Case Western Reserve University

NIH Research Projects · FY 2025 · 2025-07

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Clinical and translational (C/T) scientists are increasingly important in biomedical research as they address critically unmet health needs. Consequently, translational education is necessary to equip C/T scientists with new skill sets. These skills and intellectual proficiencies will enable students to develop innovative strategies to address unmet health needs effectively, efficiently, and economically, to engage with all communities, and to address variations in healthcare delivery. Critical factors for success include transdisciplinary skills that enable C/T scientists to work across the spectrum of laboratory science, clinical research, and public health, as well as the ability to implement advances in clinical and community settings. The CWRU predoctoral Clinical and Translational Scientist Training Program (CTSTP-Pre) will support C/T research training across several PhD programs that focus on clinical and translational research. Trainees will include students in PhD, MD-PhD and DNP-PhD training. The CTSTP-Pre will be coordinated with our CTSTP-Post (postdoctoral T32) and CTSC K12 program; the three programs have jointly developed the CTSC Research Education Program that includes shared curricular activities, shared approaches for mentor approval-assessment-development, a common CTSC Research Education Advisory Board, and shared programs in collaboration with our CTSC UM1 program for community engagement, dissemination, implementation, and investigation to ensure quality health care for all. Together, these programs provide a pipeline for the training and development of C/T scientists. The CTSTP has a successful track record of innovation in C/T research education. We have established 3 new C/T PhD programs (C/T Science, launched in 2015 central to the precursor TL1 grant; Systems Biology and Bioinformatics, launched in 2011; and Biomedical and Health Informatics, launched in 2019) that expand C/T research training beyond other relevant PhD programs, including Epidemiology, Biomedical Engineering, and Nursing. The CTSTP now proposes to develop its predoctoral programs further. CTSTP predoctoral training previously focused on training dual degree students, including MD-PhD and DNP-PhD students. We will now support more PhD students to expand training pathways and increase focus on several C/T-related programs. Trainees will participate in the CTSC Research Education Program that provides a rich set of C/T research activities, as well as PhD program-specific activities. Criteria for acceptance into the CTSTP-Pre will include a strong academic record, commitment to a research-intensive career, and evidence of research skills. The program will be governed by the CTSTP-Pre Steering Committee, with oversight by the CTSC Research Education Advisory Board, which will include representatives from all participating institutions and programs. The CTSTP-Pre has a robust mentor pool with mentors who have established training records and robust research funding. Participating institutions include CWRU, CC, UH, MH, and VA. These sites are well-equipped for cutting-edge C/T research.

NIH Research Projects · FY 2025 · 2025-07

Project Summary Hepatitis B virus (HBV) poses a persistent global health threat, affecting millions annually and leading to significant mortality. Co-infection with human immunodeficiency virus (HIV) compounds the health challenges, necessitating accurate diagnostics for effective management. Our project aims to develop a cost-effective and user-friendly point-of-care (POC) diagnostic tool, employing a novel CamoChip technology for highly sensitive and multiplex biomarker testing. This innovation, integrated with an AI-based algorithm, offers the potential to empower healthcare providers, enabling tailored treatment and the prevention of new infections. Our approach centers on a microchip utilizing color-encoded beads coated with antibodies for the capture of vital biomarkers, including HIV-1 RNA, HBV DNA, HBsAg, HBeAg, and ALT. The microchip's camouflaging mechanism ensures biomarker identification, making it an ideal candidate for widespread use in diverse healthcare settings. Our project is structured around three specific aims. Specific Aim 1 focuses on designing and coating color-encoded beads for biomarker capture. Specific Aim 2 seeks to enhance the camouflaging reaction on the microchip. Specific Aim 3 involves engineering a cost-effective and portable microfluidic device for mass production, ensuring ease of use and compatibility with diverse testing scenarios and environments. The proposed CamoChip approach integrates serological and molecular tests for HIV and HBV co- infection into a single platform, eliminating the need for separate tests and visits. It reduces delays in treatment initiation and monitoring, enhancing patient care. CamoChip's user-friendly design and simplified interpretation, utilizing color-encoding and AI, enable rapid diagnosis and monitoring within minutes, allowing healthcare providers to make timely treatment decisions during the same visit. Designed for POC testing, CamoChip is accessible in diverse healthcare settings, including remote or resource-limited areas. Its portability and ease of use ensure optimal outcomes for patients with HIV and HBV co-infection. Adhering closely to CDC and WHO guidelines, CamoChip empowers healthcare providers to deliver high-quality care with confidence and efficiency, even in challenging clinical settings.

NIH Research Projects · FY 2026 · 2025-07

PROJECT SUMMARY/ABSTRACT The overall goal of the Clinical Oncology Research Program (CORP) is to support the intent of the Paul Calabresi Career Development Award for Clinical Oncology (K12). CORP fosters interdisciplinary training in clinical and translational oncology therapeutic research for early career faculty physicians (Assistant Professor) in one of a number of oncology disciplines, including medical, surgical, dermatologic, pediatric, radiation and pathology. By designing a K12 program that brings together these broad disciplines, the Paul Calabresi Scholars themselves form a multidisciplinary group whose collaborations and interactions augment the overall training efforts under the K12 program. The two-year training program with an option for a third year for Scholars who would benefit from additional training will support 4 Scholars a year. Firm core requirements include completion of required and elective course work for a Certificate in Clinical Translational Oncology Research at Case Western Reserve University. A basic research effort is a required part of the training program and is linked to the clinical research efforts that include writing and activating a therapeutic clinical protocol and submission of a career development award application. These efforts will result in highly qualified Paul Calabresi scholars capable of independent research in clinical oncology and therapeutics with a team science orientation based in hypothesis testing of important translational questions in the field. CORP brings together strong Internal and External Advisory Committee members committed and experienced in the area of clinical translational therapeutics research in oncology. CORP and the Case Comprehensive Cancer Center provides scholars with an outstanding environment to pursue career development. Past trainees have emerged as academic physicians developing independent clinical research programs often with external funding and with active investigator-initiated clinical trial efforts.

