Weill Medical Coll Of Cornell Univ

NIH Research Projects · FY 2025 · 2024-09

Patients with advanced cancer who receive cancer care in outpatient settings have unmet spiritual needs, receive care isolated from their faith communities, and, as a result, are more likely to receive overly aggressive, burdensome, futile, and less hospice, end-of-life (EoL) care. Outpatient oncology clinics inadequately address patients’ spiritual needs and lack input from and integration with patients’ faith communities. These systemic, faith-related micro-social deprivations undermine patients’ decision-making and quality of EoL care. We have found that 88% of advanced cancer patients report that religiousness and/or spirituality (R/S) is important to them, yet most (72%) say their R/S needs were not met by the medical system. Support of dying patients’ R/S needs may especially benefit patients who rely heavily on religion to cope with their cancers. Patients whose R/S care needs were met by the medical system (e.g., who met with a healthcare chaplain) were more likely to receive hospice care, less likely to receive an aggressive intervention, and less likely to die in an intensive care unit (ICU). In stark contrast, patients whose R/S needs were met by their faith communities were less likely to receive hospice care, more likely to receive aggressive interventions, and more likely to die in an ICU. Thus, disconnected medical system- and faith community-provided R/S care appears to pull patients in dramatically opposite directions with respect to EoL care. We here propose to address patients’ unmet spiritual needs and the disconnect from their faith communities with the following specific aims: Aim 1: Determine effects of health-care chaplaincy alone and with faith community linkages on EoL outcomes among patients with advanced cancer. Strategy: Conduct a 3-arm (1:1:1 ratio) randomized controlled trial to evaluate intervention effects on EoL outcomes. Outpatients with advanced cancer (N=288) will be randomly assigned to receive spiritual care from a healthcare chaplain alone (Arm #1), a healthcare chaplain in coordination with a faith community spiritual care provider (Arm #2), or distant intercessory prayer (Control Arm). Outcomes will be patients’ spiritual wellness at 2 months post-intervention, and ICU and hospice use within one year of baseline. Aim 2: Identify mechanisms by which healthcare chaplain interventions affect patient EoL outcomes. Hypothesis: More spiritual wellness, medical trust, and readiness to engage in ACP will mediate intervention effects on hospice enrollment and ICU admissions. Aim 3: Explore barriers to implementation. Strategy: Qualitative interviews with trial participants and relevant stakeholders will explore barriers to intervention implementation. Impact: This study will provide evidence of how integration of health-care chaplaincy into outpatient oncology clinics and its linkage with faith community spiritual care providers promotes spiritual wellness and results in higher quality EoL decision-making and care for patients with advanced cancer.

