status. While ECC is an infectious disease initiated by the oral microbiota (bacteria and fungi), the interplay between host, environment, and oral microbiota affects the onset and severity of ECC. However, to date, few studies have examined the early-life longitudinal development of oral microbiota in underserved children, and none have utilized comprehensive methods to examine multiplatform (host and environmental) factors that contribute to the establishment of cariogenic microflora and onset of ECC among the underserved children. Oral Microbiome in Early Infancy (OMEI) study will address this urgent need to understand biological factors related to ECC among underserved racial/ethnic minority groups. The OMEI leverages a recently archived birth cohort that compromises 160 low-income minority infants (primarily Black/African American) and a comprehensive collection of medical/oral health records and ~1760 salivary/supragingival samples (obtained via NIDCR KL2TR001999 and K23DE027412, PI: Xiao). The OMEI builds upon our previous work that 1) revealed racial background is associated with early-life oral microbiome development in the context of ECC; 2) demonstrated oral bacterial-fungal cross-kingdom interactions and their associations with ECC; 3) identified human genes related to Host-S. mutans-Dental caries interactions; and 4) developed machine-learning prediction models for ECC. In Aim 1, we will use metagenomic analysis to define the critical assembly and functional development of the oral microbiome (bacteria and fungi) in early infancy (birth to two years) among all infants and their respective racial groups. In Aim 2, we will use computational modeling to identify determinants (maternal, genetic, and immune factors) of infants’ oral microbiome development. In Aim 3, we will use high- dimensional statistical machine learning approaches to integrate multi-platform (maternal, microbial, genetic, immune, and environmental) data to identify biological factors underlying ECC etiopathogenesis and develop ECC prediction models. The OMEI will be the first study that examines the early-life biological factors underlying ECC disparity from an infants’ oral microbiome perspective. Risk factors revealed from OMEI could be used as targets for ECC early prediction and prevention specifically suitable for underserved children. An integrated health disparities research team with investigators from multiple disciplines (microbiome, perinatal oral health, metagenomic sequencing, high-dimensional biostatistics, genetics, and health disparities), together with an outstanding internal-external advisory committee, will ensure the success of the proposed OMEI project.

NIH Research Projects · FY 2026 · 2022-05

Severe Early Childhood Caries (S-ECC) is difficult to treat effectively and has an alarming and distressing tendency to recur following treatment. S-ECC is a particularly acute form of early childhood caries (ECC) that is characterized by an overwhelming caries-promoting microbial challenge, including Mutans Streptococci (MS) and Lactobacilli (LB). The standard of care for ECC/S-ECC revolves around treatment in a surgical operating suite under general anesthesia, followed by application of 5% topical fluoride varnish, family counseling regarding feeding behaviors and oral hygiene instruction. Clinical studies demonstrate approximately 40% of children treated for S-ECC will develop new caries lesions within 12 months after dental surgery. Reducing cariogenic oral microbiota with a topical anti-microbial agent is a potential approach to reduction of recurrent disease in young children with S-ECC. Recent studies have shown that 10% povidone iodine (polyvinylpyrrolidone-iodine, 10% PVPI) appears promising in preventing dental caries in young children. A meta- analysis of antimicrobial interventions and the oral microbiota associated with ECC highlight the paucity of high- quality randomized controlled trials on the efficacy of antimicrobial agents, including PVPI. The data from the National Health and Nutritional Examination Survey (NHANES 2011-2014) indicates that the prevalence of ECC in US preschool children is 24% and ranges between 11% and 72%. The clinical, social and public health impact of ECC/S-ECC is underscored by its association with increased risk of new caries lesions in the primary dentition, a higher risk of caries onset in the permanent dentition, hospitalizations, emergency room visits, high treatment costs, lost school days, diminished ability to learn and a profound impact on a child’s quality of life. The primary objective of this UG3/UH3 application is to assess the efficacy of 10% PVPI in children with S-ECC to prevent, in part or in whole, new cavitated caries lesions that require surgical intervention after oral rehabilitation. The Specific Aims are: 1 (UG3): to finalize the study protocol, develop the Manual of Procedures (MOP), finalize quality management and data management plans, finalize study case report forms (CRFs) and set-up data management system; 2 (UH3): to conduct a single center randomized, double-blind, placebo- controlled Phase II trial (RCT) to evaluate the efficacy of topical 10% PVPI to prevent new cavitated caries lesions when applied to the teeth of children with S-ECC following oral rehabilitation; 3 (UH3): to measure severity and incidence of new dental caries in children with S-ECC following oral rehabilitation who are receiving quarterly topical 10% PVPI; 4 (UH3): to assess the effect of topical 10% PVPI on diversity and composition of oral microbiota, including cariogenic MS, LB and Candida species to better understand the mechanism of action of 10% PVPI on the oral microbiome. The primary outcome will be time from randomization until cavitated carious lesion (ICDAS code 3) is first detected post-surgery. Caries increment will be measured with the International Caries Detection and Assessment System (ICDAS). The approved FDA IND for this trial is #108961.

