University Of Michigan At Ann Arbor

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Chemotherapy causes neurotoxic damage to the peripheral (PNS) and central nervous systems (CNS) in older, taxane-treated female breast cancer survivors (OTTBCS). However, the literature has primarily attributed chemotherapy’s significant mobility disability to changes in the PNS through chemotherapy-induced peripheral neuropathy (CIPN) without accounting for the role of the CNS. There is an urgent need to understand the combined contributions of the PNS and CNS to gait in this vulnerable population since the CNS could offer a novel target for rehabilitation. My long-term goal is to become an independent physician scientist who develops mobility interventions tailored for the needs of aging cancer survivors. The proposal’s objectives are to investigate the relationships between measures of CNS function (executive function, prefrontal hemodynamics) and walking performance in OTTBCS and to provide proof-of-concept that transcranial direct current stimulation (tDCS) targeting the left dorsolateral prefrontal cortex (dlPFC) can improve walking within this patient population. The central hypothesis is that chemotherapy increases reliance on executive function for walking control by inducing PNS dysfunction, but in these patients the capacity of executive function to compensate may be compromised due to additional CNS damage. Thus, compared to their cancer-free peers, taxane-treated breast cancer survivors will have worse gait performance, particularly while dual task walking (e.g., talking while walking) because of both PNS and CNS dysfunction. The specific aims are to compare OTTBCS to controls in 1) executive function’s role in dual task cost to gait performance, 2) prefrontal cortex activation during dual task walking, and 3) the acute effects of a single exposure to tDCS targeting the left dlPFC on gait performance. In Aims 1 and 2, the study will use a well characterized data set of older, cancer-free women as a control group and compare them to a group of OTTBCS. The NIH cognitive toolbox and dual task walking paradigms recording both gait performance and hemodynamic response via functional near infrared spectroscopy (fNIRS) will be used. For Aim 3, a blinded, randomized, crossover trial will evaluate a single exposure to tDCS to the dlPFC versus sham on dual task gait performance in OTTBCS. The training objectives include developing expertise in 1) study design and analysis, 2) understanding CNS gait control with cognitive tests, fNIRS, and gait assessment, and 3) tDCS neuromodulation. The proposal is significant and innovative, because it will improve the understanding of gait in OTTBCS by moving beyond CIPN to include executive function and the prefrontal cortex and it will assess whether these are modifiable via non- invasive brain stimulation. Ultimately, understanding the contributions of executive function and the prefrontal cortex to gait may impact rehabilitation by adding executive-gait control as a target for mobility interventions.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY / ABSTRACT Diffuse Midline Gliomas (DMGs) are a type of brain tumor with a survival rate of less than 10% beyond two years from diagnosis. Approximately two-thirds of DMGs have mutations in histone H3.3 in H3.3A (H3F3A K27M). Disease monitoring for DMG patients is generally limited to periodic MRI scans, from which progression is difficult to determine. Recent work indicates that circulating tumor DNA (cf-tDNA) in cerebrospinal fluid (CSF) and plasma of patients with H3K27M-DMG can be quantified using a droplet digital polymerase chain reaction (ddPCR) assay and can offer key information that supplements and often precedes a tumor’s response to treatment on MRI. This assay has established a low-level variant allele frequency (VAF) of 0.01% that can be validated as a cf-tDNA positive state (ctDNA+) to indicate diagnosis or earlier detection of progression. However, the novel H3K27M ddPCR assay remains “research grade” and not yet designed for clinical-grade repeatability and reliability. Currently, there are no Clinical Laboratory Improvement Amendments (CLIA)-certified molecular tests (academic or commercial) for H3K27M detection that are sensitive enough to track low levels of tumor DNA (<1%) in patient plasma. Therefore, there is a critical need to establish a clinical- grade H3K27M plasma assay with sensitivity for the diagnosis and therapeutic monitoring of H3K27M-DMG therapy. The central hypothesis is that the H3K27M cf-tDNA ddPCR assay (i) will meet the necessary assay performance milestones to advance our CLIA-compliant, analytically validated LDT into clinical testing (UH2) and (ii) will have a positive predictive value of 90%+ for a positive cf-tDNA result (>0.01%) to predict or correlate with radiographic progression within 2 months. Aim 1 (UH2): To analytically validate an H3K27M ctDNA plasma assay as a lab developed test. The objective of this aim is to systematically define the analytic performance characteristics of this high-performance H3K27M cf-tDNA assay using synthetic controls, true positives, and clinical specimens for analysis in a CLIA-compliant setting. Upon completion of this aim, the assay performance milestones necessary to advance this CLIA-compliant, analytically validated LDT into clinical testing (UH3) will be met. Aim 2 (UH3): To evaluate the predictive properties of an H3K27M ctDNA lab developed test for prediction of recurrence in a cohort of DMG patients. This team co-leads an ongoing phase 2 clinical trial to explore the benefit of ONC201 and paxalisib in H3K27M-DMG [PNOC22, NCT04773782]. This project will leverage retrospective-prospective H3K27M+ DMG clinical validation cohorts drawn from PNOC22, comprising 75 (training cohort) and 50 (test cohort) patients who have completed treatment for H3K27M-DMG and provided plasma specimens every two months during therapy. This project represents a critical and feasible step towards a liquid biomarker to supplement MRI monitoring in H3K27M- DMG.