NIH Research Projects · FY 2024 · 2024-09

Chronic kidney disease (CKD) affects 10-15% of the population worldwide. More than 37 million people are estimated to have CKD in the US, and 2 in every 1000 Americans need dialysis or a kidney transplant to survive. Anemia and dysfunctional iron homeostasis frequently complicate CKD. Kidney fibrosis is the final mechanism common for all progressive kidney disorders leading to CKD. However, very few therapies are available to slow the progression of kidney fibrosis in CKD patients. Our long-term goal is to identify novel actionable drivers of kidney fibrosis, so that they can be therapeutically targeted to delay progression of CKD. Proximal tubular epithelial cells represent the key cell population implicated in the pathophysiology of kidney fibrosis and may accumulate iron in CKD. The overall objective of this proposal is to define the role of iron homeostasis in responses of these cells to fibrosis, which are responsible for CKD progression. Based on our preliminary data, we hypothesize that in CKD, tubular cells are highly sensitive to labile iron. Nonetheless, the following two cytoprotective mechanisms initially limit tubular iron toxicity in CKD by preventing an uncontrolled expansion of the tubular labile iron pool: (1) induction of tubular iron export and (2) induction of intracellular storage of iron within the tubular cells. We expect that these protective mechanisms fail during iron supplementation unless they are enhanced therapeutically. This hypothesis will be tested in two sets of experiments that will increase or decrease labile iron pool in tubular cells, and we will define the consequential changes of tubular injury, survival, and fibrosis that constitute the disease progression. Studies will be facilitated by induction of CKD in our mutant mice lacking critical iron-related proteins in proximal tubules (ferritin-H, responsible for iron storage and ferroportin, responsible for iron removal from cells) and established protocols for iron supplementation, restriction, and conservative therapeutic chelation. Successful completion of this work is expected to elucidate the fundamental mechanisms of intracellular iron regulation in the kidney, which are critical for kidney fibrosis propagation and will identify approaches capable of influencing cellular catalytic iron as a novel therapeutic target. Thus, the proposed work addresses a critical lack of knowledge essential for the development of new therapeutic approaches to iron homeostasis, which are on the critical path to halting CKD progression in patients.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT More than 24,000 children develop acute respiratory failure (ARF) and require invasive mechanical ventilation (MV) – an intrusive, painful, yet lifesaving procedure – in the US each year. There is a critical knowledge gap regarding the optimal approach for analgosedation (analgesia-based sedation) in these children. As a result, the current standard-of-care is to provide opioids for the duration of MV. Despite high-dose opioid exposure, more than 90% of these children have suboptimal pain control. Studies show that repeated episodes of acute pain and prolonged opioid exposure put children at risk for chronic pain, opioid tolerance, withdrawal, delirium, and other negative effects. Yet, few randomized controlled trials (RCTs) target optimizing acute pain management in this high-risk population. In our study, Optimizing Pain Treatment In Children On Mechanical ventilation (OPTICOM), the central hypothesis is that a protocolized strategy of administering non-opioid adjuvant therapies to children with ARF will reduce pain and decrease opioid exposure. The primary objective of OPTICOM is to define the effectiveness of supplementing opioids with acetaminophen and/or ketorolac at decreasing episodes of acute pain in children with ARF on MV. This large-scale multi-site double- blind placebo controlled RCT will enroll 644 children across 14 pediatric intensive care units (PICUs) and randomize to one of 4 arms: Acetaminophen + Placebo; Ketorolac + Placebo; Acetaminophen + Ketorolac; or Placebo + Placebo. We will systematically monitor all children for acute pain for the first 5 days of IMV and quantify total opioid exposure in morphine milligram equivalents per kg as defined by the HEAL common data elements. Effects of acetaminophen and ketorolac will be determined using a 2x2 factorial design. This innovative proposal will leverage the extensive resources and experience of the Collaborative Pediatric Critical Care Research Network (CPCCRN) at executing clinical trials in the complicated PICU environment to achieve results within the 5-year study period. CPCCRN will ensure enrollment of a geographically, racially, and socioeconomically diverse patient population to allow for wide generalizability of study findings. By expanding HEAL-KIDS research into a unique and unstudied population, this project will lead to a paradigm shift in the care provided to critically ill children. Consistent with the goals of the Acute Pain Clinical Trials Program, the OPTICOM study will advance the treatment of acute pain in a diverse population of children across the age- spectrum and advance our ultimate goal of developing comprehensive evidence-based clinical guidelines for management of pain in children with ARF.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Acute Myeloid Leukemia (AML) is a lethal hematologic malignancy characterized by impaired myeloid differentiation and blast proliferation, inhibiting normal hematopoiesis. Isocitrate Dehydrogenase (IDH) mutations are highly prevalent in AML and contribute to leukemogenesis through production of oncometabolite 2HG. Mutant IDH inhibitors (Enasidenib for IDH2, Ivosidenib for IDH1) suppress 2HG production and differentiate leukemic cells to functional neutrophils. Despite initial excitement for differentiation agents, overall survival remains abysmal as differentiation therapy fails to induce durable responses in most patients. Concomitant oncogenic Nras mutations are the most consistent predictor of primary resistance to mutant IDH inhibitors. While IDH mutations cause stem cell bias, surprisingly, oncogenic Nras mutations are associated with aberrant myeloid differentiation. The role of oncogenic Nras in modulating IDH mutant AML leukemogenesis and the mechanism by which it contributes to therapeutic resistance is completely undefined. The goal of this research proposal is to define the mechanistic contribution of Nras to IDH mutant AML leukemogenesis and characterize its role in therapeutic resistance. There are no available mouse models that recapitulate patient phenotypes and provide dynamic range to study oncogenic Nras. We developed two orthogonal mouse models (genetically engineered mouse models and patient derived xenograft models) of IDH mutant AMLs with and without concomitant Nras. We will utilize serial IDHm AML patient samples to ensure translational relevance. Preliminary data indicates oncogenic Nras causes aberrant myeloid differentiation in IDH mutant AMLs, leads to rapidly lethal disease, and is not susceptible to Ivosidenib mediated differentiation. We show in vitro inhibition of Mek signaling promotes IDH/Nras co-mutant AML susceptibility to Ivosidenib. Aim1 proposes to characterize oncogenic Nras mediated changes in IDHm AML hematopoiesis (Aim1A) and leukemic cells of propagation (Aim1B). Aim2 evaluates the mechanism by which oncogenic Nras modulates response to Ivosidenib, characterizing how oncogenic Nras mitigates Ivosidenib mediated differentiation changes (Aim2A) and evaluating the role of Mek in attenuating Ivosidenib response (Aim2B). This work carefully considers the role of DNA and histone methylation and metabolism in these processes, utilizing metabolomics, bisulfite sequencing, and RNA-Seq. Completion of these aims will elucidate novel therapeutic targets for this high-risk AML sub-group and reveal how signaling environments influence a cell’s differentiation state response to therapy. This project is ideal for an aspiring physician-scientist, given its blend of clinical and basic biological questions. The work and training plan outlined will be completed in the laboratory of Dr. Ross Levine at Memorial Sloan Kettering, with a thesis committee of physician scientists, bioinformatic and metabolism collaborators, and support of the Tri-I MDPhD program. It will prepare the applicant to achieve their goal of being an independent physician scientist.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY/ABSTRACT Expansion of Medicare coverage of telehealth services during the COVID-19 public health emergency (PHE) removed many of the barriers to telehealth provision in nursing homes (NHs). In 2020, 58% of Medicare Advantage (MA) plans covered additional telehealth benefits in NHs, beyond those reimbursed by Medicare fee-for-service (FFS). Over three years after the pandemic's onset and given that Medicare waivers supporting telehealth use in NHs will end in December 2024, new evidence is critically needed to assess the impact of telehealth on long-standing gaps in access to specialty care and overall quality of care for NH residents with Alzheimer's disease or related dementias (ADRD). For long- stay NH residents with ADRD, who make up over half of all NH residents, increased telehealth provision may allow more timely access to routine and specialty care, provide clinicians and caregivers with an important layer of audiovisual information to make more informed patient-centered decisions, and facilitate communication between residents, providers, and caregivers. While telehealth has the potential to reduce potentially avoidable hospitalizations and emergency department visits for NH residents through these mechanisms and others, there may be unintended consequences of broader telehealth use, and challenges to using telehealth for residents with ADRD. The overall objectives of this study are to leverage the natural experiments surrounding changes in access to telehealth among Medicare FFS and MA-enrolled long-stay NH residents, to examine how telehealth has been used to supplement or replace in-person patient care and to measure the relationship between telehealth use and the quality and cost of care. We will focus on the following specific aims: (1) To examine how telehealth is and has been used for long-stay residents with ADRD, using qualitative methods to generate nuanced insights into multiple predictors of, barriers to, and constraints on use. We will conduct semi-structured interviews with NH medical directors and resident caregivers to explore multiple implementation domains, including NH characteristics associated with telehealth provision.; (2) To characterize the uptake and patterns of telehealth and in-person care from 2018 through 2024 for long-stay NH residents with ADRD; and (3) To measure the relationship between access to telehealth among long-stay NH residents with ADRD and the utilization, quality, and cost of care from 2018 through 2024. This application is innovative because it will be the first to measure telehealth use for long-stay residents enrolled in both Medicare FFS and in MA. It will also be the first to quantify the potential benefits of increasing access to telehealth services in NHs for long-stay residents with ADRD. The findings from our mixed methods approach will provide nuanced qualitative insights on NH leadership decision-making surrounding telehealth, frontline facilitators and barriers to telehealth at multiple levels, and the degree to which family members and caretakers may benefit from telehealth. The proposed research is significant since Medicare coverage of many telehealth services is set to expire in December 2024. This project will shed light on the potential impacts of reducing access to telehealth for NH residents and individuals with ADRD. Importantly, it will also inform NIH goals for expanded research on the use and efficacy of telehealth to improve the delivery of care for people living with ADRD.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY/ABSTRACT Opioid use disorder (OUD) is a public health emergency impacting the lives of an estimated 5.6 million individuals in the United States. OUD is a particular concern for vulnerable populations (e.g., pregnant women, criminal- legal system involved populations, etc.), where the barriers to evidence-based care and the economic burden remain significant. Randomized controlled trials (RCTs) are considered the gold standard for identifying causal treatment effects and is the primary scientific tool to inform clinical decisions. RCT research designs are also growing in use for conducting robust health economic studies to ensure that evidence-based treatments can be cost-effective and sustainable—reaching the broadest number of individuals with OUD while efficiently using scarce healthcare resources. As such, health economic RCT research designs have become a critical tool in identifying sustainable and cost-effective solutions to prevent and mitigate the opioid epidemic. The NIH HEAL initiative has championed such research by funding economic evaluations alongside clinical trials in the Healing Communities Study, NIDA's Clinical Trials Network (CTN) and Justice Community Opioid Innovation Network (JCOIN), and The HEAL Prevention Cooperative (HPC), among others. Traditional RCTs have demonstrated the effectiveness of medications for OUD (MOUD) but have limitations in addressing the unique needs of these populations. Real-world data and evidence (RWE) research designs that use observational data from healthcare claims, electronic medical records, and other sources have been used to answer critical questions in medicine that are difficult or impossible to implement in equivalent RCTs. The 21st Century CURES Act reaffirmed the use of RWE and provided greater research flexibility of data sources for the FDA drug approval process. Despite this, significant concerns remain about the reliability of RWE due to its observational nature and potential for confounding bias. To address these concerns, RCTs have been used to inform RWE research designs (e.g., the popular “target RCT” framework) and augment RWE findings. The alternative and unconventional approach of integrating RWE to inform inconclusive RCTs to support robust and causal conclusions that can inform clinical practice has been systematically ignored but represents a potential opportunity to reduce research waste and produce more reliable findings to inform clinical decision-making and improve outcomes for at-risk populations with OUD. This project will develop novel econometric methods and unified framework for integrating RWE in the analysis of inconclusive RCTs by adapting existing econometric and biostatistical techniques into comparative economic and effectiveness assessments of OUD treatments conducted alongside RCTs. The project will evaluate multiple maximum likelihood estimation (MLE) approaches combined with propensity score- based causal inference methodologies to achieve this goal. This novel approach, which is the reverse of traditional practice, offers a unique and highly risky "out-of-the-box" solution to address emerging barriers in generating evidence for health interventions targeting vulnerable populations affected by the opioid epidemic.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent neoplastic disease of the pancreas, and it is expected to become the second leading cause of cancer related death over the next decade. PDAC has an abysmal prognosis, with only 10% of patients surviving more than 5 years from diagnosis. Interestingly, over 90% of PDACs harbor activating mutations in the KRAS oncogene and the most common KRAS mutations seen in PDAC are G12D, G12V, or G12R. G12D and G12V mutations are commonly found in lung and colon cancers, however G12R mutations are largely restricted to PDAC. 15-20% of PDACs carry G12R mutations, but the majority of preclinical animal models focus on the KrasG12D mutation, which reflects less than half of the KRAS mutations seen in human PDAC. The preliminary data shown in this work and the overall proposal aim to determine if KrasG12R may be functionally distinct from other KRAS driver mutations and how this affects disease initiation and progression. As previously described by us, unlike KrasG12D, KrasG12R mutations do not drive progression to pre-neoplastic PanIN lesions from acinar cells, instead they remain stalled during acinar-to-ductal metaplasia (ADM) and addition of a mutant p53 allele to does not accelerate disease formation in mice. However, we have found that under two specific contexts; KrasG12R / p53MUT ductal- derived organoids transplanted into mice and mice with a p53 mutant allele and loss of the other p53 allele oncogenic transformation happens and results in PDAC formation. We and others have also described decreased PI3K/AKT signaling, in KrasG12R when compared to KrasG12D.This proposed work will test the hypothesis that cell lineage and/or cooperating genetic events in the PI3K pathway impact the oncogenic potential of KrasG12R mutations in pancreas cancer. My proposal represents a significant contribution to understanding the molecular underpinnings of disease initiation and progression of KrasG12R. In the proposed studies we aim to determine if how cell-of-origin impacts disease initiation and progression and how the immediate and sustained molecular events following KrasG12R activation affects initiation and progression. We also aim to elucidate the role of PI3K mutations affect disease initiation and progression in both in vitro and in vivo. To address these questions, we will use lineage tracing mouse models that conditionally mark cells and induce mutant KrasG12R and p53 mutations in the pancreas. In addition, we will use CRISPR-Cas9 genome editing technologies to make complementary organoid and in vivo models of PIK3CA mutations and PTEN deletions that will help elucidate the role of PI3K in KrasG12R PDACs. We plan to use different histological and molecular techniques to dissect the molecular underpinnings of KrasG12R driven PDAC. We anticipate that a better understanding of KrasG12R and related cellular and molecular processes will further elaborate on the KRAS heterogeneity found in PDAC, as well as provide avenues for the development of targeted therapeutics in patient populations with varying KRAS mutations.