NIH Research Projects · FY 2026 · 2022-04

Triple-negative breast cancer (TNBC) is an aggressive cancer subtype with limited treatment options. There is an emerging interest in blocking antioxidants for cancer therapy, but how antioxidants promote cancer growth is unclear. Glutathione (GSH) is the most abundant antioxidant in the body and our previous work has shown that GSH promotes tumorigenesis of triple-negative breast cancers (TNBC). It is generally assumed that GSH acts intracellularly as an antioxidant in cancer cells. However, our preliminary studies show that blocking intracellular GSH synthesis does not impede TNBC growth. These surprising results suggest an alternative mechanism where extracellular GSH supports breast tumor growth. The overarching goal of this proposal is to determine how extracellular GSH promotes tumor growth. It is known that extracellular GSH is present in plasma but cells cannot import GSH. Instead, GSH is metabolized by gamma-glutamyl transferase (GGT1) to produce a glutamyl- dipeptide and cysteinylglycine, which yields cystine and glycine. Indeed, we find that ablation of GSH synthesis in vivo not only lowers circulating GSH but also reduces the levels of cysteinylglycine, cysteine, and glycine in tissues. Further, we show that supplementation with GSH and cysteinylglycine can rescue TNBC growth upon cystine depletion in GGT1-dependent and -independent manners, respectively. Together, these preliminary data suggest an alternative mechanism where GSH functions as a circulating source of metabolites rather than as a direct antioxidant. In this proposal, we describe experiments that will test the hypothesis that the catabolism of extracellular GSH by tumor GGT1 supports TNBC growth. In Aim 1, we will elucidate the impact of extracellular GSH on TNBC growth. In Aim 2, we identify the reliance of TNBC on GGT1-mediated GSH catabolism. In Aim 3, we will determine the mechanisms by which cysteinylglycine supplies cysteine for TNBC growth. Our research will challenge the paradigm of antioxidant function in cancer by describing a novel mechanism of GSH function as a circulating source of amino acids. Further, these studies have the potential to reveal a completely new set of unrealized targets and therapeutic strategies for TNBC.

NIH Research Projects · FY 2026 · 2022-04

Former preterm infants are exposed to oxygen (O2) after birth which results in long-term developmental impacts on the lung. Approximately 70% of infants born extremely prematurely (<29 weeks’ gestational age) will have increased pulmonary morbidity and/or early childhood wheezing disorders even though many are not diagnosed with Bronchopulmonary Dysplasia (BPD). These infants are especially vulnerable to airway hyperreactivity (AHR) after respiratory viral infections through poorly understood mechanisms. Herein, we utilize a low-dose hyperoxia mouse model and a unique pediatric human tissue repository grounded on a new discovery that neonatal O2 increases the abundance of lung megakaryocytes (MKs), an understudied myeloid cell biased toward immunomodulatory functions. After respiratory viral infection, lung MKs release profibrotic cytokines such as Thrombospondin-1 (TSP-1), a critical inflammatory regulator and activator of transforming growth factor beta 1 (TGFβ1) that drives fibrosis. We hypothesize that neonatal hyperoxia primes the lung for AHR by increasing the recruitment of lung MKs and predisposing MKs to release pro-fibrotic factors (e.g. TSP-1) after infection. Aim 1 will determine how the hyperoxic lung environment after birth effects lung MK recruitment and seeding including how O2 at different developmental ages and MK depletion affect the lung MK population. Aim 2 will determine how neonatal hyperoxia effects lung MK transcriptome before and after activation using in vitro cytokine assays and RNAseq. Experiments will also determine if AHR is MK or TSP-1 dependent by comparing Influenza infection models of MK-depleted mice to transgenic mice with the TSP-1 gene deleted from MKs. Aim 3 will determine how neonatal O2 effects the bone marrow MK pool, including its effects on platelet production. This proposal is a five-year mentored research award and training plan for Dr. Andrew Dylag, MD to investigate oxygen-induced mechanisms of airway dysfunction in both mice and procured human tissues. Dr. Dylag is an Assistant Professor of Pediatrics (Neonatology) at the University of Rochester Medical Center. The research herein builds on Dr. Dylag’s experience as a clinical neonatologist and a basic scientist interested in O2 injury and post-hyperoxia airway hyperreactivity (AHR). As part of his career development plan, Dr. Dylag will attain expertise through four (4) career aims: 1) Increase knowledge and technical skills in the investigation of lung development and repair after injury using translational in vivo models, 2) Targeted training in bioinformatics analysis including transcriptomics, 3) Develop expertise in applying in vivo laboratory discoveries to human tissues and clinical human disease, and 4) Develop the necessary skills to lead an effective translational research program. Dr. Dylag will attain his stated goals by applying new skills in flow cytometry, immunohistochemistry, transcriptomics, and targeted bioinformatics training to a mouse and human tissues. At the completion of this career development award, Dr. Dylag will have interrogated one mechanistic role of how early life O2 drives AHR, advancing our understanding of how neonatal O2 exposures drive longer-term pulmonary morbidity.

