University Of Wisconsin-Madison

NIH Research Projects · FY 2025 · 2024-09

Project Summary Contraceptive autonomy – people’s ability to decide for themselves what they want in regard to contraceptive use, and to realize that decision – is essential for reproductive health and wellbeing. The primary goal of this proposal is to develop, refine, and test a contraceptive autonomy indicator that measures the extent to which family planning programs respect and promote free, full, and informed contraceptive decision-making. The longer-term objective of this research is to incorporate a concise survey module for this indicator into existing population-based surveys for routine, standardized, and comparable monitoring across time and place. Improved measurement of contraceptive autonomy can create new health systems incentives for respectful, rights-based family planning. Specific aims of this project include 1) Developing a novel contraceptive autonomy indicator that maximizes information and minimizes respondent burden via formal psychometric analysis of novel survey data from Burkina Faso; 2) Assessing the transportability of “contraceptive autonomy” across diverse sociocultural contexts; and 3) Test and refine the updated autonomy indicator in Nepal and Kenya with cognitive interviews. To meet Aim 1, the PI will use a first-of-its-kind dataset from Burkina Faso with novel survey questions on informed contraceptive decision-making, full access to a broad contraceptive method mix, and free contraceptive choice. To achieve Aims 2 and 3, the PI will collaborate with leading researchers in Nepal and Kenya to collect new data, using semi-structured in-depth and cognitive interviews with a diverse sample of women to understand how notions of autonomy differ across context, and gather pilot data to inform a future multi-site validation study. The goal of the training and career development portion of this grant is to foster the independent research career of Dr. Leigh Senderowicz. Dr. Senderowicz is an emerging scholar of patient-centered family planning and global health metrics. With the guidance of mentors Dr. Daniel Bolt, Dr. Jenny Higgins, Dr. Corinne Rocca and Dr. Claire Wendland, Dr. Senderowicz will pursue a program of training in latent variable modeling, transnational comparative qualitative analysis, survey scale-up and research translation, and professional development at the University of Wisconsin-Madison. These training activities will grow her methodological repertoire and enhance her career as an independent reproductive health scholar. The proposed research is poised to make a substantial impact on global reproductive health, helping to expose reproductive health disparities, and provide new data to inform equitable, person-centered reproductive health programs.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Electronic nicotine delivery systems (ENDS) are used by millions of Americans, however, we do not understand their long-term health effects. Although ENDS use delivers far lower levels of carcinogens than tobacco smoking, very little is known about whether ENDS use affects the risks of developing cardiovascular (CV) or pulmonary diseases, two of the most highly prevalent causes of morbidity and mortality in the United States. This research proposal will quantify the effects of long-term ENDS use on validated and novel biomarkers of CV and pulmonary disease and how they are influenced by use heaviness, age, body weight, and co-use of other products. This research also will shed additional light on long-term ENDS use patterns and ENDS dependence. The importance of this study does not rest upon demonstrating adverse effects of ENDS use. We will recruit 400 long-term, stable users of ENDS and 200 age- and gender-matched control participants who do not use ENDS or combustible cigarettes. They will undergo comprehensive biomarker assessments over 36 months. Biomarkers assess CV and pulmonary health status and risk and include vital signs, fasting blood samples for systemic inflammation and oxidative stress, lipids, and markers of insulin resistance and cardiometabolic health. Arterial structure changes will be assessed using carotid ultrasound and brachial artery flow-mediated dilation. Sympathetic nervous system activation will be assessed by heart rate variability and arterial diameters. For pulmonary measures, we will obtain non-contrast quantitative computed tomography (CT) images to assess air trapping and texture-based measures of inflammation. We also will perform spirometry and measure exhaled nitric oxide. Integrated cardiopulmonary health will be assessed via treadmill stress testing. Other measures will include exhaled carbon monoxide, real-time measures of nicotine product use, nicotine dependence, and use of cannabis and alcohol. Biomarker status over time will be compared across groups and related to ENDS use heaviness, use of other products, and person factors (i.e., age, gender, race/ethnicity, weight, and smoking history). We will include ~130 participants who were phenotyped from 2019-2021. Our Primary Aim is to determine relationships between ENDS use heaviness and changes in our CV and pulmonary biomarkers over 3 years. We will compare biomarker status across ENDS users and non-users over time and examine associations between biomarker status and ENDS use heaviness within the ENDS user group. Our Secondary Aim is to characterize changes in ENDS use patterns and dependence over time and to determine how these are related to biomarker status changes and how they are influenced by the person factors described above. Our primary and secondary CV measures are changes in carotid intima-media thickness and grayscale median. Our primary and secondary pulmonary measures are the changes in the quantitative CT measures of air trapping and parenchymal texture. This proposal will produce the most informative evidence to date on how long-term ENDS use affects CV and pulmonary health and disease risk.