NSF Awards · FY 2025 · 2025-07

Reducing the fuel consumption of sea and air vehicles by lowering their drag could have significant economic and environmental benefits. One way to reduce drag is to maintain laminar flow of the water or air over the entirety of the vehicle surface, which for modern ships and aircraft is normally turbulent. Laminar flow causes significantly less friction than turbulent flow, which reduces drag. Methods for laminar flow control have had limited success because most either (i) involve an active device that requires energy input, (ii) are effective only in a particular range of flow conditions, or both. This project will apply a new technology to maintain laminar flow called Phononic subsurfaces (PSubs), which are architected material units placed beneath the vehicle surface engineered to passively impede the growth of flow instabilities that lead to turbulence. The project will also sponsor a computational education workshop and an art education component to train visual artists to represent physical phenomena in an engaging way for the public. Previous computation-based studies have demonstrated that properly designed PSubs can locally suppress linear instability. However, current methods lack a unified approach to eliminate the growth of perturbations downstream of the control region while also handling such perturbations over a broad-frequency range and when incident from varying directions. Furthermore, the PSub concept has not yet been experimentally validated. This project will tackle these deficiencies. An array of PSubs will be designed and distributed spatially as a lattice, and using stability theory and direct numerical simulations, the research will demonstrate that such a collective PSub configuration can extend the stabilization effect downstream of the control region while also handling instabilities approaching the control region from different directions. In addition, each PSub in the array will exhibit a novel coiled architecture that will allow it to impede the instabilities over a much broader frequency range than the nominal uncoiled case. A comprehensive experimental investigation will be conducted on the performance of the PSub in a water tunnel facility using phase-locked and time-resolved particle image velocimetry measurements. Thus, the proposed program will advance and integrate fundamental knowledge of flow control and Phononic structural design and manufacturing, experimental characterization, and evaluation of the technology in realistic laboratory conditions. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-07

Delivering therapeutic drug molecules or genes to cells requires nanoscale carriers that can interact with proteins inside the cell and navigate to the nucleus, if needed. Nanoparticles made entirely out of synthetic deoxyribonucleic acid strands have proven useful in building such delivery systems. Although they work well for drug delivery, their behavior inside the cell is not fully understood, which presents challenges to improving nanoparticles for specific applications. This project will encode synthetic deoxyribonucleic acid nanoparticles with gene sequences and measure the extent to which these nanoparticles interact with the cell’s protein building machinery to make a protein of choice. Various bioengineering and fluorescence tools will be used to study the nanoparticles in living cells. Effects of shape, design, and other features of the nanoparticles on their behavior and function as gene delivery systems will be determined. The team will engage local high school students in research for 10-week long programs at Case Western Reserve University. The project will also support educational module design using mixed reality technology to teach topics in bioconjugate chemistry. Nanoparticles created from self-assembly of synthetic deoxyribonucleic acids (referred to as DNA origami nanoparticles) are being developed for targeted delivery of drugs, bioimaging probes, and functional nucleic acids. However, the stability of these nanoparticles and how they interface with cellular processes are not understood. The main limitation thus far has been a lack of bioanalytical tools that provide sufficient resolution to study nucleic acid nanoparticles in physiological conditions. Without understanding the mechanism of nanoparticle design and its intracellular functionality, engineering application-specific nanoparticles is not feasible. The goal of this project is to determine the role of nanoparticle shape and sequence layout in their ability to express proteins in cells. The mechanistic hypothesis is that predictable shape and sequence layout of gene-encoded nanoparticles will sterically tune transcription processivity and ultimately affect their stability and function. The research will measure how gene-encoded nucleic acid nanoparticle processing depends on their shape, gene sequence routing within the nanoparticle, and their transport across the nuclear membrane. An integrated educational plan will have three synergistic activities, namely, (1) high school student workshop on how to manifest a DNA nanoparticle using makerspaces, (2) 3-dimensional printable models to illustrate how fluorescent molecules interact on DNA nanoparticles, and (3) a mixed reality teaching module to transform bioconjugate chemistry education. The project will catalyze a long-term research program that trains the next generation of scientists in bioengineering, nanotechnology, and analytical chemistry. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-07

This doctoral dissertation research studies the differential impacts and experiences of repeated natural disasters on different social groups to understand the social variations in adaptation and recovery. The investigators specifically test for the differential impacts of social and economic support, overall health status, and emergency resource management on post disaster outcomes. In addition to providing scientific training for a graduate student in anthropology, broader impacts of the project will inform public disaster management strategies and contribute to the knowledge base that addresses the variations across vulnerable populations facing repeated natural disasters. In order to understand the adaptations of different social groups to natural disasters, the investigators utilize qualitative research methods that include semi-structured interviews and behavioral observations in regions with repeated natural disasters. The research expands the anthropological science of adaptations to natural disaster management and makes clear contributions to medical and environmental anthropology, public health, and disability studies. It provides science-based insights that inform the development of sustainable and robust disaster response and recovery strategies. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-07

The estimation of unknown causes of observed consequences, known as inverse problems, is a task arising in many important real world applications as wells as in science and engineering. Medical imaging, large language models, the structural health of infrastructure, among other areas, all rely heavily on the availability of fast and robust computational methods known as inverse solvers, especially when the data are parsimonious and noisy. This project will advance Bayesian inverse solvers that constitute the mathematical tools to utilize qualitative properties of these unknowns in a natural way while simultaneously providing a measure of the uncertainty associated with the solutions. In particular, this project will develop hierarchical Bayesian methods since they are particularly attractive for finding solutions when the salient information is consolidated economically into few features of the unknowns, a methodology that is referred to as sparse coding, or when the entries need to be of a prescribed type to facilitate the interpretation of the solution. Successful completion of this project has the potential to advance research in biotechnology, health sciences, and artificial intelligence. This project will combine hierarchical Bayesian techniques in inverse problems with novel ideas leveraging data science techniques and state of the art methods to address large scale computing challenges arising in a number of important real world applications. The targeted applications include functional magnetic resonance imaging (fMRI) of the brain, hemorrhagic stroke monitoring by electrical impedance tomography (EIT), muscle control identification in biomechanics and rehabilitation, fingerprinting of resting states in brain by magnetoencephalography (MEG), semantic and linguistics studies through large language models, and investment portfolio planning. The innovative combination of matrix-free techniques with Bayesian and data science methods will be the foundation and building blocks of algorithms that are fast, yield better solutions by taking advantage of cleverly designed priors, and more energy-efficient than approaches based on machine learning and neural networks. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-07