NIH Research Projects · FY 2026 · 2022-04

Our laboratory will interrogate and/or block function in biological systems with functionalized polymers based on recent developments from our laboratory that provide insights into how to control binding and activation of receptors, and into control of ruthenium-catalyzed metathesis copolymerizations. First, cholera is still a life- threatening illness with an annual incidence of ~2.9 million cases and ~95,000 deaths annually in endemic countries. Many outbreaks of cholera would be staunched by a therapeutic that reduced cell binding and thus spreading of V. cholerae, the etiologic agent. Our laboratory and collaborators demonstrated that cholera toxin B pentamer (CTB) and a norbornyl polymer randomly displaying galactose and fucose self-assemble into cross- linked CTBn–glycopolymer networks. Larger aggregates result in better inhibition of cholera intoxication. Synthesis of different fucose/galactose polymer systems, analysis of the dependence of aggregation capture and kinetics on polymer structure, in combination with toxicity testing will be undertaken to develop simple, oral therapeutics for cholera disease. Second, about 12% of American males between the ages of 15-44 are infertile or subfertile, and failure of sperm to undergo acrosomal exocytosis (AE) is responsible for a significant fraction. Better molecular diagnostics are required to diagnose subfertility. We demonstrated that human and mouse sperm acrosomal exocytosis (AE) are activated with glycopolymers, although highly cooperative inhibition of AE is observed at higher concentrations of the dose-response curve. Polymers with different backbones, sugar densities, and sugars will be utilized to reduce cooperativity in the inhibition arm and to analyze which are best for activation of human AE. The most effective probes will be used to identify the human AE sperm receptor. Third, copolymers with well-controlled microstructure display superior morphology and enhanced properties, such as spatial organization, folding and self-assembly. We demonstrated that precisely alternating AB copolymers can be prepared from bicyclo[4.2.0]oct-6-ene-7-carboxamides (A) and large unstrained cycloalkenes (B) with Grubbs III catalyst through alternating ring-opening metathesis polymerization. The A monomer substituent and the microsequence of the polymer define surface behavior and solution structure morphologies. Mechanistic structure-activity studies with A monomer varying C7 substituents (ketone, ester, methenyl) will be undertaken to understand the source of alternating selectivity with an expanded B monomer repertoire. These SAR studies will allow further exploitation of AROMP for gradient copolymer synthesis to tune material properties and functions in one-pot polymerization reactions. The underlying chemical synthetic methodologies proposed for these three discrete projects are highly related through polymer synthesis. We anticipate synergy and support between project researchers will provide further opportunities for innovation that cross between projects.