NIH Research Projects · FY 2025 · 2025-09

Project Summary The rise of youth onset Type 2 Diabetes Mellitus (T2DM), one of the most common endocrine diseases, is an important public health concern. Current methods to identify risk of T2DM are neither specific, such as screening for elevated body mass index (BMI), nor sensitive. Most risk factors are thought to be related to lifestyle and do not account for environmental chemical exposures or individual variation in biological response to lifestyle and chemical exposures. Despite this, evidence has emerged that links endocrine disrupting chemicals such as phthalates to T2DM. Phthalates are a class of human-made compounds found in plastics and fragrances. However, analyses linking gestational phthalate exposure, an important window of susceptibility, to endocrine disruption and disease risk later in life are sparse and rely on non- specific anthropometric outcomes such as BMI. The use of multi-omics data in epidemiological research can help to identify biomarkers of disease and predict disease development, such as elevated fasting blood glucose, before clinical symptoms occur, and quantify inter-individual differences in disease risk. Epigenomics is the measurement of environmentally modifiable chemical marks on DNA and chromatin which regulate gene expression. Metabolomics, measurements of compounds circulating in the blood, provide a real-time view of metabolic activity. These analytes may elucidate early markers of disease development and potentially serve as biomarkers of disease. The central hypothesis of this work is that changes to the epigenome and metabolome are predictive of blood glucose dysregulation in adolescence, and that gestational exposure to phthalates increases this risk. We address this hypothesis in the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) longitudinal birth cohort study. Aim 1 focuses on understanding the effect of maternal phthalate exposure on the offspring epigenome and how maternal nutrition interacts with phthalates to alter the epigenome. Aim 2 applies novel computational techniques to epigenomic and metabolomic data to predict adolescents at elevated risk for elevated fasting blood glucose. Overall, this study will contribute to the scientific knowledge base about potentially preventable exposures that contribute to T2DM development and biomarkers to improve early screening efforts. Completion of this research along with the proposed training plan will equip me with a highly specialized skillset to leverage data science techniques and include omics, nutrition, and toxicant exposure in precision environmental health research.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Steatotic liver disease (SLD) prevalence in just the United States is estimated to upwards of a quarter of the population. It ranges in presentation from simple Hepatic Steatosis without evidence of liver injury to development of inflammation and fibrosis (Metabolic Associated Steatohepatitis; MASH). Those individuals that develop MASH have increased risk of progression to advanced fibrosis and ultimately cirrhosis. Understanding the cellular and molecular mechanisms of the transition from simple steatosis to inflammation and fibrosis is needed. Recent work has shown that MASH leads to high level of hepatic and systemic ammonia. Moreover, there is mounting evidence that ammonia can contribute to the progression of MASH. Ammonia levels are detoxified through the urea cycle. The liver is the major site of ammonia detoxification and consistent with the increase in ammonia in MASLD, urea cycle genes are significantly decreased in MASLD. However, the molecular mechanism driving the metabolic reprogramming to alter liver ammonia is unclear. Preliminary studies have implicated the hypoxia-inducible factor (HIF) pathway in the development of liver steatosis and fibrosis. I show that activation of hepatocyte HIF2a (but not HIF1a) signaling decrease urea cycle genes, increases ammonia levels, steatosis, inflammation, and fibrosis. Therefore, I hypothesize that HIF2α exacerbates liver injury and dysfunction by disrupting urea cycle metabolism, resulting in steatosis, and promoting an inflammatory and profibrotic response. To test this hypothesis, I propose two Aims: 1) To understand how dysregulation of HIF signaling drives altered hepatocyte gene expression and metabolism. Hepatic nuclear factor (HNF)4α is the master transcription factor for the regulation of urea cycle genes. I will understand the crosstalk of HIF2α and HNF4α signaling. 2) Define if inhibition of HIF2α is a viable target for clinical intervention in the progression to advanced fibrosis/cirrhosis. Recently a clinically relevant on-target HIF2a, beltifuzan was approved for clear cell renal carcinomas. I will test the role of beltifuzan in preclinical models of MASH. The proposed research seeks to understand the role of HIF signaling in the development of steatosis and fibrosis that if left unabated can progress end stage liver disease and to the sequalae that drive the significant morbidity and mortality of the disease.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Management of anticoagulant medication, including for the management of low-risk pulmonary embolism, is challenging and frequently does not follow evidence-based guideline recommendations. On the one hand, up to 40% of all patients with an acute pulmonary embolism are at sufficiently low risk for complication that guidelines recommend outpatient management rather than hospitalization. However, this evidence-based practice is rarely utilized in the United States. On the other hand, when oral anticoagulants are prescribed for pulmonary embolism and other common thrombotic conditions, up to 25% of prescriptions do not follow evidence-based guidance and patients are exposed to unnecessary life-threatening risks of thromboembolism or bleeding. The research activities supported by this K24 award will complement Dr. Barnes’ ongoing NIH- funded R01 project that aims to improve the use of outpatient management of low-risk pulmonary embolism across 12 health systems in Michigan. This award also leverages Dr. Barnes’ current AHRQ R18-funded project that uses both electronic health record alerts and clinical pharmacists to improve safe- and evidence- based anticoagulant prescribing. While Dr. Barnes’ career goal is to develop, implement, and evaluate anticoagulation stewardship efforts, such as the ones being tests in his current R01 and R18 projects, he also is passionate about mentoring the next generation of patient-oriented researchers who focus on implementation science methodology. Dr. Barnes will leverage ongoing NIH R01 funded projects to expose his mentees to practical aspects of implementation science, including implementation mapping and qualitative assessments of implementation adaptation. Dr. Barnes will also focus on his own career development by gaining critical training in optimization trial design and advanced mentoring skills. Dr. Barnes has assembled a senior, diverse, and highly committed set of advisors to oversee his personal career development. He has also identified several channels for increasing his mentorship opportunities with clinician-scientists eager to develop as independent patient-oriented researchers who focus on implementation of evidence-based clinical medicine.