PROJECT SUMMARY The nuclear exclusion and subsequent cytoplasmic accumulation of TAR DNA-binding protein, 43 kDa (TDP43), are hallmark features in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic accumulation of TDP43 is observed in over 50% of FTD cases and almost 95% of ALS cases. This accumulation is associated with various cellular abnormalities, including mitochondrial defects, inflammation, and neurodegeneration. While current efforts in ALS and FTD research largely target the downstream effects of cytoplasmic TDP43, understanding the mechanisms causing TDP43 cytoplasmic localization is vital for preventing disease pathogenesis and developing effective treatments for ALS, FTD, and other TDP43-related conditions. Our preliminary studies revealed a previously unidentified role for the protein ATAD3A in TDP43-mediated neuropathology. ATAD3A, an AAA-ATPase protein located at mitochondrial contact sites, regulates mitochondrial dynamics, mitochondrial genome stability, and cholesterol metabolism and trafficking. Aberrant ATAD3A levels, or mutations in the ATAD3A gene, are associated with neurodegeneration, highlighting the critical role of functional ATAD3A in mitochondrial homeostasis and neuronal survival. Expression of ATAD3A mRNA is reduced in ALS and FTD, and ATAD3A transcript is a direct target of TDP43, suggesting a link between ATAD3A deficiency and ALS/FTD pathogenesis. Intriguingly, we found that decreasing the expression of either gene (ATAD3A or TDP43) influences the expression behavior of the other. Furthermore, our preliminary studies support the scientific premise that TDP43, in healthy cells, stabilizes ATAD3A. However, in pathological conditions, it suppresses ATAD3A mRNA expression, leading to a gain-of-function aberration. This negative regulatory action on ATAD3A causes the cytoplasmic toxicity of TDP43 and the associated neuropathological manifestations seen in ALS/FTD. We will perform three aims to test our hypothesis. Aim 1 is to determine the causes and consequences of ATAD3A loss in TDP43-associated ALS/FTD models. Aim 2 is to assess whether ATAD3A replacement reduces motor neuron toxicity in ALS/FTD models. Aim 3 is to uncover the mechanism by which ATAD3A loss contributes to TDP43 proteinopathy. Success in these studies will position ATAD3A as a pivotal molecule in TDP43 pathology, linking mitochondrial defects, neuroinflammation, and neurodegeneration. This research could significantly influence ALS/FTD research by spotlighting ATAD3A as a novel therapeutic target to mitigate TDP43 toxicity in ALS/FTD.

NIH Research Projects · FY 2025 · 2025-07

Project Summary The Molecular Pharmacology Training Program is an interdisciplinary training program centered in the fundamentals of pharmacology. The mission of the MPTP is to develop innovative scientists with a strong foundation in pharmacological principles and skills required for the modern workforce. Our vision is to provide our trainees with 1.) an efficient structured path through the PhD, 2.) a strong focus on therapeutics, and 3.) excellent career and professional development activities. To accomplish our vision, the program focuses on 6 key competencies for our trainees: comprehension of pharmacology, professionalism, creativity, critical thinking, communication, and collaboration. To put this into practice, we also focus on developing strong mentoring competencies for our trainers through required mentor training and ensure that they are aligned with the vision of the program. The Pharmacology PhD program serves as the overall structure for the MPTP. To meet the growing demand for PhD scientists with a strong training in therapeutics, the MPTP has created a curriculum to augment the student’s training in related disciplines (neuroscience, biochemistry, etc). The 45 MPTP preceptors reflect this interdisciplinary approach to training as they represent five major research centers in Cleveland: CWRU School of Medicine, University Hospitals, Cleveland Clinic, MetroHealth Medical Center, and the Louis Stokes VA Medical Center. The curriculum is rigorous with clearly defined metrics that are rooted in the 6 core competencies. Training activities are designed to bring cohorts of students who are interested in therapeutics across the city of Cleveland together in shared experiences. The MPTP fosters career exploration with workshops and classes that expose students to available resources early in their training, which allows them to tailor their program of study to meet their career goals. Our desired outcomes are to graduate PhD scientists with the knowledge base and research skills to pursue a broad range of career opportunities related to pharmacology, ranging from academic and industrial bench science to scientific writing, patent law, science policy, biotech management, and teaching. We also seek to combat the increasing time to degree by modernizing the approach to PhD education through an intentionally designed program that is efficient, yet rigorous. Our goal is to be a model for other PhD programs at CWRU School of Medicine and across the country.

NSF Awards · FY 2025 · 2025-06

This project focuses on two types of mathematical problems: tomographic problems and isoperimetric problems. Tomography concerns the retrieval of information about a geometric object based on limited information arising from its cross-sections or shadows (projections). For example, think of trying to determine the volume of a mountain based on the size of its shadows at different times of the day. Isoperimetric problems arise in geometry and optimization and have been of interest for thousands of years, dating back to ancient Greece. In a modern context, isoperimetric problems can involve studying the regularity of high-dimensional information. In complex data sets, high dimensionality often results in a regularizing effect. Tomographic and isoperimetric problems have been highly influential in many scientific disciplines, including physics, engineering, and computer science. Beyond their historical significance and applicability, these problems appeal to a wide audience because they are often intuitively stated and explained, while their solutions are difficult and require sophisticated mathematical techniques. The principal investigator of this project seeks to address problems arising naturally from geometry and harmonic analysis by employing techniques involving the Fourier transform, Radon transform, and other tools from various mathematical fields. Among these proposed problems are new affine invariant estimates for mixed-Sobolev norms, estimates for Radon and Cosine transforms (each abstractly represents the cross-sections and projections of an object, respectively) and their connections to long-standing problems including the recently resolved Bourgain slicing problem and the Busemann-Petty problems, and the very illusive Petty’s isoperimetric conjecture and Schneider’s difference body conjecture. The principal investigator will also seek interactions between these problems and other mathematical disciplines, including calculus of variations, partial differential equations, and probability theory. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY/ABSTRACT Tauopathies are a group of neurodegenerative diseases that are histopathologically characterized by abnormal accumulation and aggregation of tau in human brains. In addition to dysregulation of tau post- translational modifications and other causes of tau protein pathogenicity, abnormal tau mRNA metabolism is believed to play an important role, although the underlying mechanism remains elusive. N6-methyladenosine (m6A) methylation of RNA is the most prevalent, abundant and conserved internal modification in eukaryotic RNAs and it influences fundamental aspects of RNA metabolism including degradation, translation, splicing, and nuclear export. While RNA m6A dysregulation is implicated in the neurodegenerative diseases, the potential role of RNA m6A dysregulation in Tau mRNA metabolism and tauopathy in neurodegeneration has never been investigated. Our group reported that neuronal m6A reduction contributes to neurodegeneration in Alzheimer’s Disease (AD) by affecting CCND2 mRNA stability and inducing abnormal cell cycle events. In our pilot study, we noted that Tau mRNA contains m6A modification sites. Importantly, we found decreased neuronal m6A levels along with significantly reduced expression of m6A methyltransferase METTL14 in brains from Pick’s Disease (PiD), a tauopathy-related neurodegenerative disease characterized by accumulation of 3-repeat (3R) tau isoforms in pick bodies. These results suggest that RNA m6A dysregulation may be involved in tauopathy. Along this line, we found conditional knockout (cKO) of METTL14 leads to m6A reduction, Tau mRNA hypo-methylation, and Tau accumulation in mouse brains. Based on these results, we hypothesize that METTL14 depletion-mediated RNA m6A reduction affects Tau mRNA metabolism that leads to changes in splicing and tau accumulation in tauopathy. We will determine the effect of METTL14 depletion-mediated m6A reduction on Tau mRNA metabolism by affecting its alternative splicing and stability in primary neurons and mouse brains. A new hTau KI mouse model will be used to test whether METTL14 cKO leads to abnormal tau mRNA metabolism and tau-related neurodegeneration. The successful completion of this study will provide novel mechanistic insights into tau mRNA metabolism and tauopathy. It offers a new therapeutic target of tau mRNA metabolism for tauopathy during tau-related neurodegeneration.