NIH Research Projects · FY 2025 · 2022-04

ABSTRACT Schizophrenia (SZ) is a debilitating and complex disorder with many symptoms, and current treatments often don't address the totality of the illness. One symptom that is often overlooked is social processing deficits, and these difficulties can cause significant functional impairment for these patients. Patients with SZ are also known to have subtle perceptual deficits, and it is possible that these may be related to social processing deficits. More research examining how these social and perceptual processing difficulties manifest in the brain is needed, especially research utilizing naturalistic stimuli that mimic real life. Here, we use episodes of the comedy TV show, The Office, as our stimulus because it contains a rich variety of social interactions, including some that may be violating social norms (i.e., awkward events). These episodes are also rich in speech content that will allow us to examine language at many different hierarchical levels of processing. We will use two complementary neuroimaging imaging modalities to examine social brain network differences in patients with SZ and how more basic perceptual language processing deficits may be influencing these measures. Our analysis will allow us to quantify specific stimulus parameters related to social understanding, like awkwardness, and language processing, such as low-level envelope tracking and higher-level linguistic meaning. We will then quantify how the neural signal reflects these stimulus parameters using linear methods. For Aim 1, we will use functional magnetic resonance imaging (fMRI) techniques to characterize neural dynamics of social and perceptual processing deficits in SZ. We will first assess the neural tracking of language features during the episodes utilizing a general linear model approach (GLM). Next, we will quantify group differences in how the brain tracks with social parameters, like awkwardness. We will also characterize neural dynamics between important nodes in the social processing brain network. For Aim 2 will use electroencephalography (EEG) to characterize neural tracking of speech features with more temporal precision compared to fMRI. We will also examine how social features are reflected in the neural signal and characterize functional connectivity of social processing regions within specific frequency ranges. We predict that across both aims, the brains of patients with SZ will track less with the perceptual and social features of the stimulus, and that any perceptual deficits may be contributing to social deficits. We aim to recruit the same participants for aim 1 and 2, so we can capitalize on the strengths of both methods and examine how these measures may be providing complementary information about language and social processing deficits. We hope that this research can be used to inform future research for biomarkers of SZ and ultimately improve healthcare outcomes for patients with SZ.

NIH Research Projects · FY 2026 · 2022-03

Rheumatoid arthritis (RA) affects approximately 1% of the population and is characterized by inflammation and joint damage, often leading to considerable disability and pain in both early and established stages. Key areas of unmet need in the field include the: 1) highly heterogeneous and unpredictable disease course, 2) rarity of lasting remissions, 3) failure of currently available treatments to achieve low disease activity and/or limit progressive joint damage in many patients, and 4) lack of robust biomarkers necessary to personalize appropriate treatment strategies. We propose that cellular and molecular variation in synovial tissue underlies this heterogeneity and that understanding the basis for this will improve the prediction of disease course and provide a rationale for the timely selection of precision treatment strategies with higher rates of sustained RA control. Through sustained collaborative global team-science, the AIM-for-RA Team has already developed state-of- the-art protocols that deconstructed RA synovial biopsy tissues - an innovation that profoundly advanced knowledge in cells and pathways involved in RA pathogenesis, identified novel treatment targets, identified disease biomarkers, and opened new opportunities in disease prevention. However, it remains unclear how molecular interactions in the synovium relate to the evolution of defined clinical outcomes, from the at-risk preclinical period to arthritis onset, and then through to synovitis outcome. Therefore, AIM-for-RA Disease Team (DT) aims to relate disease-relevant synovial cellular pathways and dynamic crosstalk to environmental exposures, disease outcomes and treatment response, thereby reconstructing the disease pathogenesis trajectory. In a DMARD-naïve RA cross- sectional synovial biopsy-based study of 50 RA patients across 9 sites using harmonized protocols and integrated technologies, Aim 1 will deliver high-quality multimodal clinical phenotype and histology data, along with synovial tissue and other biosamples, to evaluate how synovial cellular and molecular pathways relate to disease onset. With longitudinal follow-up and repeat biopsy of these individuals after methotrexate monotherapy, Aim 2 will address whether synovial signatures and multi-modal data predict first-line methotrexate response, or failure in patients with early previously untreated disease. Finally, in Aim 3, in patients with methotrexate inadequate response we will address whether distinct synovial cellular or molecular features predict a positive response to biologic therapies directly targeting these features. The outcomes of this program will have potential for rapid translational application to improve treatment outcomes at all RA disease stages. Collectively, the collaborative, global AIM-for-RA Team that has made seminal observations regarding RA disease pathogenesis is ideally suited to inform the key questions and meet major unmet needs in the field.