NIH Research Projects · FY 2025 · 2025-09

The University of Michigan and the Tissue Engineering and Regenerative Medicine International Society, Americas Chapter (TERMIS-AM) will be hosting and organizing the upcoming 2025 meeting of the TERMIS, Americas Chapter (TERMIS-AM) Conference and Exposition. Michigan is requesting support for travel awards for the Student and Young Investigator Section (SYIS) trainees to attend the full conference. The theme of the conference and the highlight of the meeting is “Next Generation Tools for Regenerative Medicine.” The preconference symposia will focus on strategies for accomplishing translational research and bringing regenerative medicine therapies to the clinic.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY CD8+ T cells can kill cancerous cells, but they become disabled by a suppressive tumor microenvironment (TME) that is established by pancreatic ductal adenocarcinoma (PDAC) and other solid tumors that are refractory to current immunotherapies. The TME deprives CD8+ T cells of the cytokine-induced JAK-STAT signals they require to survive and remain functional. To overcome this critical barrier to a T cell-mediated anti-tumor response and prevent T cell dysfunction, specific cytokine-induced JAK-STAT signals must be restored. However, the development of cytokine receptor agonists has faced numerous challenges, including poor pharmacological properties and severe toxicities. We have pursued an alternative strategy and developed an activator of STAT5, the downstream mediator of IL-2 receptor signaling. Our preliminary data demonstrate that a STAT5 activator delivered by retroviral transduction to T cells ex vivo sustains CD8+ T cell viability and functionality under suppressive culture conditions where the pro-survival cytokine IL-2 is absent. Moreover, RNA sequencing revealed that a STAT5 activator promoted a memory-like T cell phenotype with reduced expression of genes associated with terminal effector differentiation and T cell exhaustion. Based on these preliminary findings, I will evaluate the hypothesis that a STAT5 activator can enhance the persistence and functionality of CD8+ T cells within the TME in vivo and can be used to expand memory-like CD8+ T cells ex vivo. In Aim 1, I will perform functional assays and gene expression analysis to compare CD8+ T cells cultured with cytokines to those where STAT5 is directly activated to determine how a STAT5 activator influences CD8+ T cell differentiation. I will also evaluate the translational potential of a STAT5 activator by testing its ability to promote human CD8+T cell survival and function ex vivo. In Aim 2, I will determine whether adoptively transferred tumor- specific T cells modified with a STAT5 activator can better sustain a T cell mediated anti-tumor response using a mouse model of PDAC. Tumor infiltrating T cells and the TME cell populations will be interrogated to address the mechanism that underlies an in vivo response. The experiments of these specific aims will address a fundamental barrier to the treatment of refractory solid tumors, such as PDAC, and provide me with robust foundational training in the field of cancer immunology.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Molecular markers have transformed the diagnosis, prognosis, and treatment of human cancers. However, ac- cess to molecular testing is uneven and often delayed because of the complex laboratory infrastructure required to obtain molecular data from surgical cancer specimens. These and other multifaceted barriers result in <10% of patients receiving molecularly targeted therapies that improve patient survival. Rapid, point-of-care molecular screening would transform the treatment of human cancers by identifying patients at the earliest possible point in their cancer care, ensuring easy access to molecular testing and allowing for immediate delivery of molecu- larly targeted surgical and medical treatment. There exists a critical need for innovative and scalable methods for molecular cancer screening. Stimulated Raman Histology (SRH) is an emerging and innovative optical imag- ing method that produces fast, high-resolution, label-free microscopy images of fresh surgical specimens at the patient’s bedside. We recently demonstrated that SRH combined with artificial intelligence (AI) models can accu- rately detect tumor infiltration and predict the key molecular markers in brain tumors within two minutes of tumor biopsy (Nature Medicine 2023, Nature 2024). However, earlier SRH-AI models are limited in that they require extensive data annotations, lack clinical context, and cannot adapt to other organs or cancer types. Address- ing these limitations through advanced AI methods is an essential step towards developing scalable SRH-based molecular cancer screening methods. Here, we aim to develop DeepSRH, an integrated, point-of-care, SRH- based screening system for rapid and accurate molecular marker prediction using deep neural networks. Driven by our preliminary data and motivated by recent work on vision-language AI models, we hypothesize that large- scale, self-supervised foundation model training on a diverse SRH dataset plus efficient model fine-tuning can produce SRH-AI models for accurate molecular marker prediction. The central objective of this proposal is to vali- date DeepSRH across cancer types (brain, lung, prostate) for AI-based molecular cancer screening and real-time clinical decision support. Firstly (Aim 1), we aim will develop a self-supervised learning strategy, called Slide Pre- trained Transformers (SPT), for DeepSRH foundation model training. Next (Aim 2), we will optimize DeepSRH foundation models for molecular marker prediction through efficient and multimodal fine-tuning methods. Lastly (Aim 3), we will test fine-tuned DeepSRH performance in a multi-center, multi-organ cohort of cancer patients. Using College of Pathology and DECIDE-AI guidelines, our milestone is a balanced diagnostic accuracy of ≥95% with a calculated target sample size of 424 total patients. The expected contribution is an autonomous SRH-based molecular cancer screening workflow. This proposal aims to bridge the gap between rapid optical imaging and real-time molecular screening by strategically addressing multiple challenges using state-of-the-art AI techniques. Translating SRH using advanced AI could revolutionize access to molecular testing in today’s precision medicine landscape. We aim to create a new standard for the accessibility of molecular diagnosis in human cancers.

NIH Research Projects · FY 2025 · 2025-09

Why do we age and why do some of us stay healthy longer than others? Thanks to the development of shorter-lived aging model organisms, much has been learnt about the processes that contribute to our inevitable demise, and the tight connection between these processes and the development of age-associated diseases, including Alzheimer’s and Parkinson’s Disease. Our recent genetic and biochemical studies in C. elegans have revealed a novel longevity paradigm, triggered by early-in-life oxidative stress and mediated by the redox sensitivity of the histone 3 lysine 4 trimethylating (H3K4me3) COMPASS complex. We discovered that modulation of the H3K4me3 landscape in C. elegans led to the activation of at least two highly conserved longevity factors, heat shock factor-1 (HSF-1) and the starvation response regulator HLH-30 (TFEB in mammals), both of which essential for the lifespan-extending effects. Mechanistic follow-up studies revealed that the observed increase in lifespan depends on a non-canonical role of HSF-1 in modulating lipid homeostasis and fatty acid oxidation and involves a hitherto unknown regulatory interaction between HSF-1 and HLH-30. We found this interplay between transient ROS accumulation, changes in H3K4me3 levels and transcription factor activation to be conserved from C. elegans to mammalian cells and, most recently, to select tissues of post-weaned mice, which were exposed to oxidants for the first three weeks of their life. Based on these exciting data, and recent reports that in a range of different model organisms, including mice, early-in-life time windows exist in which lifespan can be set, we now propose that mild oxidative stress, when experienced at the right time in life, triggers a hormetic response that manifests itself through stable changes in the epigenetic landscape, gene expression and physiology. In this proposal, we will take a multipronged approach to determine the molecular mechanism by which ROS-mediated changes in developmental H3K4me3 levels promote lifespan extension in C. elegans (Aim 1), explore the long-term epigenetic and transcriptional changes that are elicited by short-term oxidative stress treatment in C. elegans as well as mitotic and postmitotic mammalian cells (Aim 2), and evaluate the molecular and physiological consequences of early-in-life oxidative stress treatment in mice (Aim 3). These studies have the clear potential to provide us with previously unknown mechanistic insights into how ROS-sensitive epigenetic circuits transform transient events in early life into long-lasting, and potentially universal, health- and lifespan extending processes. Our studies in C. elegans and cell culture models will furthermore serve us to guide parallel explorations in mice and provide new leads useful in the search for drugs that slow aging in mammals.

NIH Research Projects · FY 2025 · 2025-09

Abstract: Meaningful impact on the prevalence and incidence of substance use disorders (SUD) and HIV requires an array of evidence-based interventions that address individuals’ changing needs, circumstances, and strengths. Digital adaptive interventions (DAIs) that leverage advances in digital technologies such as mobile devices, wearable sensors, and artificial intelligence have shown great promise in improving outcomes for managing SUDs and preventing HIV, as well as for improving outcomes in other health domains. However, such interventions remain difficult and resource- intensive to build, and existing approaches to building them fail to support dissemination of best practices in both methodology and building the evidence base. In this project we will build and make available JustIn: a sustainable open source software (OSS) platform and community for advancing research in adaptive interventions. Within the scope of this project we will develop and release an initial version of JustIn that supports the majority of the functionality required to create existing state of the art adaptive interventions. Along with the initial release we will provide comprehensive documentation, tutorials, and working sample application code to bootstrap the adoption of JustIn for future intervention development. Following best practices for creating sustainable OSS communities, we will develop guidelines and procedures for integrating code contributions from the wider research community and implement governance structures that facilitate community input on features and priorities for future versions of JustIn. JustIn will democratize research to optimize digital adaptive interventions in SUD/HIV and other domains of health, allowing investigators to keep pace with emerging technologies and leverage them to produce radically effective and resource- efficient interventions. The growth in systematic development of novel digital adaptive interventions has the potential to reduce the burden of SUD/HIV and other chronic disorders.