NSF Awards · FY 2025 · 2025-06

Controlling the growth of unwanted bacteria in our water systems is costly. This project plans to use viruses, the natural killers of bacteria, to control the bacteria growth. In nature, every type of bacteria can be infected by at least one type of virus known as a bacteriophage. This CAREER project will develop methods to discover the mixtures of naturally occurring bacteriophages (called bacteriophage cocktails) that are effective at killing bacteria. The research will identify why some bacteriophage cocktails work better than others. The project will also build relationships between researchers and the water industry to teach practitioners how to use bacteriophages to control bacteria in water systems. The project will provide opportunities for high school students, undergraduates and graduate students to participate in the research. New methods of microbial control are needed to protect public health from exposure to disinfection byproducts, opportunistic pathogens, and antibiotic resistance in drinking water, while reduce the economic costs of biofouling and biocorrosion control in water distribution system. One alternative to traditional microbial control processes is to specifically tune the bacterial community of water systems using mixtures of bacteriophages to kill the bacteria. Currently, the design of these mixtures (bacteriophage cocktails) is slow and laborious, relying on trial and error to identify the most effective combinations of bacteriophages. This CAREER project will develop a platform for the rational design of bacteriophage cocktails, based on the hypothesis that safe and effective bacteriophage cocktails will have specific gene and transcript (mRNA) profiles that are distinct from those that have antagonistic or off-target effects. The research will address the following objectives: (1) identify genetic and transcriptomic markers of synergistic versus antagonistic bacteriophage cocktail interactions and (2) assess off-target infection risks using experimental and computational approaches. The education objectives will (1) ensure that students have the skills for further developing bacteriophage biocontrol technologies by creating educational materials and hands-on bacteriophage discovery experiences for high school and college students and (2) encourage knowledge exchange between researchers and practitioners by convening a practitioner advisory board. This project will contribute to the development of a systematic understanding of the features of safe and effective bacteriophage cocktails. Together, the tightly coupled research and educational objectives of this CAREER project will accelerate the development of improved microbial control technologies, reducing the costs of unwanted microbial growth and better protecting human health. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-06

Abstract: Supplemental O2 therapy and non-invasive ventilation such as continuous positive pressure support (CPAP) are two common life-saving modalities of respiratory care for the treatment of preterm infants with respiratory distress. However, most methods of respiratory care contribute to major life-long unintended consequences such as airway hyperreactivity (AHR) disorders associated with wheezing and asthma. Supplemental O2 therapy and invasive mechanical ventilation have long been recognized as primary contributors to the pathogenesis of wheezing in former preterm infants – these observations have driven efforts to titrate and minimize the usage of O2 in the NICU setting while favoring the use of non-invasive positive pressure support such as CPAP. As a result, there is a growing number of preterm infants who receive CPAP and many without supplemental O2. Although CPAP is on the gentler end of the spectrum of positive pressure modalities, know very little is known about its effects on lung development. Emerging clinical evidence, however, implicates CPAP in poor respiratory outcomes associated with restrictions in airflow and also wheezing in former preterm infants into childhood. We have corroborated these findings using a novel mouse model of neonatal CPAP which is sufficient, without hyperoxia exposure, to elicit AHR via a mechanism involving airway smooth muscle proliferation – a phenotype functionally analogous to that seen with neonatal supplemental O2. We have also demonstrated a role of airway smooth muscle (ASM) proliferation, Ca2+ signaling, and the extracellular matrix, specifically low molecular weight hyaluronan (HALMW) in CPAP effects. Together with the limited clinical data, these observations are at the forefront of identifying the potential adverse effects of CPAP and how it could be a significant contributor to poor respiratory system development seen in former preterm infants. In this application, we utilize the same in vivo mouse (CPAP) model, complemented with a human fetal ASM (fASM) in vitro stretch model which mimics CPAP, to test the overall hypotheses that stretch-induced effects on ASM proliferation and hyperreactivity are initiated by multiple mechanosensitive pathways involving: 1) the newly identified piezo (PZ) family of mechanosensors; 2) extracellular matrix and stretch sensitive HALMW; and 3) plasma membrane caveolae. A novel feature of this proposal is the identification of an apparent feedforward mechanism by all three pathways, while distinctly different, converge and reinforce each other’s effects to cause the persistent AHR. Therefore, this proposal will reveal novel mechanosensitive pathways as a primary mechanistic feature of the unintended consequences of CPAP on airway hyperreactivity, with will be crucial in guiding the clinical care of preterm infants in a way that minimizes the adverse effects of these respiratory interventions and maximizing their benefits.