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract The project will enroll 180 persons with the autosomal dominant gene for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) to investigate retinal imaging measures as potential diagnostic, prognostic, and disease monitoring biomarkers for clinical trial readiness. CADASIL is a rare disease and the most heritable monogenic form of vascular cognitive impairment and dementia. The research design will allow the examination using the full spectrum of vascular dementia from presymptomatic gene carriers through dementia. This research is novel from any other in its efforts to study a single-gene vascular dementia group throughout the life span in an effort to reduce vascular dementia heterogeneities selecting persons enriched for certain future vascular disease secondary to NOTCH3 gene mutation. CADASIL has been considered a good single-gene model of small vessel disease and vascular dementia. By improving our understanding of CADASIL and its progression, we will be better able to understand the more common sporadic vascular dementias. Since many known neurodegenerative diseases are determined at autopsy to be mixed dementias with a vascular component, the findings from the proposed research may also impact the large cohorts of neurodegeneration in our aging population. We have established an NIH-funded U.S. multi-site longitudinal natural history study of CADASIL (www.cadasil- consortium.org). The proposed grant aims to build on this ongoing CADASIL study by adding multifaceted retinal imaging to investigate as a biomarker in CADASIL. Studying the retina – a region that shares numerous embryological and anatomical similarities with the brain – will advance our understanding of various pathologies caused by different NOTCH3 pathogenic variants (PVs). The retina's structural and vascular features can be demonstrated non-invasively with high resolution optical coherence tomography (OCT) and OCT-angiography (OCT-A). In this project, we will focus on three primary retinal assessments: 1) retinal capillary bed pathology using OCT-A with measures of vessel density (VD), foveal avascular zone (FAZ) area/effective diameter, vessel tortuosity index (VTI); 2) retinal arteriolar changes using spectral domain (SD) OCT with measures of mean wall thickness (MWT) and lumen diameter (LD) of the superior temporal retinal arteriole; and 3) inner plexiform layer (IPL) thickness as a measure of synaptic injury. At the conclusion of this research, data will be available to determine the strength of each potential measure as a biomarker for clinical trials in neurodegenerative diseases with cerebrovasculopathies. Findings will facilitate determination of the contexts of use for non-invasive, low-cost retinal imaging biomarkers.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY / ABSTRACT Macrophages play a pivotal role in maintaining homeostasis by tightly regulating the inflammatory response. In response to endotoxins like lipopolysaccharide, they undergo dynamic reprogramming, transitioning from a pro-inflammatory to suppressive to tolerant state, resulting in endotoxin tolerance. In this tolerant state, the inflammatory response to repeated endotoxin exposure is dampened. This can be protective, but insufficient or excessive tolerance can cause hyperinflammation or immunosuppression as seen in sepsis. The underlying mechanism of this process, particularly the contribution of long-term metabolic change, continues to be a key knowledge gap. We found there is a persistent and sustained long-term decrease in acetyl-CoA levels in stimulated macrophages based on preliminary data. However, the role of acetyl-CoA metabolism – a central metabolic pathway – in endotoxin tolerance remains unknown. This proposal aims to investigate the role of acetyl-CoA metabolism in mediating endotoxin tolerance induced by classical activation in macrophages. The specific aims are to (1) determine how acetyl-CoA availability affects histone acetylation in endotoxin tolerance, (2) profile the global effect of acetyl-CoA metabolic reprogramming on non-histone protein acetylation in endotoxin tolerance, and (3) characterize the role of acetyl-CoA metabolism in endotoxin tolerance in murine models. To achieve these aims, endotoxin tolerance will be recapitulated in cell lines, primary cell cultures, and murine models, while acetyl- CoA availability will be modulated using different genetic perturbation and treatment approaches. Identification of histone acetylation changes will be achieved through immunoblotting for selected acetylation sites and genome wide histone acetylation changes identified by chromatin immunoprecipitation sequencing with resulting gene expression changes determined by quantitative PCR. The global acetylated proteome will be profiled by mass spectrometry. Furthermore, the in vivo characterization of endotoxin tolerance will be accomplished by measuring serum cytokine levels and clinical phenotyping. This study focusing on the reprogramming of acetyl-CoA metabolism in macrophages aims to provide mechanistic insights into how the metabolic state of macrophages influences endotoxin tolerance. By understanding this relationship, we can gain valuable knowledge about how metabolic reprogramming impacts immune cell function and identify potential therapeutic targets within acetyl-CoA metabolism to regulate the inflammatory response. The Morgridge Institute for Research and the University of Wisconsin-Madison offer a strong foundation for conducting this project, given their extensive metabolism research. With the support and guidance from Dr. Jing Fan and collaborators, the project is expected to be completed efficiently. Through this training plan, the applicant will develop essential technical, scientific communication, and additional cli nical skills and knowledge, paving the way for a successful career as an academic physician-scientist.