NIH Research Projects · FY 2025 · 2025-09

Abstract: It has been well documented that disease activity in inflammatory mucosal diseases including inflammatory bowel disease is linked to the transepithelial migration of neutrophils through the mucosal epithelium and ultimately into the intestinal lumen. Co-incident with massive luminal influx of neutrophils is uncontrolled release of toxic tissue damaging metabolites that contribute to mucosal and/or transmural injury including edema, loss of goblet cells, decreased mucus production, crypt cell hyperplasia, ulceration and crypt abscess formation. The complex signaling mechanisms that regulate neutrophil transepithelial migration and inflammatory function in mucosal tissues have not been fully elucidated even though excessive neutrophil activation is heavily implicated in disease pathology of IBD and other inflammatory disorders. Preliminary data identifies the tyrosine phosphatase CD45 as an important regulator of neutrophil intestinal infiltration and inflammatory function. This proposal will determine effects of neutrophil specific loss of CD45 on intestinal inflammation and repair using novel neutrophil specific CD45 deficient mice. We will also determine how CD45 phosphatase activity regulates neutrophil intracellular signaling pathways and inflammatory effector functions including migration, degranulation, and superoxide release. Finally using specific antibodies and glycan binding proteins we will determine how specific CD45 isoforms and glycoforms can be targeted to regulate neutrophil activation and inflammatory responses. Elucidating beneficial effects of targeting neutrophil CD45 phosphatase activity during colitis will help to develop novel strategies to ameliorate pathological intestinal inflammation.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/ Abstract Although most epilepsy research focuses on neocortical and limbic structures – i.e., typical seizure onset zones – subcortical regions that significantly regulate the onset and spread of seizures may also be effective therapeutic targets in epilepsy. The nigrotegmental pathway, consisting of the substantia nigra pars reticulata (SNr) and its connections to the cholinergic brainstem pedunculopontine nucleus (PPN), plays a crucial role in the regulation of movement and arousal, and may also represent a promising target for seizure modulation. The SNr is predominantly composed of GABAergic neurons and exerts powerful control over both forebrain and midbrain networks through its inhibitory output. This effectively positions the SNr as a central “choke point” within the basal ganglia and many lines of evidence demonstrate that SNr inhibition produces robust seizure suppression across multiple epilepsy models. Although activating cholinergic PPN neurons promotes cortical desynchronization and Rapid Eye Movement (REM) sleep – both of which are considered seizure-protective – pharmacological manipulation of the PPN during seizures has yielded mixed results, with both pro- and anti- convulsant effects observed. This highlights the need for further research into the mechanisms responsible for SNr-mediated seizure suppression and the role of its downstream cellular targets in the PPN during seizures. The goal of this proposal is to establish the role of the nigrotegmental circuit in seizure initiation and severity using a well-characterized Scn1a+/- mouse model of Dravet Syndrome, a severe developmental and epileptic encephalopathy distinguished by pharmaco-resistant and temperature-sensitive seizures. First, we will activate the SNr→PPN circuit both in slice and in vivo to confirm that SNr activation leads to inhibition of the PPN. Next, we will record from each region while evoking seizures (with hyperthermia) to determine the endogenous activity of the SNr and PPN, in addition to the effect of SNr activation on PPN activity during the peri-ictal period. Finally, we will determine the impact of SNr inhibition and PPN activation on seizure initiation and severity in Scn1a+/- mice. We will achieve these aims using a combination of techniques – in vivo fiber photometry, slice and in vivo electrophysiology, circuit-specific opto- and chemogenetics, and seizure-triggered closed-loop optogenetics. This approach will allow us to gain cell-type specific knowledge of SNr projections to the PPN and to manipulate these regions with superior spatial and temporal resolution. The proposed research will meaningfully advance our understanding of nigrotegmental circuitry and its role in modulating seizures in Dravet Syndrome. The findings gleaned from this proposal will collectively form the basis for novel, targeted therapies for the treatment of seizures in Dravet Syndrome and other forms of epilepsy.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract The Panel Study of Income Dynamics (PSID) is a longitudinal, nationally representative survey of US families. The study began in 1968 and has collected 43 waves of data over 56 years on the original families and their descendants, and has added two major immigrant refresher samples in 1997–1999 and 2017–2019. PSID serves as a cornerstone for empirical social and behavioral research through its long-term measurement, over the life course and across generations, of economic, social, demographic, and health processes. The data are available free of charge to the research community, with outreach and support to new and established data users. These features have led PSID to become one of the most widely used social science data sets in the world. The study’s innovative design, broad content, and long duration have been central to understanding many key research and policy issues. The data support increasingly rich models of child and adult outcomes over the life course and across multiple generations of the same family. NICHD has co-funded the biennial Core PSID for each of the last 11 waves, from 2003 to 2023. This project builds upon this investment through the following specific aims: First, to collect data on three modules—family dynamics, fertility and newborns, and education—as part of the 2025 wave of the Core PSID survey. Second, to incorporate new measures of personal perceptions of unfair treatment due to demographic, social, and/or economic characteristics. Third, to process, document, and disseminate these data without charge to the research community while providing outreach and support to new and established data users. This project will make several major contributions. It will extend the longest-running household panel survey in the world, supporting new and up-to-date research on family dynamics, investments in children, and well-being over the life course, across generations, and over time. PSID data from 2025 will support research on the medium-term effects of the global pandemic of 2019 on behavior and well-being, and will facilitate future studies on how life course trajectories were altered by exposure to the pandemic. The rich data to be collected on education will support detailed analyses of the determinants of schooling decisions within the family context as well as the effects of these decisions on life course outcomes. Information from the newborn module will allow research on birth outcomes and on the consequence of birth outcomes and very-early life experiences on life course trajectories. Continuing data collection on the dynamic processes of family formation and dissolution, fertility, and living arrangements will allow researchers to understand the evolving complexity and circumstances of families in the U.S. The new data on personal perceptions of unfair treatment will immediately support innovative analyses of the social, economic, and contextual factors that shape these perceptions and will subsequently support research on their health and well-being consequences. Lastly, data user outreach and assistance will stimulate and support research using PSID and engage a new generation of scientists.