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY: Of the estimated 46,220 patients who will be newly diagnosed with rectal cancer in 2024, patients with locally advanced rectal cancer will undergo total neoadjuvant therapy (TNT) to reduce tumor burden followed by standard-of-care surgical excision of the rectum. Up to 50% of these patients exhibit near complete clinic response (CR, i.e., very few/no tumor cells) on the post-surgical specimen. These patients are therefore ideal candidates for a “watch-and-wait” (W&W) approach, a treatment regimen that replaces unnecessary morbid surgery with intensive surveillance; which results in a significantly improved quality of life while maintaining current disease-free survival rates. However, due to a lack of consistent clinical criteria and variable evaluation of routinely acquired MRIs, the 50% of rectal cancer patients that present with CR cannot be reliably distinguished from non-CR patients. Thus, the key clinical challenge in rectal cancers is accurately and non- invasively identifying patients that exhibit CR after TNT and are candidates for W&W. TNT is known to induce desmoplastic stromal reactions in the tumoral and peritumoral environments due to treatment effects and tumor regression. These pathologic tissue changes are very subtle and difficult to objectively discern on routine MRI. Deep learning (DL), a form of artificial intelligence that utilizes large neural networks to extract textural, morphological, and other attributes, could enable more quantitative characterization of treatment response on imaging. Applying DL approaches for accurate identification of CR in rectal cancers while also maintaining clinical interpretability would require (a) ensuring the DL model uses specialized image filters to capture surrogates of subtle desmoplastic reactions to TNT on routine MRI, (b) biological validation of DL predictions against underlying histology via spatial fusion of MRI and digitized pathology specimens, and (c) rigorous external evaluation of DL performance on a clinical trial cohort of patients who were administered TNT. In this proposal, I will engineer and validate a novel DL framework that leverages wavelet texture filters, called RadWaveNet, to comprehensively quantify TNT response of rectal cancers on MRI. Aim 1 will first develop and optimize RadWaveNet on pre- and post-TNT MRI scans across multiple acquisition planes from a diverse patient population to ensure equity in performance in race- and age-based subgroups. Aim 2a will focus on biologically validating that RadWaveNet signatures captured imaging surrogates of tissue responses associated with CR via spatial co-registration of the post-surgical pathology and pre-operative imaging. In Aim 2b, RadWaveNet will undergo rigorous clinical validation with comparison against gold-standard pathologic response markers for rectal cancer datasets retrospectively curated from the NCT02688712 clinical trial. My project will build upon my promising preliminary results for developing DL models to characterize the rectal lesion environment on MRI, as well as constructing wavelet DL models for predicting response to neoadjuvant chemoradiation; towards a clinically reliable, non-invasive tool for personalizing treatment in rectal cancers.

NIH Research Projects · FY 2026 · 2025-06

PROJECT SUMMARY/ABSTRACT Type 1 diabetes (T1D) is a chronic autoimmune disease that results in destruction of pancreatic islet beta cells by autoreactive T lymphocytes. T1D is the most common form of diabetes in children less than 15 years of age. Intensive insulin therapy is the current standard of treatment for T1D. Yet, insulin treatment does not address the underlying autoimmunity present in T1D. As such, there is a critical need for T1D therapies that target autoimmunity, which will prevent beta cell loss in early stages of T1D and allow for survival of remaining beta cells in later T1D stages. We have previously shown that spontaneous autoimmune diabetes is accelerated in non-obese diabetic (NOD) mice deficient in NF-kB c-Rel. Interestingly, c-Rel knockout NOD mice show significantly increased levels of microRNA146a (miR146a), which is a microRNA that is highly expressed in immune cells and is involved in post-transcriptional regulation of key NF-κB signaling proteins. Similarly, miR146a is increased in the serum of T1D patients at the time of diagnosis. Hence, we generated miR146a- knockout (miR146a-KO) NOD mice to study the role of miR146a in T1D. We discovered that deficiency of miR146a prevents spontaneous autoimmune diabetes in NOD mice. In this proposal, we will (a) investigate the role of miR146a in regulation of autoimmunity in T1D with a focus on T cells and T regulatory cells, and (b) study inhibition of miR146a as a potential therapy for T1D. We hypothesize that miR146a deficiency results in decreased T cell autoreactivity and enhanced T regulatory cell function, and as such, treatment with anti- miR146a will prevent autoimmunity in T1D and halt progression of T1D. We will use NOD wildtype mice and our novel miR146a-knockout NOD mice to investigate the role of miR146a in T1D, with a focus on T cell autoreactivity to T1D autoantigens and T cell polarization. We will also investigate the role of miR146a in T regulatory cell number and function in these mice with an emphasis on the direct regulation of NF-κB c-Rel by miR146a given the critical role of c-Rel in Treg development and function. Furthermore, we will use an anti-miR146a inhibitor to study the effect of miR146a inhibition in T cells and T regulatory cells from NOD mice, healthy human blood, and T1D patient blood. In vivo, we will study anti-miR146a treatment in both prediabetic and early diabetic NOD mice to examine the efficacy of miR146a inhibition for prevention and treatment of T1D. Altogether, this proposal uses novel miR146a-knockout NOD mice, T1D patient samples, and an anti-miR146a inhibitor to study the regulatory role of miR146a in autoimmunity in T1D and the efficacy of miR146a inhibition as a therapeutic for T1D. These studies have the potential to lead to a long-sought-after therapeutic approach to control T cell-mediated autoimmunity in type 1 diabetes.

NIH Research Projects · FY 2026 · 2025-06

ABSTRACT Hypertrophic cardiomyopathy (HCM) is a common disorder that affects 1 in 300 individuals and is characterized by abnormal cardiac morphology and function leading to an increased risk of heart failure and sudden cardiac death. HCM is often caused by inherited variants in genes that regulate force generation and contractile function in cardiac myocytes. Mutations in the gene encoding cardiac myosin binding protein C (cMyBP-C) are the most common, accounting for more than half of all known cases of inherited HCM. Mutations in MYBPC3 that result in truncated proteins reduce sarcomeric expression of cMyBP-C, however, missense variants are typically incorporated into the sarcomere and alter cMyBP-C function. The vast majority of cMyBP-C missense variants are classified as variants of unknown significance as there is not enough information to accurately predict whether patients with these variants will develop disease. A primary reason for our inability to predict cMyBP-C variant pathogenicity is our poor understanding of cMyBP-C’s complex structure and function. cMyBP-C is a large ~140kDa, 11-domain molecule that modulates contractile function through interactions with multiple binding partners, though the precise molecular mechanisms that govern these interactions are yet to be determined. Therefore, it is unclear how missense variants in different domains of the molecule that have specialized roles affect contractile function and cause HCM. Therefore, the central goal of this proposal is to define the effects of cMyBP-C missense variants on cardiac sarcomere molecular structure and function, and to link these mechanisms to altered whole organ structure and function and development of HCM. To accomplish this goal we have devised a comprehensive experimental plan that defines the consequences of cMyBP-C missense variants from atom to whole animal levels. In Aim 1 we will utilize cryo-electron microscopy (cryo-EM) to solve near-atomic structure of cMyBP-C variants. In Aim 2 we will elucidate the domain-specific effects of missense variants on ligand binding, cross-bridge behavior, and myocardial force generation and relaxation. In Aim 3, we will determine the in vivo effects of missense mutations on development and progression of cardiac hypertrophy, and contractile and hemodynamic dysfunction. By integrating studies of cardiac sarcomere structure, cellular biophysics, and in vivo function, we will uncover the mechanisms by which missense cMyBP-C variants cause HCM, thereby, improving our ability to predict which variants are most likely to cause disease. We anticipate that these studies will advance our understanding of fundamental processes that regulate cardiac contractile function, which may motivate the development of novel therapies to treat cMyBP-C related cardiomyopathies.