NIH Research Projects · FY 2025 · 2024-09

The microbiome has emerged as a functional microbial organ system that plays a key role in human health and disease including obesity, cancer, and inflammation. Dietary and host factors broadly regulate the composition and function of the microbiome and are associated with health outcome, but the tools available to profile this organ system in humans are limited. Despite advances in sequencing technologies that infer microbial metabolic function, there remains a significant unmet need for the direct characterization of functional metabolic pathways within the microbiome that play a pivotal role in human health and disease. This proposal application aims to use activity-based probes in the study of the microbiome. This novel approach allows for direct measurement of protein function, bypassing the reliance on downstream metabolites as indirect indicators of microbial activity. By focusing on functionally active enzymes and linking them to specific taxa, the study will achieve a level of molecular resolution and specificity not previously attainable, thus revolutionizing our understanding of the microbiome's functional role. We will further leverage this technology to enrich for microbial consortia or isolate specific taxa with functional capabilities that will be translated to pre-clinical and clinical studies to complete the pipeline of precision microbial therapeutics. Successful execution of this research will have a profound impact on scientific understanding of the microbiome's contribution to human health and disease, specifically highlighting the impact of diet and intestinal inflammation. By uncovering the specific microbial metabolic pathways associated with clinical response and treatment efficacy, the study opens up new avenues to develop targeted therapies to modulate the microbiome, enhancing treatment outcomes for patients. This technology has the potential to revolutionize how we investigate microbial function, emphasizing the microbiome's function and resultant activities due to disease, thus paving the way for personalized therapies and interventions targeting specific microbial metabolic pathways.