NSF Awards · FY 2024 · 2024-09

Rapid population growth and rising living standards have caused the depletion of global water sources and other valuable resources. Separation technologies that can purify saline or contaminated water and recover valuable components are urgently needed. Separation using nanofiltration (NF) has been widely used for water purification and desalination, but emerging challenges such as the extraction of lithium from brines to satisfy the booming lithium-ion battery market go beyond the capabilities of current NF membrane technology. Thus, the overarching goal of this collaborative project is to explore a novel mechanism known as ion dehydration that can be applied using modified NF membranes to carry out challenging separations. This project leverages expertise in computational simulation, laboratory experimentation, and NF membrane fabrication in an international collaboration with researchers at the Technion - Israel Institute of Technology. Successful completion of this project will advance our understanding of NF separation to address pressing societal needs. Beyond the technical focus, the project will benefit society by educating the public through outreach activities to increase scientific literacy and awareness of water and resource sustainability. NF membranes have been used for water purification and desalination processes for many years. Recently, there has been increasing demand for high membrane selectivity between solutes to enable energy-efficient separation for water purification and resource recovery. However, achieving precise separation between similarly sized and charged ions using current polyamide NF membranes remains a significant challenge. Addressing this challenge requires leveraging mechanisms beyond those prevailing in current water-solute separation. Accordingly, the project will pursue three primary thrusts to regulate the transport and selectivity of monovalent ions in polyamide NF membranes: 1) investigate the role of ion dehydration on the transport and selectivity of ions in state-of-the-art NF membranes; 2) delineate the effect of membrane surface hydrophobicity and charge on ion dehydration using self-fabricated membranes with tunable surface properties; and 3) use molecular dynamics (MD) simulations to support the results of ion dehydration and membrane selectivity experiments. Thrust 1 will utilize a custom-made diffusion cell to probe the ion-ion selectivity for a series of ions with distinct hydration properties at different temperatures, pressures, and solvent types. Thrust 2 will focus on fabrication of thin-film composite polyamide (TFC-PA) NF membranes with systematically altered surface hydrophobicity and surface charge. Thrust 3 will apply MD simulations of water and solute ion transport through a TFC-PA NF membrane, which can be used to understand the relationship between the membrane structure and ion transport/rejection. Beyond the direct technical thrusts, the project will include outreach and educational activities that broaden its impacts by providing research training opportunities to graduate and undergraduate students, especially those from underrepresented groups. The team will also perform outreach activities for K-12 students from local communities of Colorado and Wisconsin to increase scientific literacy and support the Nation’s STEM workforce. 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 2024 · 2024-09

Building on prior efforts to shift organizational culture within the geosciences field and dominant approaches to postsecondary teaching and learning, this project makes a much-needed contribution to literature in education and the geosciences by addressing two urgent yet underexplored dimensions of equity-minded pedagogical change work in higher education: 1) the need to prepare instructors to historicize curriculum to more readily address and combat the racialized foundations of their field of study, and 2) the need to support academic departments’ organizational capacity to facilitate sustained change around teaching and learning. With this approach, the project will advance knowledge and practice for cultural change in a seminal portion of the learning and training ecosystem for geoscientists. The researchers plan to leverage methodological tools from the learning sciences, namely formative interventions, to facilitate tangible change in academic departments through the design and implementation of two learning environments: 1) an 8-hour short course, where participants will learn about and identify how racial exploitation and settler colonialism have shaped not only the history of the geosciences, but also its current practices and disciplinary culture, and 2) a 2-day, in-person workshop, where researchers will provide participants with tangible tools to identify and work through a problem of practice related to implementing pedagogical change in their department. This research will yield a conceptual model and establish a set of design principles for advancing equity-minded pedagogical change, contributing to improved learning experiences and outcomes for historically marginalized students in the geosciences. 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 2024 · 2024-09