NIH Research Projects · FY 2026 · 2025-05

PROJECT ABSTRACT This research advances the measurement of sibling relationship quality by rigorously developing the Sibling Prosocial Relationship Questionnaire (SPRQ), a child- and parent-report measure of sibling relationship quality for children between the ages of 8 to 17, and establishing its reliability and validity. Sibling relationships, being one of the longest-standing relationships across the life course, significantly influence human development and behavior, serving as a critical foundation for later social development, including peer and romantic relationships. Despite strong evidence linking social connection to child health and well-being, inadequate measures hinder exploring the potential of sibling relationship quality. The validity of existing measures is compromised due to serious limitations in their development such as narrow conceptualizations of family (i.e., primarily white, two-parent, middle-to-upper class), inadequate item development and refinement (i.e., minimal use of content expert consultation), reductionist operationalization of relationship quality (i.e., dichotomy of positive/negative or conflict/warmth), and limited analytic approaches (i.e., reliance on reliability estimates and principal components analyses rather than factor analysis and item response theory [IRT]). An innovative conceptual work by Kramer provides a framework to expand upon and update existing measures of sibling relationship quality by shifting the focus from occurrences of behaviors (conflict/warmth) to social processes that promote prosocial forms of sibling interactions within the context of the family system. For example, how sibling conflict is resolved, rather than the occurrence or absence of conflict itself, is instrumental for the development of child social, emotional, and cognitive competencies. This study addresses the limitations of existing measures by using the rigorous and contemporary PROMIS® methodology for the first time in sibling relationship research, which will enhance measurement precision and reliability. The specific aims are: Aim 1: Develop the SPRQ, an English and Spanish child- and caregiver-report measure of sibling relationship quality, through thematic analysis, expert interviews, and cognitive testing. Aim 2: Establish the measurement properties of the SPRQ using factor analysis, item response theory, and differential item functioning assessments. Aim 3: Determine associations between the SPRQ and child outcomes, validating it against measures of behavioral and emotional attributes, and examine the direction and magnitude of association of the SPRQ with emotional and behavioral regulation, and other social relationships.This innovative approach has the potential to transform research and clinical practice by providing robust, actionable insights into the mechanisms and trajectories of sibling relationships, thus identifying malleable components that can be targeted in interventions. By capturing prosocial forms of sibling interactions, the SPRQ can lead to more effective strategies for enhancing social connections and improving child and adolescent health and well-being.

NIH Research Projects · FY 2025 · 2025-05

The key histopathological feature of frontotemporal lobar degeneration (also known as frontotemporal dementia) and amyotrophic lateral sclerosis is accumulation of aggregated TDP-43 protein in brain. Similar aggregates (filaments) are also associated with a number of other neurodegenerative diseases, including Alzheimer's disease, dementia with Lewy bodies, hippocampal sclerosis and chronic traumatic encephalopathy. An important recent development in the field was determination, by cryo-electron microscopy, of high resolution structures of these TDP-43 filaments derived from brains of individuals afflicted with two different types of frontotemporal lobar degeneration. The overall goal of this exploratory research is to develop and experimental model and establish conditions for generation of amyloid fibrils with structures identical to those of brain-derived filaments from the recombinant TDP-43 in vitro. Upon initial screening by low resolution methods, structural similarity of selected synthetic fibrils to brain-derived filaments will be verified at a high-resolution level by cryo-electron microscopy. Generation of synthetic replicas of TDP-43 filaments associated with different phenotypes of the disease would represent a very important development: it would not only provide a stepping stone for mechanistic studies on disease- relevant TDP-43 aggregation pathways, but also open new avenues for development of drugs (TDP-43 aggregation inhibitors, disaggregating agents) as well as diagnostic tools for early detection of TDP-43 proteinopathies in patients.

NSF Awards · FY 2025 · 2025-05

Indoor air quality is affected by a variety of chemical and biological factors. For example, building materials and furniture surfaces inside homes are sources, sinks, and temporary reservoirs for chemicals. At the same time, microbes such as bacteria, viruses and fungi can grow on these surfaces. Usually, researchers study the chemical factors and biological factors affecting air quality separately. This project will investigate them in combination by exploring, for example, how chemical compositions on surfaces or in the surrounding air can trigger changes in the way microbes grow on various surfaces typically found in a home. By studying the chemical and biological factors together, the project will produce results that can inform air quality guidelines to improve indoor environmental quality. The project will also introduce local middle school students to air quality issues by helping them build environmental sensors that will be deployed on campus to monitor environmental conditions. This project will determine how perturbations to indoor surface chemical composition and indoor air pollutant distribution impact microbial gene expression and microbial volatile organic compound (mVOC) emissions, to better understand and mitigate the chemical and biological drivers of poor indoor air quality. Laboratory chamber experiments, volatile organic compound measurements, and microbial gene expression analysis will be performed to support the following research objectives: (1) Establish how building material surface composition influences microbial gene expression and emissions; and (2) Build networks to connect environmental pollutant exposures to microbial gene expression and emissions. This research will expand knowledge in indoor chemistry and microbiology by revealing how indoor surface and air composition influence indoor microbial communities, and vice-versa. The study will use RNA sequencing to connect microbial community metabolism with surface chemical composition and pollutant exposure in the built environment. Indoor environmental conditions, especially increased humidity in non-climate-controlled homes, could impact the chemical composition of indoor material surfaces and thus alter fluxes of chemicals between surfaces and air, as well as create favorable growth conditions for microbes. This study will advance our fundamental understanding of the connection between surface conditions and pollutant exposures, microbial gene expression, and mVOCs in the evolving indoor environment. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-05