NIH Research Projects · FY 2025 · 2024-09

Abstract Impaired urinary outflow that causes damage to the urinary tract and kidney is a major cause of kidney disease, which affects 15% of the population and costs $100B annually. For instance, hydronephrosis, a pressure mediated dilation and damage of the renal tissues, is the leading cause of pediatric kidney failure. Major gaps remain in our understanding of the causes that underlie impaired urinary outflow and urinary tract damage. For instance, approximately 50% of all urinary tract dilation occurs in the absence of a physical obstruction, yet the functional abnormalities causing these cases remain obscure. Indeed, the upper urinary tract (UUT) is a continuous muscular organ that contracts to propel waste from the kidney to the bladder. Defects in this peristaltic process, such as vesicoureteral reflux (VUR), or retrograde backward urine flow from the bladder to the kidney, are pathological. VUR affects 2% of children, and can lead to urinary tract infections, hydronephrosis, and chronic reflux nephropathy that leads to end-stage renal disease in 10-25% of cases. Despite the essential physiological role of the UUT, the mechanisms driving UUT peristalsis remained unknown. Our group discovered that HCN ion channels underlie UUT pacemaker activity, that HCN+ pacemakers co-express T-type Ca2+ channels that control contractile rate, and most recently, that the HCN+ pacemakers are evolutionarily conserved and drive peristalsis of the unique multicalyceal UUT exhibited by humans. To date, however, the role of pacemaker defects in functional urinary tract disorders remains elusive. Thus, the overall goal of this proposal is to provide a mechanistic framework of UUT physiology, as a critical step to developing diagnostics and drugs to treat conditions such as VUR and hydronephrosis. To fill the current knowledge gaps, we will use a novel mutant mouse model that exhibits UUTs that lack pacemakers, exhibit normal smooth muscle, and develop VUR and hydronephrosis. We will use this novel mouse model to define the pathophysiology of pacemaker defects that cause urinary dilations. In aim 1 we will define the transcriptional signaling mechanisms that are required for pacemaker formation and functional UUT peristalsis. In aim 2, we will define the transcriptional protein complexomes that assemble to control UUT pacemaker development. Notably, the transcriptional complexomes required for UUT formation remain a major knowledge gap in our understanding of the UUT. Taken together, the proposed studies will provide critical insight into functional peristaltic defects that impede urinary outflow, and results will generate new genetic and protein markers that can serve as putative targets for future diagnostics and treatments for UUT pathologies, such as VUR and hydronephrosis.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Alzheimer’s disease (AD) is the leading cause of dementia, with the number of cases estimated to rise to 13 million by 2050 in the US alone . While amyloid-beta (Aβ) and tau are known to be the key neuropathological hallmarks of the disease, imaging and postmortem studies highlight significant variability in disease severity and progression even in subjects with similar burdens of Aβ and tau accumulation. This uncertainty in the trajectory of disease progression results in substantial challenges for patients and their families in understanding disease prognosis, as well as the research community in understanding heterogeneity in the rate of Aβ and tau accumulation, cognitive decline and likelihood of progressing to dementia. Building upon prior work from our group and others, we will develop a prognostic score, termed the Tau Progression Index (TPI), a multi- component and multimodal measure that can predict tau accumulation, neurodegeneration, and cognitive/functional decline. Two components of the TPI are based on MRI measures of structural and functional connectivity that have been shown in recent reports to explain the rate and pattern of spread of tau pathology. The other two components are based on regional patterns and interactions between Aβ and tau accumulation in the early stages of AD. For instance, a recent report by our group highlights the importance of co-localized (overlapping) and non-co-localized accumulation of Aβ and tau in predicting conversion from cognitively normal to mild cognitive impairment (MCI) and/or AD. In this project, we will recruit 130 non-demented participants with evidence of Aβ and tau pathologies based on 18F-florbetaben and 18F-MK6240 PET scans from 10 ongoing NIH-funded studies with more than 1700 planned and 650+ existing enrollments. Our laboratory serves as a central neuroimaging processing hub for these 10 NIH studies, allowing us a unique opportunity to identify subjects with PET-confirmed evidence of AD pathology at no additional cost. These selected subjects will then undergo our advanced MRI acquisition protocol and processing pipeline to extract reliable subject-specific functional and structural connectivity. Subjects will also undergo detailed cognitive and clinical assessments. Subjects will be evaluated at baseline and at a 2.5-year follow-up visit, which will include Aβ and tau PET, our advanced MRI and clinical/cognitive assessment. By combining subject-specific structural and functional connectomes with the patterns of Aβ and tau accumulation, our developed TPI will give a single prognostic score for each individual. We aim to show that this score will predict the trajectory of tau spread and disease progression. By incorporating spatial/network-based patterns of tau deposition and brain connectomes into a prognostic tool for patient counseling and clinical trials, our TPI is an important step towards personalized medicine for AD.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Dr. Daniel Shalev is an Assistant Professor of Medicine and Psychiatry at Weill Cornell with expertise in psychiatry, palliative medicine, and behavioral geriatrics. His career goals are to 1) become a leading investigator in mental health delivery for older adults with serious illness and thereby 2) to improve mental health outcomes for older adults with serious illness. Research: Over 70% of deaths in the United States are due to chronic illness. The burden of serious medical illnesses like cancer, heart failure, and chronic lung disease falls disproportionately on older adults. As the population of older adults grows, so too will the impact of serious chronic illnesses. The standard of care for older adults with serious illness includes geriatric palliative care, a multidisciplinary approach to palliative care that emphasizes longitudinal care, multimorbidity, and quality of life. Psychiatric and psychological symptoms like depression and anxiety are common among older adults living with serious illness and have a significant impact on outcomes such as quality of life. Mental health is a core focus of palliative care. Older adults face distinct barriers to accessing mental health care that make them particularly likely to depend on palliative care clinicians for mental health services. However, palliative care clinicians may face barriers to assessing and managing such symptoms leading to gaps in care. The objective of this proposal is to adapt the Collaborative Care Model to the palliative care setting to improve depression and anxiety care for older adults. The Collaborative Care Model integrates mental health services into medical care that has been validated in over 90 clinical trials. The model involves embedding a social worker and psychiatrist in a medical setting to provide direct patient care and guide medical clinicians in improving their mental health skills and knowledge. This study will utilize the Method for Program Adaptation through Community Engagement, an intervention adaptation method co-designed by Dr. Shalev’s primary mentor Dr. Cary Reid, to create the Collaborative Care Model for Palliative Care (CoCM-PAL) (Aim 1) and to conduct a pilot randomized controlled trial of CoCM-PAL (Aim 2). Completion of the proposed study will generate key pilot data for a large efficacy trial of CoCM-PAL. Career Development: Dr. Shalev has assembled a multidisciplinary team of mentors (Primary Mentor: Dr. Cary Reid, Co-Mentors: Dr. Vicki Jackson, Dr. Jesse Fann, and Dr. Catherine Riffin) and advisors (Dr. Harold Pincus, Dr. Kelly McConnell, Dr. Mark Lachs) with expertise in geriatric serious illness care, geriatric mental health, and Collaborative Care. His career development plan focuses on training in 1) behavioral intervention/design and clinical trials for older adults with serious illness 2) integration of implementation science into early phase of intervention research, 3) clinical care of older adults with both serious illness and mental health needs, and 4) leadership and grant writing. This Beeson award will provide Dr. Shalev with the skills, experience, and mentorship to become a leading investigator in mental health services for older adults with serious illness.

NIH Research Projects · FY 2024 · 2024-09

PROJECT ABSTRACT Almost half of the 1.7 million hospice enrollees have Alzheimer's disease and related dementias (ADRD) as the principal diagnosis or a comorbidity. Although hospice care is particularly beneficial to support ADRD patients and their caregivers at the end of life (EoL), one in five hospice enrollees with ADRD experience discharge from hospice prior to death, also known as “live discharge.” Hospice live discharge has a profound impact on EoL care of ADRD patients due to their complex EoL conditions, highly uncertain prognosis, and difficulty in communicating EoL care preference. Despite two recent policy changes, hospice live discharges remain persistently high among ADRD patients. The changing hospice market landscape may keep boosting live discharges among ADRD patients and lead to frequent care transitions and other adverse EoL outcomes after hospice live discharge. To date, critical gaps exist in understanding outcomes after hospice live discharge among ADRD patients. Little is known about the longitudinal patterns of care transitions in all care settings, functional decline, and overall healthcare utilization after hospice live discharge. Although Medicare Advantage (MA) covers half of Medicare beneficiaries, there is scant evidence about outcomes after hospice live discharge among MA enrollees. No validated tools are available to predict patient outcomes after hospice live discharge to facilitate discharge planning and post-discharge care coordination. This mixed-methods project aims to fill these gaps by characterizing and predicting patient trajectories after hospice live discharge among ADRD patients. In Aim 1, we will apply longitudinal clustering methods with national Medicare fee-for-service (FFS) claims and MA encounter data to identify patient subgroups with heterogenous trajectories after hospice live discharge. In Aim 2, we will develop and validate prediction models for patient trajectories and other clinically important outcomes after hospice live discharge. We will use Medicare FFS claims, MA encounter data, electronic health record (EHR) data from two large hospices, and linked claims/encounter data and EHR data to develop prediction models and ensure fairness of model accuracy by patient race/ethnicity and socioeconomic status. In Aim 3, we will conduct in-depth qualitative interviews with different stakeholders (e.g., physicians, patients and caregivers, and informatics staff) who are involved in the implementation of the prediction models in care delivery. Evidence from this aim will facilitate the transition from model development to real-world implementation in the future that can benefit ADRD patients and their caregivers. This project is well aligned with the National Institute on Aging's priority to better understand the burden of ADRD on patient outcomes. The proposed research will generate novel evidence to improve patient outcomes after hospice live discharge and inform the ongoing pilot programs to develop novel hospice care models that are better suited for the EoL care needs of ADRD patients.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Type I Diabetes (T1D) is a T cell mediated autoimmune which is dramatically increasing in incidence. The pathogenesis of T1D is complex and involves the infiltration of β cell-specific CD8 T cells into the pancreas and progressive destruction of insulin-producing b cells, resulting in loss of glucose homeostasis. Utilizing the clinically relevant Non-Obese Diabetic (NOD) mouse model of T1D, the Schietinger lab recently discovered a β cell-specific stem-like CD8 T cell population in the pancreatic lymph node (pLN) which self-renews and gives rise to differentiated progeny that migrate to the pancreas and destroy β cells; pancreatic T cells are short-lived and stem-like T cells in the pLN must continuously seed the pancreas to sustain β cell destruction. In this application I aim to understand the underlying molecular and cellular mechanisms that determine autoimmune T cell differentiation. In aim 1, I will determine how and where stem-T cells self-renew and differentiate, employing imaging cytometry and spatial transcriptomics technologies. In aim 2, I will define the functional role of transcription factors associated with T cell stemness through gain and loss of function approaches. Finally, in aim 3, I will ask whether perturbation of pLN intranodal positioning or inhibition of stem-T cell associated signaling molecules disrupt autoimmune T cell differentiation and prevent T1D onset. These proposed studies are designed to obtain a deep mechanistic understanding of the spatiotemporal and molecular factors that determine autoimmune T cell differentiation which could lead to novel therapeutic targets for T1D and other T cell-mediated autoimmune diseases.