Microbial communities and microbiomes occur everywhere and impact soil health, environmental processes, human health, and many other process that impact climate resilience and the bioeconomy. To date, is has been difficult to predict how the addition of new microbial species into a community impacts microbiome function, and as such, it has been difficult to design microbiomes with desired functions. The prediction of microbiome functions from the genotypes of constituent species remains a longstanding, unsolved problem in microbiome science and engineering. The long-term goal of this project is to develop and apply an integrated experimental and computational approach to uncover the design principles at the molecular and cellular level that govern microbiome function. These models would be able to then be used in a variety of applications to solve problems related to climate resilience, human health, and the bioeconomy. In addition, the investigators will increase the inclusion and public participation in STEM by partnering with a well-established informal science education program at the Morgridge Institute for Research, serving thousands of youths per year. This project will integrate advanced machine learning techniques with high-throughput microbial community construction and metabolomics in order to elucidate design principles of molecular networks involving any cellular process (e.g. metabolism, stress, signaling) that govern microbiome functions. Notably, the proposed framework will enable the prediction of new and uncharacterized species on microbiome functions, which has not been previously demonstrated using a data-driven model. The investigators will apply this multi-scale modeling framework to study the effects of diverse bacteria on community composition and anaerobic metabolic states. While this proposal focuses on the genotype-function mapping of microbial communities, the data-driven framework will provide a foundation for the prediction of microbiome functions from omics data including transcriptional profiling data, proteomics and beyond. The novel systems biology framework could be applied more broadly to any microbiome or microbiome function. Deciphering the molecular-level design principles of microbiomes would provide a deeper insight into the organizational principles of these energetically efficient and resilient systems. 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 2024 · 2024-09

Memory fabrics, an emerging and powerful cluster interconnect technology, are revolutionizing the construction of the modern data center. Albeit promising, this infrastructure shift fundamentally changes decade-long system design assumptions and challenges conventional wisdom on how to build efficient rack-scale systems. This project aims to develop a new computing paradigm that views the memory fabric as a first-class citizen on which to instantiate, orchestrate, and reclaim computations. The project’s novelties are that a memory fabric-aware intermediate system stack allows applications to effectively harness the capabilities of memory fabrics and hide their limitations. The project’s broader significance and importance are laying out the system foundation for building next-generation sustainable and cost-efficient computing infrastructures for enterprise on-premise and cloud-scale data center systems using memory fabrics. This project introduces the technology to a broader audience via the LegoCluster program and BigComputer workshop education activities. This project rethinks the rack-scale system design from memory, computing, and communication perspectives. The first thrust classifies remote memory nodes into four categories and develops a benchmarking framework to characterize their performance. It builds an active remote memory system that transparently and dynamically moves a memory object to a suitable memory node at runtime based on the object’s access profile and the underlying node’s capabilities. The second thrust applies idempotent tasks as the fault-tolerant computation abstraction and develops a language system to generate them. It designs hardware cooperative engines and an execution framework on which to schedule idempotent tasks. The third thrust introduces new communication primitives, translates them into the memory fabric’s commands, and builds a transport layer for end-to-end traffic control. Together, these efforts produce a new open-source software system over memory fabrics encompassing APIs, libraries, programming systems, and software runtimes. 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 2024 · 2024-09