NON-TECHNICAL SUMMARY: Piezoelectric polymers are unique materials that generate electricity when they are compressed or stretched. Since their discovery in 1969, they have shown great promise for use in important technologies, including sensors, transducers, actuators, and energy harvesters. However, their adoption has been limited by their low performance when compared to piezoelectric ceramics, which are predominantly used today. This project addresses a key scientific question: how do piezoelectric polymers work at the molecular level? Specifically, which part of these semicrystalline polymers contributes primarily to the observed piezoelectricity - the crystalline regions, the amorphous regions, or the interphase between the two? To tackle this challenge, the project will employ computer simulation, advanced polymer processing, structural analysis, and property characterization to uncover the mechanisms behind polymer piezoelectricity. With the resolution of this fundamental question, researchers would be able to develop advanced piezoelectric polymers that can rival, or even exceed, the performance of piezoelectric ceramics. The products of this research could have far-reaching impacts. High-performance piezoelectric polymers could enable more efficient and lightweight medical devices for ultrasound imaging and therapy, enhance wearable electronics, and drive innovations in robotics. Beyond the scientific benefits, this project prioritizes education and outreach to inspire and train the next generation of scientists and engineers. It also includes hands-on research opportunities for high school and undergraduate students. TECHNICAL SUMMARY: Since the discovery of chain-folding in single lamellar crystals, a two-phase model (i.e., crystalline and amorphous phases) has been used to describe semicrystalline polymers. However, for melt- and solid state-processed semicrystalline polymers, studies using temperature-modulated differential scanning calorimetry have revealed a third component: the rigid amorphous fraction (RAF). It is suggested that chain-folding may not be the predominant packing scheme for these materials. Instead, a substantial portion of the polymer chains extends directly from the crystalline basal planes, forming an oriented amorphous fraction (OAF) that gradually transitions into the isotropic amorphous fraction (IAF). The tethering of OAF to rigid crystals results in reduced mobility, making it an RAF. By integrating computer simulation and experimental studies, this project aims to elucidate the OAF structure in semicrystalline ferroelectric polymers, such as poly(vinylidene fluoride) (PVDF). It is hypothesized that the electrostrictive OAF is the major contributor to the piezoelectric property. Initially, computer simulation will be used to calculate the structural factor of OAF in PVDF and compare it with the experimental X-ray diffraction patterns to gain insights into the OAF structure. Subsequently, a revised nanocomposite model, consisting of crystals, OAF and IAF will be utilized to simulate the piezoelectric response. Additionally, nanocrystalline PVDF will be explored to increase the OAF content and enhance the piezoelectricity. Finally, multiblock copolymers, composed of ferroelectric copolymers and electrostrictive terpolymers of PVDF, will be synthesized to investigate new opportunities. The goal of this research is an improved fundamental understanding of the structure-piezoelectric property relationship in semicrystalline ferroelectric polymers. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY/ABSTRACT Brain development requires intricate regulation of transcription, splicing, translation, and chromatin remodeling, but how these processes interconnect is not understood. We propose to elucidate how posttranscriptional alternative splicing regulates the epigenetic programs of brain development. During brain development, alternative splicing of a subunit of the chromatin remodeling BAF (BRG1/BRM-associated factor) complex, DPF2, switches from the canonical DPF2-Short (S) to a longer brain-specific DPF2-Long (L) isoform due to the inclusion of a highly conserved exon 7. This alternative splicing switch impacts transcriptional regulatory programs in embryonic stem cells (ESCs) and neural progenitor cells (NPCs), where DPF2-S and -L isoforms exhibit discrete binding preferences to chromatin regions marked by different histone modifications, selectively recruiting the BAF complex to specific genomic enhancers or promoters. Failure to switch from DPF2-S to -L during ESC differentiation into glutamatergic neurons promotes the proliferation of non-neuronal cells and reduces differentiation into neurons. However, how the brain-specific DPF2-L isoform functions in the epigenetic regulation of the brain remains unknown. We propose to determine how the splicing switch of DPF2 controls transcriptional and chromatin regulatory programs and neuronal maturation during brain development. By utilizing CRISPR/Cas9-mediated genome-edited ESC lines and mouse models expressing either DPF2-S or DPF2-L, we aim to determine the heterogeneity of different neuronal and non-neuronal lineages and the transcriptional regulatory programs driven by alternative DPF2 isoforms in in vitro glutamatergic differentiation cultures, as well as in mouse brains. Because DPF2 functions as part of the BAF complex, we propose to map genome-wide BAF complex recruitment and accessible open chromatin regions at different developmental time points from embryonic to adult brains. We recently discovered that DPF2-associated BAF complexes reorganize into smaller subcomplexes in older adult brains, and now propose to determine the subunit composition and modular organization of these subcomplexes and map their chromatin recruitment to understand their specific roles in regulating epigenetic programs associated with brain aging.

NSF Awards · FY 2025 · 2025-04

This I-Corps project is based on the lab to market translation of a novel wearable health monitoring device that provides continuous, real-time monitoring of vital signs and early detection of health-critical events. This technology provides a cost-effective and energy-efficient solution that enhances accessibility to real-time health data for individuals with anxiety disorders, cardiovascular conditions, and other medical concerns requiring continuous monitoring. This solution addresses the lack of affordable, real-time, and continuous health monitoring for individuals at risk of critical health events, such as panic attacks or cardiac irregularities. Current wearable solutions either lack accuracy due to motion interference or require high power consumption, limiting their usability for long-term monitoring. With the U.S. facing an increasing prevalence of chronic health conditions and a growing demand for remote patient monitoring, there is need for an energy-efficient, reliable, and scalable solution that bridges the gap between clinical-grade monitoring and consumer accessibility. Commercializing this solution has the potential to benefit society and the economy by reducing healthcare costs, improving early intervention outcomes, and expanding access to personalized health tracking, which can ultimately enhance public health and well-being. This I-Corps project utilizes experiential learning and first-hand industry engagement to assess the commercialization potential of an ultra-low-power wearable health monitoring system that integrates advanced biometric sensors, near-sensor artificial intelligence (AI) processing, and novel signal processing techniques. This solution consists of a hybrid computational framework that leverages emerging stochastic computing (SC) and hyperdimensional computing (HDC) to reduce energy consumption while enhancing real-time signal processing. Unlike conventional wearables, which rely on high-power computation, this approach enables efficient near-sensor AI processing, minimizing data transmission delays and computational overhead. Additionally, the fusion of multi-modal sensor data with deep learning models improves signal integrity and detection accuracy for health-critical events. The benefits of this approach include longer battery life, lower manufacturing costs, and enhanced accuracy in detecting physiological anomalies. By eliminating energy-intensive digital conversions and leveraging low-complexity AI models, this technology ensures scalability and affordability for widespread adoption in clinical, consumer, and remote patient monitoring applications. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-04