NIH Research Projects · FY 2025 · 2025-09

Abstract Cellular and organismal homeostasis requires the integration of diverse environmental cues by cell signaling networks, the disruption of which contributes to pathological conditions. The kinase mTOR, which comprises the catalytic core of two distinct complexes (mTORC1 and mTORC2), responds to nutrients (amino acids (AAs); glucose), growth factors (EGF), hormones (insulin), and energetic stress to control fundamental cellular processes that impact cell metabolism, growth, proliferation, and survival. Not surprisingly, aberrant mTOR signaling contributes to diverse pathologic states including type II diabetes, cancer, and immune and neurodegenerative disorders. Despite the physiological importance of mTOR, major gaps exist in our understanding of mTOR regulation and function, in particular how mTOR communicates with other regulatory systems. Our research focuses on how non-canonical functions of the energy sensing kinase AMPK and the innate immune kinase TBK1 control mTOR signaling and function in cells and in mice in vivo. While it is well- established that AMPK inhibits mTORC1 during energetic stress, our prior work revealed that AMPK paradoxically i) phosphorylates mTOR on a site that promotes mTORC1 signaling and ii) supports mTORC1 signaling during prolonged amino acid (AA) deprivation, a stress condition that induces autophagy and liberates AAs, a nutrient that supports mTORC1 signaling in response to growth factors and hormones. These results reveal AMPK as a previously unknown sensor of cellular AA levels. Thus, this proposal will define how AMPK supports mTORC1 signaling and function in specific cellular contexts rather than universally opposing mTORC1, which would invoke a paradigm shift to the AMPK and mTOR fields. While TBK1 is best known to initiate host defense responses against microbial pathogens, TBK1 also contributes to tumorigenesis and glycemic control during obesity. How TBK1 mediates these non-canonical processes remains poorly defined, however. Our prior work revealed that i) TBK1 phosphorylates mTOR to promote mTORC1 and mTORC2 signaling in response to microbial-derived signals and insulin and ii) the TBK1-mTOR axis protects against hyperglycemia and insulin resistance in obese but not lean mice. Our preliminary results also indicate that AAs increase TBK1 activity, revealing TBK1 as another previously unknown sensor of cellular AA levels. Thus, this proposal will also determine how AAs increase TBK1 activity to promote mTORC1 signaling and better define how the TBK1- mTOR axis promotes glucose homeostasis and insulin sensitivity in specific physiological contexts, i.e., in the obese but not lean state. This research will provide conceptual advance, as it will shift how we think about AMPK and TBK1 in metabolic control and their relationship to mTORC1. Molecular understanding of mTOR network regulation and how mTOR engages in crosstalk with other signaling systems will provide critical insights that will advance our understanding of mTOR in health and disease, which may identify new therapeutic targets for treatment of mTOR-linked disorders.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Microsurgery is at the forefront of modern surgical practice. The quest for ultra-precise resection of invading tumors, durable anastomosis of severed neurovascular structures, and overall minimization of invasiveness has driven the scale of surgical maneuvers below a millimeter and firmly into the microsurgical domain. Applications of microsurgery abound, commensurate with the potential patient benefits, including tissue sparing, better margins, function restoration, and reduced pain. Uniting its diverse procedures is the defining characteristic of microsurgery and the source of its challenges: the sub-millimeter scale of surgical maneuvers and target tissues. The human motor and perception systems are ill-equipped to operate in this regime, and microsurgeons thus reach intrinsic limits of human performance and encounter shortcomings of surgical aids at microsurgical scales. Fortunately, advances in robotics, virtual reality (VR), and artificial intelligence (AI) promise to solve these fundamental challenges from manipulation, visualization, and workflow standpoints, respectively. These incredible advances and, in some cases, commercial products fail microsurgeons from the perception standpoint, however. The project therefore proposes to develop an adaptive perception system based on optical coherence tomography (OCT) to satisfy this unmet need in microsurgery. Specifically, adaptive perception leverages an AI-derived understanding of the surgical scene and its dynamics to build a high-fidelity 3D reconstruction from intelligently distributed image acquisition effort. Critically, OCT is the only live volumetric medical imaging modality routinely acquired during surgery and thus presents a unique opportunity in microsurgery for 3D surgical feedback. Leveraging adaptive perception to guide surgery for natural and artificial agents, this project will create an OCT-integrated robotic microsurgery system capable of autonomous and VR tele-microsurgery modes. Its core capabilities include an OCT-based adaptive perception system that predicts and responds to the microsurgeon’s or AI’s visualization needs, immersion of the microsurgeon in a life-size VR environment constructed from live volumetric OCT upsized 100-1000x to human scale, and AI-guided automated microsurgical suturing without fiducial markers. This project further proposes to compare this system to conventional techniques in simulated and ex vivo microsurgical procedures. This platform promises to empower microsurgeons to complete their tasks faster, commit fewer technical errors, require less training to reach proficiency, and enjoy improved ergonomics. These benefits would translate into the downstream patient benefits of improved outcomes, reduced anesthesia time, faster recoveries, and easier access to care for hundreds of thousands of microsurgery patients each year. These innovations and applications promise to transform microsurgery in ways that could not be envisioned even a few years ago.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Our laboratory focuses on the structure and function of human membrane cytochrome P450 enzymes using a set of integrated structural and biochemical techniques. These monooxygenases play important roles in either the metabolism of drugs or as drug targets for prevalent diseases such as cancers, diabetes, and cardiovascular conditions, as well as rare diseases such as neuromuscular spastic paraplegia and Bietti's Crystalline Dystrophy. Many drug-metabolizing and steroidogenic P450s have been well characterized functionally and structurally by our lab, supporting improved drug design, but many other P450 drug targets are very poorly characterized. In some diseases inappropriate P450 action is implicated and inhibitors are likely to be an advantageous treatment, but the active site knowledge to design them is unknown until we determine structures. In other cases P450 mutations cause a disease, but not knowing whether the defect is in protein stability or some aspect of catalytic function similarly impedes effective progress toward developing effective therapeutics. We have a 20- year track record defining P450 interactions with ligands for various drug-metabolizing and steroidogenic human enzymes. For most we generated the first structures by X-ray crystallography. The overall goal of the proposed research for the next five years is to generate initial X-ray structures and corresponding biochemical information of a selected set of validated disease-related P450 enzymes to enable viable pursuit of drug design A subset of poorly-characterized human P450 enzymes with significant evidence supporting their roles in one or more disease states were identified and will be pursued using an overall strategy including recombinant expression and purification, identification of new ligands as necessary, evaluation of clinical mutations when appropriate, followed by integrated determination of substrate and inhibitor binding affinities, substrate metabolism, inhibitor efficacy, and active site topology, primarily by X-ray crystallography and/or pharmacophore generation. These P450/ligand interaction studies, along with proposed studies of P450 interactions with their catalytic partner proteins and membranes, are expected to provide critical foundational knowledge facilitating broad impacts across a number of major and rare diseases. The feasibility of this work rests not only on the strong premise for the selected P450 enzymes, but the investigator track record, laboratory expertise, and access to all of the required instrumentation and resources in an exceedingly strong research environment. With this combination of resources we have previously accomplished similar feats for a number of other human membrane P450 enzymes. Our overall vision is to creatively employ multiple techniques to answer some of the most critical questions about how this diverse enzyme superfamily functions and can be modulated to improve human health.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Chronic pelvic pain (CPP) affects 15-20% of U.S. women of reproductive age and is linked to gynecological conditions, such as endometriosis and dysmenorrhea. Accumulating evidence suggests that altered pain processing in the brain (i.e., nociplastic pain, which predicts persistent comorbid pain disorders and treatment resistance) is an underlying cause in some cases. Despite the emergence of CPP during puberty, very little is known about how nociplastic pain manifests in adolescents, and neuroimaging studies are scarce. Furthermore, drastic changes to the CNS occur during puberty, with substantial heterogeneity that usually goes unexamined. Heterogeneity also characterizes the etiology, presentation, and neuroendocrinology of CPP in dysmenorrhea and endometriosis in adults. Thus, empirical research that centers on development and variability is necessary for meeting the unique needs of individuals who walk into clinics. The overarching goal of this proposal is to map the personalized neural variability underlying reproductive health-related CPP, informing important clinical outcomes by identifying risk factors and eventually improving early detection and intervention. The specific aims are to: 1) examine personalized neural networks involved in gynecological CPP in adult females; 2) identify individualized trajectories of dysmenorrhea pathogenesis, before and after menarche, and consequently, predict new pain onset in adolescence; and 3) conduct a longitudinal neuroimaging study to determine the heterogeneous neurobiological correlates of developing one or more Chronic Overlapping Pain Conditions from dysmenorrhea alone in adolescence. The main goals of the K99 portion are focused on providing the candidate innovative training in: a) pain phenotyping and neurobiology; b) idiographic methods, including developmental trajectories and personalized neural network analyses; and c) pubertal assessment. The K99 phase will take place at the University of Michigan (UM), under the mentorship of Dr. Adriene Beltz, a world-renowned expert in behavioral neuroendocrinology and developmental idiographic science. Drs. Chelsea Kaplan, Andrew Schrepf, and Daniel Clauw, internationally recognized experts in chronic pain mechanisms and neuroimaging, and Dr. Sawsan As-Sanie, an expert in clinical management of endometriosis and other CPP conditions, will also be mentors. The UM is an ideal training environment because of its extensive interdisciplinary resources, including the Department of Psychology, Chronic Pain and Fatigue Research Center, and the Department of Obstetrics and Gynecology. UM faculty mentors are leaders in their fields, have a history of successful collaboration, and are dedicated to data sharing and training. Upon completing the K99 portion, the candidate will be well-prepared to transition into an independent tenure-track faculty position studying neurobiological correlates and individualized mechanisms underlying the development of CPP conditions during adolescence. This work is crucial for women’s well-being, and highly novel in its focus on heterogeneity in the adolescent development of pain-related reproductive health disorders.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Cardiovascular disease (CVD) is the leading cause of death in the US, accounting for nearly 1 in 4 deaths and over $400 billion in annual health care cost in the US. Platelet-mediated thrombosis is most common underlying pathophysiology of cardiovascular diseases and leads to life-threatening clinical cardiovascular events, such as myocardial infarction or stroke. Under normal physiological conditions, platelet activation is critical for maintaining normal blood flow following vascular injury, however in pathologic conditions hyperactive platelets can form occlusive thrombi. Fish oil supplements are one of the most common over-the-counter supplements due to previous research showing their ability to slow the progression of cardiovascular disease. Fish oil supplements are highly enriched in the omega-3 polyunsaturated fatty acid (PUFA), eicosapentaenoic acid (EPA). Supplementation with EPA alone reduces the risk for major cardiovascular events, suggesting the cardiovascular protection is regulated by EPA, however the exact mechanisms regulating these benefits remain unknown. Our group has shown that several PUFAs inhibit platelet activation, and these antiplatelet effects are realized through the production of 12-lipoxygenase (12-LOX) metabolites. Further, we have shown both EPA and its 12-LOX metabolite, 12-hydroxyeicosapentaenoic acid (HEPE) inhibit platelet activation. However, the exact signaling mechanisms regulating the antiplatelet effects of EPA and 12-HEPE, as well as the role of 12-LOX in regulating the effects of EPA on thrombosis are unknown. We will use both pharmacological and genetic techniques to determine the role of peroxisome proliferator activated receptors (PPARs) and Gαs-coupled GPRCs in regulating the antiplatelet effects of EPA and 12-HEPE, both of which have been implicated in the signaling of other 12- LOX metabolites. Finally, we will investigate the effects of supplementation with EPA and icosapent ethyl (IPE), an FDA approved esterified form of EPA, on the ability to alter plasma 12-HEPE concentrations, platelet membrane lipid composition, ex vivo platelet activation, in vivo thrombosis, and hemostasis. Additionally, 12- LOX knockout mice will be utilized to determine if 12-LOX is required for the regulation of platelet activation and thrombosis by EPA and IPE. Successful completion of this project will, for the first time, elucidate the mechanisms regulating the ability of EPA to alter platelet function. The findings will be used to inform the use of fish oil supplements and IPE as a therapeutic intervention for thrombotic diseases to improve cardiovascular outcomes. Improved use of already available and widely used supplements could reduce the overall burden of CVD.