The broader impact of this I-Corps project is based on the development of new diagnostic and detection technology that is a simple and easy to use point-of-care drug test to aid in overdose prevention and treatment. This innovative testing solution has the potential to provide rapid results, allow immediate clinical action, and reduce emergency department stays. Rapid and accurate drug screening is crucial for patient management and treatment decisions, especially in emergency settings, pain management centers, and maternal fetal medicine clinics. By reducing diagnostic time, this technology can improve patient outcomes and reduce costs for patients, hospitals, and insurance companies. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of the technology. The solution is based on the development of methods to design and characterize protein-based sensors for small molecules. Candidate sensors are screened in a high-throughput cell-based assay which couples the chemically sensitive binding of protein and deoxyribonucleic acid (DNA) to gene expression. Using methods in high throughput sequencing, the sensitivity of proteins to different molecules is measured using relative gene expression as a proxy. These protein-based sensors could be formatted as paper-based drug panels, yielding the benefits of reduced assay complexity and higher information density for diagnosing patient conditions, such as the presence of drugs of abuse in clinical settings. 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 · 2024-09

Project summary The primary focus of research in my laboratory centers on unraveling the causal relationship between common genetic variants in humans and susceptibility to complex diseases. We aim to understand how single nucleotide polymorphisms (SNPs), often residing in the non-coding portion of the genome, influence cellular physiology, the determination of cell fate, and the alterations in cell state. We employ a unique human-specific genetic framework, utilizing induced pluripotent stem cells (iPSCs) and genome editing techniques to investigate non-coding regions of the genome whose functions are not yet defined. SNPs frequently exhibit correlations with neighboring variants, forming clusters known as haplotypes through a phenomenon called linkage disequilibrium. Haplotypes are shared within the same ancestral group and exhibit significant variations across different genetic ancestries. This genomic diversity translates into varying degrees of correlation between genetic variants and the risk of developing complex diseases across diverse ancestries. While this genomic diversity is deeply rooted in human evolutionary history, our understanding of its functional implications at the cellular level remains incomplete. The elucidation of haplotypes function and the effect of their diversity are crucial to uncover unexplored biological processes impacted by the non-coding genome and for enhancing the accuracy of predicting complex disease risk within different populations. In this proposal, we outline a research strategy to investigate human-specific haplotype diversity and its cellular consequences across diverse cell types. Our overarching goal is to determine the physiological significance of haplotype diversity in cell fate determination and the maintenance of cell states, shedding light on haplotype functionality and its role in disease susceptibility. By examining the impact of ancestrally diverse haplotypes at the cellular level, this proposal aims to identify critical factors contributing to ethnicity-based disease risk and cell-type-specific vulnerabilities. We will employ human iPSCs obtained from diverse ancestral backgrounds, induce differentiation into various cell types, perform haplotype editing, and utilize a wide range of assays to evaluate how diversity at specific genomic loci influences cell fate determination and the maintenance of cell states in response to various stimuli. The tools we develop will serve as a versatile platform for investigating non-coding genetic risk factors in various complex diseases, expediting the translation of functional genomics findings into advancements in human health.

NIH Research Projects · FY 2025 · 2024-09

Project Summary: Alzheimer's Disease (AD) and AD Related Dementias (ADRD) continue to present serious challenges in the aging population and there is a significant need to identify and reduce risk factors. A well-recognized and promising approach to reducing AD/ADRD comprises reduction of vascular injury often found to occur concomitantly with AD pathology. Less appreciated facets of this disease include large systemic changes in physiology, including alterations in the gut microbiome that occur with age and disease. Recent studies from our group and others suggest that gut microbes play a key role in shaping vascular biology and AD pathology. Gut microbes influence the host in part through production of metabolites that act on specific receptors expressed in distant organs, impacting multiple cellular signaling cascades, including inflammation, thrombosis, and cellular senescence. Our research group has recently identified associations between plasma levels of the gut microbiome-derived metabolite imidazole propionate (ImP) and increased cerebrospinal fluid levels of neurofilament light chain (NfL), a biomarker of neurodegeneration. Increased ImP was also detected at higher levels in individuals with accelerated decline in performance on tests of executive function. Furthermore, we discovered that ImP impairs endothelial cell function and disrupts the integrity of the blood-brain barrier (BBB). Validating these associations and establishing causal and mechanistic links with AD-pathology will have significant translational impact as there is a toolkit at our disposal to change the gut microbiome, including dietary changes, fecal transplants, and small molecule inhibitors targeting the bacterial ImP production pathway, which is not present in the host. The central hypothesis of this proposal is that ImP modulates AD and ADRD progression by altering vascular endothelial function and BBB permeability. To test this hypothesis, we will characterize the relationship between ImP, BBB disruption, and AD pathology in conventional and gnotobiotic mouse models of disease. We will also leverage existing samples and data collected among participants in the Wisconsin Alzheimer’s Disease Research Center to determine the extent to which ImP is associated with fluid AD biomarkers and vascular injury as measured by MRI. The examination of the microbiome as a critical component that shapes AD/ADRD pathology through its effects on vascular function represents a novel perspective that we are uniquely positioned to examine.