NIH Research Projects · FY 2025 · 2024-08

Coiled-helix-coiled-helix domain containing protein 10 (CHCHD10, D10) is the first mitochondrial protein to be associated with familial frontotemporal dementia and amyotrophic lateral sclerosis (ALS). The normal function of D10 remains unknown, but to date several pathogenic D10 mutations have been reported. Our most recent studies have demonstrated that mutant D10 forms fibrillar amyloid aggregates that could participate in the pathogenesis of D10 frontotemporal dementia and may even contribute to Alzheimer’s disease. We propose that accumulation of mutant D10 amyloid aggregates disrupt mitochondrial proteostasis and activate mitochondrial integrated stress response (mtISR), leading to widespread metabolic alterations in affected tissues. Gaps in knowledge remain on how D10 mutations affect protein structure, folding, and interactions with mitochondrial membranes, leading to protein aggregation, amyloid formation, mitochondrial dysfunction, and neuronal degeneration in frontotemporal dementia. The first aim of this MPI R01 application proposes to elucidate the structural and molecular basis of D10 aggregation using an array of state-of-the art biochemical and structural approaches. It will investigate whether D10 fibrils occur in the brain of mouse models and human postmortem samples and whether their atomic resolution structures differ from those of D10 fibrils formed in vitro. We propose to test whether D10 disease mutants are associated with distinct structural strains, and if D10 fibrils can lead to seeding and spreading of aggregation in cells and in vivo, as in other forms of dementia associated with amyloid. The second aim is translational in nature and exploits the lack of detrimental consequences of downregulating D10 in vivo. In collaboration with Ionis Pharmaceuticals, it will test the neuroprotective and systemic effects of antisense oligonucleotides against D10 in an animal model of mutant D10 neurodegeneration, the D10 S55L knock in (KI) mouse. The goal is to decrease the protein aggregation burden and alleviate mtISR and pathology in this mouse model of D10 pathology. The third aim will investigate autophagy in vivo to assess whether it is altered in D10 S55L KI mouse and test approaches to enhance autophagy in the CNS to eliminate D10 aggregates. Moreover, since general autophagy can eliminate both cytosolic aggregates and mitochondria, to discriminate between these two components, we will use a genetic approach to selectively enhance mitophagy. The proposed project takes advantage of the complementary expertise of Dr. Kawamata, an expert in modeling and studying neurodegenerative diseases and Dr. Eliezer, an expert in protein structure and biochemistry and in alterations of protein folding and aggregation in neurodegeneration. Successful outcomes of this project could pave the way to clinical development of therapeutic strategies for D10-linked frontotemporal dementia.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY/ABSTRACT Alzheimer's disease and related dementias (ADRD) affect 5.5 million people in the US and account for $305 billion in health care spending annually. Nearly half of all Medicare decedents have an ADRD diagnosis prior to death. Nursing homes play an important role in end-of-life (EOL) care for individuals with ADRD. Among the 1.4 million nursing home residents in the US, 68% have some degree of ADRD, with the prevalence expected to increase. More than two-thirds of all ADRD-related deaths occur in nursing homes. Nursing home ownership has been associated with the quality of EOL care for residents with ADRD. Among US nursing homes, 12% have investment from real estate investment trusts (REITs). It is not known whether REIT investments in nursing homes are associated with the quality of EOL care. The prevalence and increasing rates of these corporate investments have raised concerns among policymakers and oversight agencies including the Government Accountability Office, MedPAC, the House Ways and Means Committee, the Senate Finance Committee, and The White House. The Centers for Medicare and Medicaid Services have proposed a new rule that would require public reporting of REIT investments in nursing homes. REITs are for-profit public or private corporations that invest in income- producing properties. They are “pass-through entities” which qualify for tax exemptions if they satisfy requirements related to sources of income and assets, including disbursing 90% of their taxable income to shareholders as dividends. These corporations purchase a nursing home's property and lease it back to the nursing home operator. Under this arrangement, the operator pays all of the expenses of the property, including real estate taxes, building insurance, and maintenance. These expenses are in addition to the cost of rent and utilities that are paid to the REIT by the operator. REITs are not directly involved in nursing home operations, though they may provide guidance to help the operator achieve profitability goals. Selling a nursing home's property to a REIT provides the operator with an infusion of capital that can conceivably be used for facility improvements and/or to provide more resources for resident care. However, annual rent escalations that are typically included in the leases may make rent unaffordable for nursing home operators over time and potentially lead to reductions in staffing, supplies, or equipment that negatively impact the quality of EOL care. Preliminary analyses indicate that registered nurse staffing levels in nursing homes are often reduced following REIT investment. For this project, a nationally representative database of nursing home residents with ADRD will be constructed from Medicare claims and Minimum Data Set assessments and merged with a novel database of REIT investments in nursing homes for the period 2012-2022. This will be the first study of the relationships between REIT investments in nursing homes and the quality and cost of care at the EOL for residents with ADRD. The project addresses priority areas of the National Institute of Aging by identifying economic and organizational factors associated with the use and quality of health care services for individuals with ADRD. The results will provide important insights sought by policymakers that will also benefit payers and nursing home residents with ADRD and their families.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY/ABSTRACT: Alzheimer's disease (AD), the most common type of dementia worldwide, is a rapidly increasing public health concern. There is an urgent need for the validation of novel targets and therapeutic strategies for AD. Given the heterogeneity of AD pathogenesis, targeting the connection between amyloid pathology, tau pathology, and neuronal cell death in AD is gaining increasing interest as a therapeutic strategy for AD. In this context, CAPON (the carboxy-terminal PDZ ligand of neuronal nitric oxide synthase (nNOS)) has been recently identified as a novel tau-binding protein that represents a promising target to break the connection between amyloid beta (Aβ), tau, and neurodegeneration. In tauopathy models, CAPON/tau interaction induces tau aggregation and neurodegeneration, while CAPON deficiency ameliorates AD-related pathological phenotypes. Moreover, the interaction between CAPON and nNOS mediates A-induced neurotoxicity in AD animal models. However, there are no small molecules reported to date that target the multifaceted role of CAPON in AD pathogenesis. Our goal is to establish targeting CAPON with small molecules as a promising therapeutic strategy for AD. Our hypothesis is that CAPON-targeted small molecules with dual inhibition of CAPON/tau and CAPON/nNOS interactions can ameliorate neuronal cell death and tau pathology. Building on our previous work focused on the discovery of small molecule modulators of tau and amyloid aggregation, we propose to screen a central nervous system (CNS)-focused chemical library of small molecules for the ability to bind CAPON using a temperature-related intensity change (TRIC)-based assay. Subsequently, we will use time-resolved fluorescence energy transfer (TR-FRET) assays to identify small molecule CAPON binders that inhibit CAPON-centered interactions (Aim 1). We will validate the identified hits using a panel of screening assays for CAPON-targeted small molecules and perform structural optimization guided by molecular modeling and site-directed mutagenesis (Aim 2). In Aims 2 and 3, we propose to evaluate the therapeutic potential of the optimized leads using a combination of in vitro assays and two AD mouse models. The selection of three leads for the AD mouse models will be guided by the assessment of the pharmacokinetic (PK) profiles and in vivo target engagement of the investigated compounds. The proximal expected outcome of this work is validating the potential of small molecules to target CAPON and efficiently block CAPON/tau and CAPON/nNOS interactions in vivo. The optimized leads from this work will serve as the basis for future target-based drug development programs and preclinical AD studies.