NIH Research Projects · FY 2025 · 2025-08

Food allergies affect approximately 11% of US adults and 8% of US children. The current standard of care is largely food avoidance. However, accidental exposures can lead to life-threatening allergic reactions, which have financial and quality of life burdens. Measurement of allergen specific IgE levels are the major means by which risk of allergic reaction is assessed, yet IgE levels do not predict response. Furthermore, individuals with an initially mild response may progress to develop severe responses. The immunological differences between mild and severe reactions, or the transitions associated with progression are unknown, yet are critical to identifying the patient population that is most at-risk and the development of therapies that can prevent the development of life-threatening reactions. We have devised a novel technology – a scaffold that serves as a synthetic immunological niche (IN), which captures the systemic immunological changes during disease progression in models of cancer and autoimmune disease. We propose to employ the scaffolds to monitor immune responses to distinguish the heterogeneity of allergic responses, and subsequently for monitoring the responses following therapeutic treatment with an allergen-specific immunotherapy: allergen- encapsulating nanoparticles (NPs). The scaffold allows for longitudinal analysis of immune dynamics within tissues that are distinct from those in blood, and analysis can monitor disease progression and inform the use of targeted therapies such as NPs. The proposed studies are developed in two Aims. Aim 1 will develop a prognostic signature of systemic immune dynamics for IgE/Th2-mediated food allergies. IgE levels indicate the potential for an allergic response but cannot differentiate between sensitized individuals who are tolerant or allergic. We investigate scaffolds as an IN to monitor and predict immune and physiological changes during OFC in allergen-sensitized mice. These dynamic analyses can identify the biological differences underlying severe and mild allergic reactions. Biopsied scaffolds will be characterized by flow cytometry for immune cell types and by gene expression using bulk RNA and single-cell sequencing. A gene expression signature predicting severity of allergic reactions will be developed and validated. Finally, the scaffold analyses will be compared with that from the intestines, demonstrating that the IN recaptiulates the GI environment. Aim 2 will investigate the use of IN to monitor response to NP immunotherapy. NP immunotherapy has been able to attenuate responses in sensitized mice. The scaffold will be analyzed for a signature associated with this either mild or no allergen reactivity. This signature will be used to predict efficacy and identify the therapeutic mechanisms of the NPs, and thus, elucidating the biology associated with a partial or complete response to immunotherapy. Our platform overcomes this critical barrier of predicting severity of allergen reactivity by analyzing immune processes within synthetic tissues, which are reflective of the sensitized organs and can be analyzed for disease biology or identify therapeutic mechanisms of action.