NSF Awards · FY 2024 · 2024-09

Approximately half of the ice lost from the Antarctic and Greenland Ice Sheets to the ocean occurs in the form of icebergs that break off glaciers and ice shelves. Icebergs melt and release freshwater far from the coast, thereby altering the local ocean waters as well as the large-scale ocean circulation. This has impacts on the climate and ecosystems, motivating current efforts to represent icebergs in climate models. However, past efforts have been hampered by limited knowledge of the size of icebergs when they break off of ice sheets and glaciers, and how their drift, breakup, and melt controls iceberg trajectories and freshwater and nutrient release to the ocean. The project will address these shortcomings by advancing our knowledge of how icebergs are created, how they drift, and how they decay. This will be done using mathematical and computer models of ice and climate processes and comparing the results to observational measurements. The iconic image of icebergs as harbingers of climate change will be leveraged for the educational part of this project, which will explore best practices to communicate risks and uncertainties associated with climate change. This will be done by developing two new university courses: “Ice & Climate Dynamics” for physical science graduate students and “Climate Risks & Uncertainties - how to communicate successfully between scientists, journalists, and the public”. The project will further offer two summer programs bringing together students, early career researchers, and journalists. Iceberg size distributions are a key initial condition in modeling efforts, determining where icebergs will drift, their meltwater is deposited, and sediment is released. To better constrain iceberg size distributions this project will (i) use process models and observational data to quantify present-day calving characteristics of glaciers and ice shelves, both in Greenland and Antarctica; (ii) bring together climate models and state-of-the-art ice sheet model output to estimate how iceberg size distributions will evolve over the coming decades and centuries and what the resulting global and regional climate impacts will be. Current representations of iceberg sizes in models are largely based on sparse, decades-old observations and do not consider spatial and temporal variations. This project is designed to advance these models by resolving spatial and temporal variations of iceberg size distributions. This research leverages recent advances in observing glaciers and icebergs to improve constraints on iceberg simulations and ultimately reduce uncertainties in climate projections. 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 2024 · 2024-09

Researchers and engineers worldwide are racing to build quantum computers to solve computationally challenging problems, enabling new scientific discoveries and generating valuable intellectual property and data. Decades of research have shown that wherever valuable or sensitive information is on a computer system, it's at risk of being stolen or attacked. To understand and mitigate security risks, this project proactively studies system security for quantum computers. The project focuses on fundamental security vulnerabilities that can affect existing noisy intermediate-scale quantum computers and upcoming fault-tolerant quantum computers. This project also studies remediation for both hardware-specific and agnostic side-channel vulnerabilities. The project's broader significance and importance are rooted in the need to democratize access to costly and scarce quantum hardware by sharing it efficiently among multiple users while ensuring secure and confidential computations to foster innovation. The team also integrates the research into educational components by conducting tutorials and workshops and developing course materials. The project studies and develops a secure execution model for quantum computers by building prototypes of a novel quantum trusted execution environment and developing a systematic understanding and defenses for physical attacks on quantum computing systems. Given rapid advances in quantum error correction, the project targets fault-tolerant quantum computing architectures, specifically focusing on developing remediation techniques to prevent physical attacks, including timing, power-based, and other side channels arising at large scales. 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 · 2024-09