NIH Research Projects · FY 2025 · 2024-08

Metabolic dysfunction associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), and its progressive form, metabolic dysfunction associated steatohepatitis (MASH), is the leading cause of cirrhosis and liver transplantation in women, yet it is often undiagnosed until overt complications have developed. Non-invasive tests can now identify “at-risk” MASH, defined as having the highest risk for liver disease progression. Women of reproductive age commonly engage with healthcare systems during their pregnancy care, providing a unique opportunity to identify “at-risk” MASH early, particularly because metabolic changes in pregnancy may initiate and/ or worsen MASLD progression. As such, we first conducted a multidisciplinary protocol to screen for MASLD in pregnant individuals, Fatty Liver in Pregnancy (FLIP) I, in which we identified 1) a 14% overall prevalence of MASLD in pregnant individuals, 2) Hispanic ethnicity and pre-pregnancy weight as key predictors of MASLD in pregnancy, and 3) in a pilot study of postpartum assessment, found that 83% of individuals had worsening MASLD grade post-delivery. Given that hepatic lipid metabolism dysregulation plays a central role in MASLD initiation and progression, in a preliminary lipidomics analysis in FLIP I participants, we identified distinct lipidomic profiles in individuals with MASLD in pregnancy (compared to non-pregnant individuals with MASLD), and clustering of polyunsaturated fatty acid-derived oxidized fatty acids in individuals with MASLD, gestational hypertension and preeclampsia, emphasizing the potential shared role of these lipid pathways in the pathogenesis of MASLD and these adverse pregnancy outcomes (APOs). With our findings from FLIP I, we are now poised to study the longitudinal influence of MASLD in pregnancy, and associated lipid parameters, on women's health. In the proposed FLIP II study, we seek to evaluate the evolution of MASLD in pregnancy and its influence on pregnancy outcomes, identify predictors for the development of “at-risk” MASH after pregnancy, and evaluate the MASLD driven lipid based mechanisms that predict these events. We will prospectively screen 1540 pregnant individuals for MASLD (by ultrasound and Fibroscan) in early pregnancy and enroll them for longitudinal follow up for up to one year postpartum. We will administer detailed questionnaires collecting sociodemographic, dietary, and clinical data and collect and bank serum specimens for analysis. Our specific aims are 1) To determine the association between MASLD in pregnancy and APOs; 2) To evaluate antepartum factors that predispose to “at-risk” MASH post-pregnancy; and 3) To investigate the lipidomics-based mechanisms underlying MASLD in pregnancy and its association with post-delivery “at-risk” MASH. By uncovering novel insights into the natural history of MAFLD/ MASH in women in the pregnancy/ postpartum period, our study will help stratify risk factors for MASH progression and provide valuable information for future targeted interventions in this subgroup. Ultimately, this research will enhance our understanding of how MAFLD influences both the course of pregnancy and the subsequent progression of maternal liver disease.

NIH Research Projects · FY 2025 · 2024-08

Project Summary Aging involves a gradual clinical decline in cognitive and physical function and often the development of various comorbidities. However, significant life events, such as cancer diagnosis and treatment, can potentially accelerate clinical decline and aging. Various individual-level and neighborhood-level social determinants of health (SDOH) can also accelerate aging in cancer survivors, but a comprehensive approach to identifying and intervening on multilevel aging risk factors for cancer survivors is lacking. To investigate multilevel aging risk factors, a reliable measure is needed to quantify aging and monitor dynamic changes in aging-related health status over time. An electronic deficit accumulation index (eDAI) measures aging-related clinical declines over time by counting the accumulation of aging-related deficits using electronic health records (EHRs). However, the eDAI in cancer research has primarily been used at the time of diagnosis to manage comorbidity and reduce treatment toxicity, but it has been understudied in the context of cancer survivorship and aging trajectories. The broad goal of this project is to evaluate dynamic changes in aging-related clinical decline in cancer survivors using eDAI through real-world data analytics, identify multilevel determinants associated with SDOH disparities in clinical decline, and highlight potential interventions for healthy aging. Lung cancer is an ideal disease setting for achieving these goals. Lung cancer is the leading cause of cancer death, with a median age at diagnosis of 71 years. With recent increases in survival due to screening and new treatment paradigms, this disease is becoming a chronic disease of older age. More importantly, while cancer survivors are traditionally defined as people who survive long after treatment completion, many lung cancer patients live for a long time while still undergoing active treatment, highlighting the importance of longitudinal exposures to treatment or other time-varying risk factors on aging. Given that aging is also an evolving process, studying dynamic longitudinal risk factors for aging in lung cancer survivors could serve as a useful model in aging epidemiologic research. The study cohort will comprise >89,000 survivors (age≥65) with early-stage non-small cell lung cancer who are healthy (i.e., including both robust [eDAI<0.2] and pre-clinical decline [eDAI: 0.2- 0.34]) at diagnosis in SEER-Medicare (2013-2017). The primary outcome will be the time to clinical decline (eDAI≥0.35). The aims are (AIM 1) to identify key individual-level risk factors affecting clinical decline, (AIM 2) to investigate neighborhood-level SDOH to develop a comprehensive risk prediction model for clinical decline, and (AIM 3) to conduct real-world validation using an integrated EHR database of academic and community healthcare systems. Completing these research aims and training goals (in real-world data analytics, SDOH disparities, and aging epidemiology) under the strong mentorship team in Stanford’s rich environment will be critical for me to become an independent investigator at the intersection of aging, cancer survivorship, and disparities with key skills for the era of expanding real-world big data and comprehensive disparities research.