NIH Research Projects · FY 2025 · 2025-08

The goal of this project is to develop an efficient 3D, contrast-free, low-field Magnetic Resonance Imaging (MRI) pipeline to detect pulmonary embolism (PE), leveraging the unique physics of low-field MRI and denoising via deep learning. PE is a major cause of acute cardiovascular mortality worldwide, surpassed only in frequency by myocardial infarction and stroke. When patients present in the Emergency Department (ED) with PE symptoms, immediate diagnosis is critical to enable prompt and appropriate treatment. Computed Tomography Pulmonary Angiography (CTPA) is the current imaging gold standard for PE diagnosis, but its use is limited in settings where exposure to ionizing radiation and the associated cancer risk is severely undesirable (i.e. for children or pregnant patients). CTPA also requires the injection of iodinated contrast media which is contraindicated in a significant fraction of the population. Magnetic Resonance Imaging (MRI) is a radiation-free alternative for diagnostic imaging, although the lungs are traditionally not imaged using MRI due to poor image quality. However, MRI does not require ionizing radiation, and vascular evaluation often can be performed without the need for contrast agents. An efficient, simple, contrast-free, whole-lung MRI method for the assessment of the pulmonary vasculature would enable the detection of PEs without the disadvantages of CT. Recent advancements in MRI hardware, primarily the availability of FDA-cleared lower-field 0.55T MRI systems, have revitalized lung MRI as a field of study. The proposed project aims to develop a fast, contrast-free, 3D whole-lung low- field MRI protocol for PE detection that is both comfortable for the patient and simple to perform: Aim 1: Develop and optimize a data collection and image reconstruction pipeline for rapid, free-breathing, high- resolution, contrast-free, 3D whole-lung MRI at 0.55T with high vessel conspicuity for PE detection We will develop a 3D balanced steady-state free-precession MRI (bSSFP) acquisition which can be used during free- breathing for whole-lung imaging (covering a field-of-view of approximately 400x400x300mm) with a resolution of 1mm3 in an acquisition time of less than 10 minutes. Following optimization of the acquisition/reconstruction pipeline, images of the lung vasculature will be collected in 10 healthy subjects and assessed by three cardiothoracic radiologists for visibility of first and second-order pulmonary branches and the ability to track vessels and distinguish pulmonary arteries from veins. Aim 2: Compare the PE detectability of low-field MRI to that of CTPA in a cohort of ED patients We hypothesize that the low-field, contrast-free 3D whole-lung MRI imaging pipeline developed in Aim 1 will enable PE detection in the first and second-order pulmonary branches comparable to that of CTPA. A cohort of 40 patients presenting in the ED with suspicion of PE scheduled to undergo a CTPA scan will be recruited for an additional low-field MRI scan. Three radiologists will compare the CTPA and MRI images to assess the number of clots, and their location and size; they will also evaluate diagnostic confidence using a Likert scale. Outcome: When successful, this project will provide preliminary data showing the potential for rapid, contrast-free lung PE screening using a low-field MRI technique that is easy to perform in the ED.

NIH Research Projects · FY 2025 · 2025-08

Kenya’s population is aging rapidly, with the number of adults aged 60 and older projected to increase 4- fold in the next 30 years. However, there is little population level data from Kenya or neighboring countries to inform economic, policy and public health planning. Our team seeks to address this gap through the development of the Longitudinal Study of Health and Ageing in Kenya (LOSHAK-Core), which joins a growing global network of harmonized panel studies of health, economics, and aging modelled on the U.S. Health and Retirement Study (HRS). Likewise, the LOSHAK-Harmonized Cognitive Assessment Protocol (LOSHAK-HCAP) will join a group of more than 15 HCAP studies around the world on epidemiology and risk factors for cognitive impairment and Alzheimer’s disease and related dementias (AD/ADRD). Our team’s LOSHAK feasibility and pilot studies (R21AG077042) demonstrate our ability to collect and analyze complex survey data, blood-based biomarkers, and data from wearable sensors in older Kenyan adults. Wave 1 of the LOSHAK-Core and -HCAP studies will be led by the University of Michigan/Aga Khan University team in close collaboration with the Kenya Ministry of Health, Kenya National Bureau of Statistics (KNBS), and Kenya Medical Research Institute. The long-term objective of LOSHAK is to generate longitudinal population representative data on health, economics, wellbeing, and AD/ADRD among older Kenyans. LOSHAK-Core will be nationally representative of Kenyans aged 45 and older, with a sample size of 6,580. LOSHAK-HCAP will be representative of Kenyans aged 60 and older in the Coast Region (6-county administrative designation), with a sample size of 2,375. We will use KNBS sampling frames that are based on the national census and have been used in prior national studies. In Aim 1, we will collect Wave 1 LOSHAK-Core data in 16 regional ethnic languages. The survey will include key HRS health and economic domains and innovative modules, collect data using wearable activity and air pollution monitors, and assess anthropometrics. We will also collect whole venous blood to assay biomarkers of inflammation, chronic health conditions, and AD/ADRD, as well as to store blood for future analyses. In Aim 2, we will collect data on cognitive health and AD/ADRD using the HCAP and will estimate the prevalence of AD/ADRD in the Coast Region, while leveraging overlap between the Core and HCAP samples to make national estimates. In Aim 3, we will make data publicly available to the scientific community for comparison with other HRS/HCAP studies and disseminate findings to key stakeholders. In Aim 4, we will engage in capacity strengthening across all components of LOSHAK, consistent with our commitment to accelerate the pace and rigor of aging research in Kenya. LOSHAK will make vital contributions, providing harmonized population representative data on individual, policy, and structural risk and resilience factors that influence late-life health and economic wellbeing in Kenya.

NIH Research Projects · FY 2025 · 2025-08

Project Summary In the United States, women experience a significantly higher prevalence of severe obesity (BMI ≥40 kg/m2) than men. Among these women, individual differences in susceptibility to weight gain positively correlate with an underlying predisposition for enhanced Pavlovian motivation for food. In addition, the magnitude of striatal activation to food cues positively correlates with subsequent weight gain. However, directly examining relationships between striatal function and propensity for weight gain in humans is difficult. To address this gap, our laboratory uses selectively bred rats that are obesity-prone (OP) and obesity-resistant (OR). The proposed studies will provide significant insight into how excitatory neurotransmission is regulated in response to diet and ovarian hormones to influence cue-triggered urges to seek food. Glutamate is the primary excitatory neurotransmitter within the central nervous system (CNS) and exerts its actions through binding of ionotropic (i.e., NMDA, AMPA, kainate) and metabotropic (e.g., mGluRs) receptors. Glutamate receptors within the striatum, and in particular the nucleus accumbens (NAc), are important for both natural reward processing and addiction. Thus, differences in excitatory neurotransmission within the NAc may contribute to a vulnerability for enhanced food-cue motivation and propensity for weight gain. Furthermore, there is abundant and compelling evidence of sex differences in both feeding behavior and NAc function. Work from our laboratory has demonstrated sex differences in excitatory neurotransmission mediated by calcium-permeable AMPA receptors (CP-AMPARs) within the NAc. Specifically, we have shown that NAc CP-AMPARs are upregulated by brief exposure to moderately fatty, junk-food (JF) diets in obesity-prone (OP) rats, and that the persistence of this effect differs in males and females. This plasticity is critical because NAc CP-AMPARs also underlie cue- triggered food-seeking in OP males. However, very little is known about these behaviors and their underlying mechanisms in females, or how they may be influenced by ovarian hormones including estrogens. To address these gaps in knowledge, studies in this proposal will characterize Pavlovian motivation across the cycle in OP and OR females, as well as identify a potential role for NAc CP-AMPARs in cue-induced food-seeking (Aim 1). In addition, this proposal will directly examine the influence of estrogen on excitatory neurotransmission in the NAc (Aim 2). This work will provide significant insight into the neurobiology food motivation and glutamatergic plasticity in females.