NIH Research Projects · FY 2025 · 2022-03

ABSTRACT Psoriatic Spectrum Diseases (PSD) affect over 8 million individuals in the U.S. living with psoriasis (PsO) or psoriatic arthritis (PsA) and encompass heterogeneous phenotypes of disease, ranging from plaque, guttate, palmoplantar, inverse, pustular, and erythrodermic forms of psoriasis, to synovial, enthesial, and axial forms of PsA. Here, we assembled a world class multidisciplinary team of scientists in PSD cohort assembly, clinical phenotyping, biosample acquisition, pathology, statistics, and bioinformatics, for the Accelerating Medicines Partnership Autoimmune and Immune-Mediated Diseases (AMP AIM) PSD Disease Teams (DTs). The major scientific goals of the PSD DT are to understand the cellular and molecular composition of distinct PSD endotypes and how they link with phenotypes, to identify how key pathogenic or regulatory cells spatially interact with each other and with environmental cues (i.e., microbiome), and to define at a single-cell level how the transition to PsA unfolds in the setting of PsO. To accomplish the goals of the PSD AMP, we propose the creation of the ELLIPSS (ELucidating the Landscape of Immunoendotypes in Psoriatic Skin and Synovium) Disease Team (DT). The AIMS of the ELLIPSS Team are to 1) to enroll diverse PSD cohorts and perform clinical phenotyping, data capture, and tissue collection. 2) to implement an effective management plan for the ELLIPSS multidisciplinary team. 3) to optimize interface of ELLIPSS team with AMP-AIM network. Lastly, a robust Opportunities Fund (OF) management program is proposed under the direction and leadership of Dr. James T. Elder at University of Michigan. The ELLIPSS PSD DT will efficiently integrate with the AMP AIM Network, facilitate collection of PSD biosamples, and help provide an unprecedented view of cell types and states, along with spatial and tissue interactions (skin, joint, blood, microbiome) to deconstruct/reconstruct the psoriatic disease spectrum.

NIH Research Projects · FY 2026 · 2022-03

Project Summary/Abstract Applicant: I am a consultation-liaison psychiatrist keenly interested in delirium and the role that sleep-wake disturbance (SWD) plays in delirium vulnerability, its pathogenesis, and its relationship with subsequent Alzheimer’s disease and related dementias (ADRD). My mission is to improve the care and clinical outcomes of those with and at risk for delirium and to be a champion for excellence in care for older adults. This application is designed for me to obtain expertise in longitudinal study conduct and design, assessment of SWD, neuropsychological training relevant to delirium and the two neurocognitive disorders associated with it (Alzheimer’s disease and vascular neurocognitive disorder), and a solid background in statistical methods to become an independent physician-scientist. Project: I am proposing a prospective cohort study of subjects undergoing surgical aortic valve replacement with the goal of investigating objective SWD before surgery—both actigraphy and unattended type II home sleep tests (HST)—for its association with postoperative delirium and subsequent ADRD. This study represents a novel application of type II HST, which provides comprehensive assessment of sleep architecture, to characterize preoperative SWD as a marker of delirium risk and evidence in support of a mechanistic link between delirium and subsequent Alzheimer’s disease or vascular neurocognitive disorder. Professional development: I will obtain practical experience in empirical methods by conducting a longitudinal study with expertise in assessing SWD using unattended methods, neuropsychological testing, and relevant statistics. My training plan incorporates hands-on experiences in sleep medicine, neuropsychology, and statistics, complemented by coursework and directed readings that will provide the necessary theoretical foundation. Goals: My career goals are to establish an interdisciplinary research program at URMC with cardiac surgery and sleep medicine, to explore how SWD is mechanistically involved in delirium risk, onset, and its dire outcomes, and to advance the science of delirium pathophysiology and subsequent risk of ADRD.

NIH Research Projects · FY 2025 · 2022-02

Our concepts of platelet and megakaryocyte (Mk) origins and functions continue to expand. Mks are found in extramedullary tissues, including the lungs and spleen. We have shown that platelets initiate, accelerate, and regulate all phases of the immune responses and have now discovered that Mks have immune plasticity and functions that are dependent on their tissue environment. This includes our discovery that lung Mks take up, process, and present pathogen derived antigens to T cells. Our studies lead us to now hypothesize that: Mk differentiation is responsive to, and dictated by, environmental pathogens and/or stimuli. Our data also presents questions related to extramedullary Mk origins and differentiation. We will leverage the unique expertise of our collaborative team by using disease relevant in vitro and in vivo mouse model systems to explore this novel research inquiry. Proposed studies in this application will explore whether Mks differentiate from hematopoietic stem cells outside the bone marrow, determine the environmental regulators of Mk phenotype plasticity, and potential roles for extramedullary Mks in all phases of the immune responses. These studies will establish that tissue resident Mks have environmentally regulated roles in immune responses, changing how we view Mk and platelet functions, thereby impacting our understanding of major causes of morbidity and mortality. This includes infectious diseases such as bacterial pneumonias or viral infections (examples; influenza and coronavirus). To accomplish these paradigm shifting goals, we will pursue the following Aims: Aim #1. To demonstrate mechanisms of tissue dependent Mk differentiation. Aim #2. To demonstrate megakaryocyte immune regulatory roles.