NIH Research Projects · FY 2025 · 2024-08

OVERALL: ABSTRACT Diffuse large B-cell lymphoma (DLBCL) is an aggressiveand clinically heterogeneous malignancy derived from B-cells transiting the germinal center (GC) reaction. Indeed, the biological heterogeneity of DLBCL aligns with a continuum of developmental states within and subsequent to the GC reaction. The genetic hallmarks of DLBCL are somatic mutation in chromatin modifier and transcription factor genes and immune synapse signaling mediators. Examining mechanisms of action for these mutations has provided insights into discrete cell-intrinsic processes that are deregulated in DLBCL, but do not account for how these mutations function, when they occur together in the same lymphoma cells, how they shape the lymphoma microenvironment LME, how the LME influences lymphomas, and how critical host features such as age influence and define the nature of these lymphomas and their LME. DLBCLs are thus complex entities from the systems biology and immunological standpoint and a paradigm shift in our thinking about these tumors is necessary to arrive at a definitive understanding of disease pathogenesis and effective and precise therapeutic strategies. To address this challenge we have assembled a team of experts with distinct spheres of expertise, suites of cutting edge technologies and powerful and physiologically accurate model systems. They have worked together as a team to develop a compelling body of preliminary data supporting the conceptual framework of this proposal, and have developed critical resources such as shared genomics databases, primaryhuman PDX repositories, genetically engineered mouse models, computational pipelines and graphical user interfaces, and others. They will address the central hypotheses that i) chromatin is the key integrator, rheostat and executor of cell-intrinsic and cell- extrinsic pathways regulating key GC cell fate decisions downstream of immune synapse signaling, ii) DLBCLs reflect a continuum of malignant states with each tumor aligning with one or more points along GC B-cell epigenetic trajectories, iii) GCB and ABC DLBCLs are defined by crosstalk between their chromatin landscapes and other immune populations to shape the LME, iv) that these chromatin to LME effects vary in specific ways with mutation profiles and with aging age, and that v) rational targeting of DLBCLs must take into account and specifically antagonize these specific chromatin-immune synapse - LME scenarios to achieve long term tumor eradication.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Patients with hematologic cancer are at increased risk of morbidity and mortality from severe lung infections due to both disease and treatment-associated defects in cell-mediated and humoral immunity. CD8 T cell immunity is critical for survival from these infections, as evidenced by our laboratory’s findings in patients with hematologic cancer and severe COVID-19 infection. However, persistent antigen exposure during severe infections leads to loss of T-cell cytotoxic effector function and proliferative capacity, leading to inefficient pathogen clearance. Therefore, strategies to reverse CD8 T cell dysfunction represent a critical unmet need in patients with hematologic cancer and severe lung infections. Our laboratory previously demonstrated that mitochondrial redox stress drives CD8+ T-cell dysfunction during persistent antigen exposure in a manner that can be reversed by the antioxidant N-acetylcysteine (N-Ac) and recently completed a clinical trial of N-Ac in cancer patients with severe COVID-19 infection. In my preliminary studies, I found that circulating CD8 T cells from patients with cancer and severe COVID-19 had significantly reduced expression of Pellino-1 (PELI1) following N-Ac treatment. PELI1 is an E3 ubiquitin ligase known to negatively regulate CD8 T-cell activation. However, its role in limiting CD8 T-cell function during severe infections remains unknown. Therefore, my hypothesis is PELI1 is a redox-sensitive E3 ligase that limits CD8 T cell immunity during severe respiratory infections by selectively degrading substrates essential for self-renewal and cytotoxicity. We will address this hypothesis through the following Specific Aims. In Aim 1, I will test the hypothesis that PELI1 limits CD8+ T cell immunity during severe respiratory infections in vivo, by analyzing primary samples from hematologic cancer patients with a variety of respiratory infections as well as by determining the impact of PELI1 knockout on T-cell mediated pathogen clearance in mouse models of severe pneumonia. In Aim 2, I will determine the mechanism by which PELI-1 restricts CD8+ T-cell function during persistent antigen exposure. By performing biochemical and proteomic analyses to identify both PELI1 substrates and redox-dependent post- translational modifications in PELI-1 to gain insight into mechanisms of PELI1 function and regulation. The information obtained from this project will lay the groundwork for understanding of how redox regulation impacts T-cell dysfunction, thereby paving the way for innovative therapeutic strategies for patients with severe respiratory infections, including those with concurrent hematologic cancers.