Project Summary This funding application aims to acquire a state-of-the-art, integrated mass spectrometry-based system for hydrogen/deuterium exchange (HDX-MS) studies on complex protein systems. The system will support a large community of biomedical researchers at Case Western Reserve University and neighboring institutions, including the Cleveland Clinic Learner Research Institute, University Hospitals, the Veteran Affairs Hospital, the MetroHealth Rammelkamp Center for Education and Research, and Cleveland State University. Currently, we have eight main users and nine minor users, with six already utilizing or recently using HDX-MS for their projects. However, the existing equipment, now over 15 years old, is outdated and does not facilitate efficient, sensitive, or reliable experiments compared to the proposed instrument. Remarkably, there is no state-of-the-art HDX-MS equipment dedicated to hydrogen/deuterium exchange studies in the entire Greater Cleveland area or even in Ohio. The HDX-MS approach is vital for characterizing highly complex and challenging systems, including large protein-protein complexes, protein aggregates associated with neurodegenerative disorders, membrane channels, membrane-associated proteins, and protein-nucleic acid complexes. This technology will be an invaluable tool for structural biology research, benefiting numerous NIH-funded investigators working on fundamental biological and biomedical problems. It will expand the scope of biomedical research and foster collaborative interactions. More than 30 NIH-funded research projects will immediately benefit from this instrument. These include studies on misfolded protein aggregates, protein-protein complexes involved in cell signaling, self-assembling proteins in synaptic vesicle endocytosis, GPCRs, large multimeric membrane channels (ligand-gated channels, aquaporin channels), membrane and water-soluble receptors, and inflammasome signaling complexes. These projects contribute to a better understanding of the pathogenic processes associated with these systems. Moreover, the insights gained will aid in developing novel therapeutic strategies for various diseases, including neurodegenerative disorders, cancer, cardiovascular diseases, pain, visual impairment, bacterial and viral infections, and inflammation.

NIH Research Projects · FY 2025 · 2025-04

PROJECT SUMMARY/ABSTRACT Prenatal screening for genetic conditions (PGS) has changed the landscape of prenatal care by offering noninvasive indication of some fetal genetic conditions. PGS should be clearly distinguished from prenatal diagnostic testing using microarray analysis of amniotic fluid, which is considered the gold standard for fetal genetic assessment. While other routine screens are not held to the standard of fully informed consent, the ethics literature on PGS, from maternal serum screening to cell-free DNA and other technologies, has argued that PGS requires higher levels of consent based on the exceptional nature of its informational impacts, including potential abortion decisions based on fetal characteristics. Multiple studies examining the patient experience have described or proactively expressed concern at the routinization of PGS, including insufficient pre-test counseling and ethical reflection on whether PGS was the right approach for the patient and family, consistent with their values on disability and abortion. However, our own research on the implementation of PGS in low-resource settings in the U.S. has found that there are few resources to attempt, let alone achieve, fully informed consent prior to screening. Furthermore, for the great majority of pregnancies that do not receive a high-probability PGS screen, attempting fully informed consent introduces mental and psychological stress on pregnant individuals that may be unnecessary and undesirable. Patients who receive screen-positive results do require extensive information and support for pregnancy and parenting decision-making, but they represent a tiny minority of all those screened. Thus, we argue that a model of just-in-time consent (JITC) for PGS, incorporating simple consent with shared decision-making, better fulfills the goals of prenatal screening and locates intense moral decision-making in a more appropriate place in the pregnancy journey. JITC acknowledges the increased moral weight that prenatal screening may have over other routine screens without burdening pregnant individuals and health systems with unnecessary consent procedures. We propose a clinical trial over three demographically and geographically diverse sites that serve a large pregnant population from historically underserved communities to compare a novel JITC mechanism to current care. Our Aims are: (1a) Conduct community engaged research with patients and providers to understand the necessary components of JITC for PGS; (1b) Design and pilot a mobile-based intervention to deliver knowledge elements necessary for JITC for cfDNA; (2) Using a stepped-wedge design, implement the mobile-based intervention at three diverse sites and evaluate outcomes of feasibility and decisional satisfaction; and (3) Develop data-based, ethically informed recommendations regarding implementation of a just-in-time consent model for patients receiving high risk PGS screening test results.

NIH Research Projects · FY 2026 · 2025-04

Project Summary_Abstract Acute myeloid leukemia (AML) thrives through the persistence of self-renewing leukemic stem cells (LSCs). A central challenge in AML treatment lies in the failure of conventional therapies to eradicate LSCs, which can trigger AML reoccurrence. The promise of AML eradication hinges on identifying and targeting pivotal molecules driving LSC self-renewal. Heat shock transcription factor 1 (HSF1) is a stress-responsive transcription factor pivotal in shielding cells from stress-induced demise. It aids cancer cells in managing stress, facilitating oncogenic signaling, DNA/protein synthesis, oncogenic energy metabolism, and immune evasion. Our studies using Hsf1 knockout mice underscore HSF1’s unique role in AML stem cell maintenance, while sparing normal hematopoiesis. Importantly, AML prognosis worsens with elevated HSF1 levels per TCGA data and our data show that nuclear HSF1 levels correlate with therapeutic responses and AML progression. While HSF1 inhibitors have been tested in cellular and mouse xenograft cancer models, many either indirectly affect the HSF1 pathway or have an unknown mechanism of action. SISU-102, a direct and selective small-molecule nuclear HSF1 degrader, physically engages HSF1 and selectively promotes the degradation of its active, nuclear form. Importantly, our research has shown that SISU-102 effectively targets human AML LSCs. More recently, Sisu Pharma has developed new more potent HSF1 nuclear degraders with better drug-like properties. Our preliminary data indicate that these advanced HSF1 degraders exhibit enhanced binding to HSF1 and effectively suppress the proliferation of human LSCs. The aim of this proposal is to further investigate the impacts of these newly developed HSF1 degraders on LSC self-renewal, identify sensitive and resistant AML subtypes, and explore the underlying mechanisms, facilitating their translation into clinical use. Our working hypothesis posits that nuclear-specific HSF1 degraders have broad therapeutic potential against AML stem cells by disrupting multifaceted molecules and pathways driven by HSF1 that are critical for LSC maintenance. Aim 1: Determine the cellular impact of the newly developed small molecule nuclear HSF1 degraders on human AML stem cell self-renewal. Aim 2: Elucidate the mechanism of action of HSF1 degraders in LSCs and identify associated biomarkers that can identify AML patients susceptible to HSF1 degrader therapeutics. This research could advance HSF1 degraders for clinical trials in treating AML patients.