NIH Research Projects · FY 2025 · 2025-08

Clinical researchers increasingly recognize the potential for mobile health (mHealth) technologies to transform health and medicine by facilitating real-time data collection, self-management, and information sharing between patients, researchers, and clinicians. Yet despite their great promise, use of mHealth technologies – i.e., smartphones and wearables – in clinical settings remains challenging. This is in part due to the high cost and technical demands of the development of mHealth solutions, as well as the lack of inclusion of representative samples in many mHealth studies, which limits the overall generalizability and impact of research results. This has led to poor quality studies and difficulty in accumulating a robust evidence base over time. To address these problems, we propose establishment of the mHealth Outcomes in Behavioral Interventions & Longitudinal Evaluation (MOBILE) Platform at the University of Michigan. The MOBILE Platform will be a specialized clinical and translational science program that serves as a “hub” for innovative mHealth studies. Through this project, we will develop research processes and technical infrastructure to conduct mHealth studies and then work to disseminate these resources to investigators through our established UM1 Clinical and Translational Science Award (CTSA) program. In this project, we will: 1) understand barriers and facilitators to recruitment and retention of individuals from all communities, resulting in development of the Participant Enrollment & Engagement Resource (PEER) toolkit – a suite of best practice guidelines and resources to facilitate mHealth research; 2) build robust and reusable open-source software, the Digital Health Technology Framework (DHTF), that will facilitate collection of mHealth data at scale and development of novel mHealth systems for research; and 3) assess the platform’s functionality in two demonstration projects among cancer survivors (thyroid cancer and prostate cancer) and heart failure patients. Ultimately, the MOBILE Platform will accelerate mHealth research by enhancing the ability of clinical researchers to recruit, enroll, and retain representative participant samples. Finally, this platform will be designed to provide approaches for early dissemination to researchers through the Michigan Institute for Clinical and Health Research (MICHR), our UM1 CTSA program.

NIH Research Projects · FY 2025 · 2025-08

PROJECT ABSTRACT The ATHENA trial represents a new paradigm to slowing the progression of disease in people with pulmonary arterial hypertension (PAH). With our clinical coordinating center (CCC) collaborators, we propose a phase 2, multi-center, randomized, double-blind, placebo-controlled trial of tiprelestat (recombinant human Elafin) to evaluate its impact on pulmonary vascular resistance (PVR) and safety. Participants will be stratified by baseline PVR and baseline REVEAL Lite 2.0 risk score. The primary endpoint of the study is the change in PVR from baseline to week 24. Our clinical collaborators have successfully demonstrated the safety and tolerability of Elafin in a phase 1 trial of 30 healthy individuals (NCT 03522935), and have assembled a group of clinical sites with experience in PAH and clinical trials. The ATHENA trial will extend their promising pilot data to a formal phase 2 clinical trial among PAH patients. An experienced data coordinating center (DCC) with strong statistical leadership and expertise is key in both design and analysis, particularly when unanticipated issues arise during the conduct of a clinical trial. The University of Michigan (UM) Statistical Analysis of Biomedical and Educational Research (SABER) unit within a top-ranked department of biostatistics will serve as DCC, bringing together an experienced group of faculty and staff in biostatistics, project management, study monitoring, database design and data management, software development, and research administration. SABER has a strong track record of collaborations with a CCC under this funding model. The overarching goal of the UM DCC is to collaborate with study investigators, the CCC, and NHLBI to enable successful achievement of the study on time and within budget. We will accomplish these goals through the three specific aims: (1) Enhance scientific rigor by providing statistical and clinical trials methodological expertise to design, analyze, and disseminate research findings; (2) Ensure the collection of timely, accurate and reproducible data, and maximize adherence to the study protocol; and (3) Provide established infrastructure and services for study administration and operations and for communication among study stakeholders. Our leadership, experience, and expertise will promote collaborations, encourage scientific productivity, and facilitate timely dissemination of findings on the benefits of Elafin in patients living with PAH. We anticipate that upon completion of this proposed study, our data will support the role of Elafin as a safe and efficacious PAH therapy, with the potential to be a disease-modifying agent with therapeutic effects sustained even after the treatment is discontinued. It will inform the design of the Phase 3 pivotal study of this novel PAH therapy.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY This proposal seeks to support the Vortex open-source project which meets a progress-limiting need for software in optical coherence tomography (OCT) research. OCT is a laser-based imaging technique for real-time in vivo volumetric microscopy that has transformed the diagnosis and management of eye disease. Modern OCT instruments are complex mechatronic systems that match carefully designed hardware with application-specific software to achieve real-time display of high-quality images. Lack of appropriate software hampers scientific efforts as novel OCT hardware requires similarly novel software, although the latter is infrequently the research focus or subject of publication. We launched the Vortex open-source project to provide a collection of well-designed and interoperable C++ components which the user can assemble into application-specific OCT software in Python or C++. Since development began in 2020, Vortex-powered software has produced multiple peer-reviewed publications in academic research and accelerated the technology development process in multiple startup companies. This proposal now seeks to continue Vortex’s maturation as an open-source library through the following specific aims. (1) Restructure Vortex’s memory management scheme to improve flexibility and functionality. By implementing standards-compliant buffer manipulation routines following a test-driven development strategy, we will simplify hardware support and lift data type restrictions for Python bindings. (2) Update Vortex’s Python and logging interfaces to improve interoperability. In migrating Python bindings from pybind11 to the newer nanobind, we will standardize memory sharing, eliminate dependencies, streamline integration of logging, and increase performance. (3) Complete Vortex’s documentation and automated testing suite to improve usability. Through full documentation of Vortex’s Python bindings and high code coverage for testing, we will provide an accessible library that is robust and reliable. Work on each aim will occur in Vortex’s Gitlab public repository, where we will use issues, pull requests, and milestones to manage the software development process, in accordance with software industry best practices. We will disseminate these updates to Vortex through public releases on Gitlab, publication of manuscripts, and presentations/workshops at conferences. Completing these aims will yield substantial improvements in Vortex from a software engineering standpoint and produce a library that is both verifiably correct and well-documented. We believe these improvements will position Vortex as a turnkey tool on which OCT researchers and developers can rely as they advance the state-of-the-art.