NIH Research Projects · FY 2025 · 2024-08

Cognitive impairment is highly prevalent in patients with multiple sclerosis (MS) and increases in severity with disease progression. Unfortunately, treatment options for MS-related cognitive impairment are limited in that they are not neurobiologically-based or personalized. Moreover, to date there are no approved pharmaceutical treatments to manage chronic cognitive symptoms. Brain network studies using diffusion MRI (dMRI) to measure white matter structural connectivity (SC) and functional MRI (fMRI) to measure functional connectivity (FC) have identified specific networks related to cognitive impairment in MS. However, both increased and decreased FC have been associated with lower cognitive performance, leading to unresolved questions regarding the response of brain networks to the pathology of MS. There is an urgent, unmet need to understand the directionality of this relationship, and mechanisms driving these brain activity changes, if we are to design neurobiologically-based cognition-preserving therapies. Our overall objective is to utilize a multi-scale, multi-modal, longitudinal imaging approach to examine the association of cognitive function with both macroscopic and microscopic changes in brain function, anatomy, and neuronal integrity, and to create clinically applicable models that can identify patients at risk for cognitive decline. We will utilize MRI to examine FC and SC brain networks (macroscopic) and [11C] Flumazenil (FMZ) positron emission tomography (PET) to measure concurrent receptor-level neuronal integrity (microscopic). We our hypotheses are based on a three-stage trajectory of cognitive decline in MS i) early “adaptive” stage where increased FC is related to intact neuronal integrity and cognitive resilience, ii) middle “adaptive exhaustion” stage of cognitive decline wherein FC continues to increase but with decreasing efficacy due to loss of neuronal integrity and continued SC damage and, finally, iii) “decline” or network collapse stage wherein all imaging markers decline with cognition. Here, we focus on the first two stages of the trajectory, as our aim is to identify mechanistic targets prior to overall decline. In Aim 1, we will examine the association between cognition and each imaging modality (and their changes) over 4 years in 66 people with MS and 30 controls. Our hypothesis is that larger FC/FMZ-PET binding potential and more intact SC/gray matter volume will be related to preserved cognition in the “adaptive” stage of cognitive decline, while higher FC and reduced SC/FMZ-PET and gray matter volume will be related to worse cognition in the “adaptive exhaustion” stage. In Aim 2, we hypothesize multi-modal, multi-scale imaging will reveal i) positive correlations between neuronal integrity and FC and ii) negative correlations between neuronal integrity and SC in the “adaptive” stage; both of these relationships will reverse in the “adaptive exhaustion” stage. Lastly, in Aim 3, we will use MRI-based measures of SC/FC/brain atrophy to identify patients at high risk for future cognitive decline and provide a clinically feasible tool for clinicians. The overall impact of this proposal is to create a clear path to develop and deliver personalized, effective therapies to prevent cognitive decline in people with MS.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT Over one-half the population of childbearing age women are cytomegalovirus (CMV) seropositive. More than 90% of CMV-seropositive women will shed the virus in their breast milk during the first month of lactation without clinical signs of systemic infection. Postnatal cytomegalovirus (pCMV) infection occurs in 4-20% of preterm infants, manifesting as a sepsis-like syndrome and respiratory decomposition. Developing novel strategies to eliminate the risk of pCMV infection or adverse host responses to CMV+ human milk in preterm infants is a critical step to maximize the safety of human milk delivery. The overall objectives of this study are to (1) test the potential of an added CMV neutralizing antibody to minimize cellular infiltration and infection, and to (2) characterize the human milk compositional differences in CMV+ versus CMV- milk and its impact on preterm health outcomes. We will conduct two complimentary specific aims: (1) Evaluate the pharmacokinetics and neutralizing efficacy of an anti-CMV antibody added to CMV+ milk. (2) Investigate the impact of mammary CMV reactivation on the human milk lipidome and determine the impact of receiving CMV+ human milk on neonatal outcomes. This proposal brings together leading experts in neonatology, neonatal nutrition, human milk lipidomics, infectious disease, CMV, and vaccine development. Adding anti-CMV neutralizing antibodies in CMV+ human milk has the potential to reduce the risk of postnatal CMV transmission in preterm infants who rely on breast milk for optimal nutrition. In addition, human milk compositional changes will be identified that will identify targets to mitigate the risk of lipidomic and inflammatory driven secondary disease outcomes related to CMV reactivation in breast milk and serve as efficacy biomarkers for future intervention trials to interrupt human milk CMV reactivation and infectivity.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY / ABSTRACT Prostate cancer (PCa) is a clinically and molecular heterogenous disease, with distinct subtypes. These subtypes are associated with characteristic genomic alterations, gene expression profiles, and treatment responses, implying truly distinct biology. We have defined one such molecular subclass of PCa characterized by recurrent missense mutations in the ubiquitin ligase SPOP -- representing about 10-15% of PCa, in both primary and metastatic disease. These SPOP mutant cancers display distinct biology and response to therapies. However, other key players in the SPOP pathway influencing its action in PCa, and the broader ability to specifically target this axis for patient benefit, remain incompletely understood. Preliminary data generated by our multidisciplinary, collaborative group have defined novel elements of the SPOP signaling pathway, including the upstream regulator G3BP1, and suggest that the subclass of PCa defined by deregulation of SPOP signaling are preferentially targetable with novel therapeutic interventions. The overall objective of this proposal is to define the mechanistic, biological, and therapeutic consequences of alterations to the SPOP signaling pathway, including its upstream regulator G3BP1. Using novel models and human prostate cancer samples, our preliminary data demonstrate that a novel endogenous inhibitor of the SPOP ubiquitin ligase, G3BP1, can potentially phenocopy the oncogenic effects of SPOP mutation, and that modulation of this effect with small molecule inhibitors can be a viable therapeutic strategy. Furthermore, we show that modulating SPOP activity reprograms androgen receptor (AR) function through key downstream substrates, altering chromatin accessibility and transcription driven by AR and making these cancers highly reliant on AR activity. This project will elucidate the molecular details underlying these phenomena through the following Aims: 1) define the role of G3BP1-driving prostate tumorigenesis in model systems and human prostate cancer, and the ability to target this upstream axis. 2) establish the therapeutic potential of targeting the SPOP axis by modulating targetable downstream signaling nodes. To accomplish this, we will leverage unique, biologically and clinically relevant model systems, novel small molecule inhibitors, innovative approaches to modulating ubiquitin ligase signaling, and data from human prostate cancer samples. This project will define the critical dependencies in specific subtypes of prostate cancer and broader applicability to treatment response, and provide the foundation for precision clinical trials and novel strategies to attack this subclass of cancer.

NIH Research Projects · FY 2026 · 2024-08

Deforestation is a critical global issue that leads to extensive macro-level changes in our environment. While past literature has linked sudden or expansive environmental changes to substance use, a knowledge gap exists on how deforestation may influence tobacco and alcohol consumption. The objective of this K99/R00 is to establish clearer linkages and quantify effects and associations between deforestation and tobacco and alcohol use, using Indonesia as the geographic focal area. The K99 phase is designed to achieve this objective and augment the candidate’s prior research experience by providing training in: (a) the determinants and epidemiology of substance use and mental health, (b) satellite remote sensing and image classification, (c) advanced methods for environmental epidemiology, and (d) causal designs and software for reproducibility and accessibility. This training is critical to the candidate’s long-term goal of becoming a leading epidemiologist who builds and uses rigorous statistical approaches to examine environmental exposures and social and behavioral health outcomes in the United States and in low- and middle-income countries. The proposed research will draw upon satellite imagery to detect changes in forest cover and composition and 10 years of data (2012-2022) from a nationally and sub-nationally representative, repeat cross-sectional survey. Aim 1 (K99 phase) will examine associations between forms of deforestation (wildfire and logging) and tobacco and alcohol use in the general population and among subgroups. It will subsequently estimate tobacco and alcohol use under different forest loss scenarios to estimate what would be the population-weighted burden of use attributable to incremental increases in deforestation, compared to the counterfactual of stably forested areas. Aim 2 (R00 phase) will develop a new causal inference method for estimating the “pure” effect of deforestation on tobacco and alcohol use. Economic incentives from palm oil production introduce unmeasured confounding and lead to differential exposure probability when illegal wildfires are set to clear land. A longitudinal extension of differential comparison design, also known as “negative or secondary controls,” will be created in a simulation study to contrast three groups (wildfire zones with and without palm oil plantations and stably forested zones) and parse the “pure” effect of deforestation. The new method will then be applied to the real data for estimation. A software package and tutorial will be developed to facilitate use and accessibility. Aim 3 (R00 phase) will examine which combination of factors clustered within regencies are most important in tobacco and alcohol use and model joint effects in probit Bayesian kernel machine regression. The proposed research aligns with NIEHS’ Mission, Vision, and Strategic Plan.

NIH Research Projects · FY 2026 · 2024-08

Summary The development of the human body involves cell specification and cell fate transition starting from the embryos. Precise coordination of gene expression networks is required: lineage-specific genes are transcriptional activated during early development, while genes for ectopic lineages are repressed in the process. The precise control of gene expression is governed by epigenetic chromatin modifications. Recent advances showed that genes encoding epigenetic “writer” and “eraser” enzymes are frequently mutated in human diseases. However, treatment or early prevention methods are hampered by the lack of knowledge on how the epigenetic landscape is precisely regulated. We are investigating how a critical histone methylation (trimethylation of lysine 27 on histone H3, or H3K27me3) is precisely regulated. H3K27me3 is the hallmark for facultative heterochromatin, which dynamically regulate gene repression during body development. During early differentiation, H3K27me3 is deposited on pluripotency genes, erased on cardiac genes, and maintained on other developmental genes for ectopic lineages. The dynamic level of H3K27me3 across the genome is essential for the ON/OFF switch of gene expression, but it remained unclear how H3K27me3 is regulated in a coordinated temporal and spatial manner. We hypothesize that key macromolecular interactions including protein-protein and protein-nucleic acid interactions regulates the specificity of the H3K27me3 “writer” enzyme – Polycomb Repressive Complex 2 or PRC2. Recent progress and our preliminary data show that the dynamic interactions between PRC2 and its accessory proteins play key roles in the spatiotemporal regulation of epigenetic silencing specificity. To test the hypothesis, we propose to fully interrogate the mechanism by employing a series of separation-of- function mutants. Understanding the mechanism will open to door to further identification of novel therapeutical targets to manipulate gene expression through epigenetic mechanisms.