PROJECT SUMMARY/ABSTRACT Clonal hematopoiesis of indeterminate potential (CHIP) broadly describes the clonal expansion of blood cells derived from hematopoietic stem cells (HSCs) with somatic pre-leukemic mutation(s). CHIP is strongly linked to aging and confers to an increased risk for blood cancers, non-hematological diseases, and all-cause mortality. ASXL1 is one of the commonly mutated genes in CHIP. ASXL1 mutations are predominantly nonsense or frameshift mutations. In particular, the hotspot frameshift mutation at codon 646 (corresponding to codon G643 in mice-Asxl1tm) represents a pathological CHIP mutation with high risk to drive myeloid diseases. We recently discovered that Asxl1tm/+ bone marrow (BM) cells and HSCs underwent significant expansion in old/aged recipients (20-24 months) but not in young recipients (2-4 months old). This expansion was associated with alterations in epigenetic landscape. Further characterization of young vs old BM microenvironment (BMM) and serum revealed local and systemic inflammation and expansion of mesenchymal stromal cells (MSCs) and endothelial cells (ECs), two important regulatory components of BM niche. MSC expansion was likely due to enhanced MSC survival, while both accumulation of senescent cells and increased survival attributed to EC expansion. Consistent with our observation, treatment of ABT-263, a potent inhibitor of anti-apoptotic proteins Bcl-2 and Bcl-xl, reduced the senescent MSCs in vitro. Moreover, ABT-263 effectively removed accumulated MSCs, moderately reduced number of ECs, and partially mitigated the expansion of phenotypic HSCs in the old mice. CITE-Seq analysis of RNA and ~120 immune cell surface proteins at single cell level identified aging- associated cellular and molecular changes in old BM cells, including expansion of inflammatory neutrophil subsets and overexpression of IL-1β. These alterations can be mitigated by dietary supplementation of nicotinamide riboside (NR), a NAD+ precursor. In addition, human myeloid leukemia cells with ASXL1 mutations were sensitive to GSK525762 (GSK), a pan-BET inhibitor. Based on our preliminary results, we hypothesize that aged BMM promotes the expansion of Asxl1tm/+ HSCs. Targeting aged BMM and Asxl1tm/+ hematopoietic cells through NR, ABT263, and/or GSK may prevent and/or inhibit Asxl1tm/+ HSC expansion. In this grant application, we propose the following aims to test our hypothesis: 1) To investigate how aged BMM interacts with Asxl1tm/+ HSCs to promote their expansion; and 2) To determine whether targeting aged BMM and Asxl1tm/+ hematopoietic cells alter Asxl1tm/+ HSC expansion in old recipients. Our proposal is in response to the SHINE Program from NIA (PAS-22-096), aiming to provide new insights into the pathogenesis, prevention, and potential treatment of nonmalignant hematologic diseases.

NSF Awards · FY 2024 · 2024-09

Research has shown that educational games can increase student motivation, support critical thinking, problem-solving, and communication skills. This project will explore what approaches to the design of virtual labs, games and bridging curriculum can most effectively support middle-school student development of interest and learning of scientific practices and contribute to the development of a science identity. In three game-inspired, immersive Virtual Research Labs created for the project, students will take on the goals, methods, tools and practices of three different life sciences-focused research projects. A co-design process involving teachers and students will be conducted with three yearly cohorts of 10 teachers each, paired with practicing scientists and educational media designers. These labs will be developed by an award-winning team at the University of Wisconsin-Madison, Field Day Lab, whose educational games are played over 1.5 million times yearly. Based on previous experience with over a dozen digital educational media products, the Virtual Labs will be used by thousands of students and their teachers for years to come. The project will provide grants for teachers to attend and present their experience at the annual Play Make Learn conference. By adopting the instructional framework of bridging and culturally sustaining pedagogy, the project will use the virtual research laboratories to study how virtual laboratories can (1) bridge student thinking between abstract and specific science practices; (2) connect remote research to local contexts; and (3) empirically study design elements. Research will be supported by an existing infrastructure to recruit, co-design, and test the labs with teachers and students and a mature analytics infrastructure that currently captures and processes 5-10 million points of learner activity data every school day from Field Day's games. This project will use iterative data-driven design methods, utilizing analytic data from play testing with 600 students to inform development. In collaboration with performance assessment experts, the project will develop and disseminate new assessment tools to measure students' expertise in the practices of science: data collection, experimentation, and modeling. In the fourth year, a quasi-experimental study will be conducted with 360 students in 6 schools. The project will also conduct a series of randomized control experiments will be conducted online with 70,000 students nationally. The project is supported by the Discovery Research preK-12 program (DRK-12), which seeks to significantly enhance the learning and teaching of science, technology, engineering, and mathematics (STEM) by preK-12 students and teachers, through research and development of innovative resources, models, and tools. Projects in the DRK-12 program build on fundamental research in STEM education and prior research and development efforts that provide theoretical and empirical justification for proposed projects. 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 2024 · 2024-09

PROJECT SUMMARY/ABSTRACT The objective of this proposal is to purchase a state-of-the-art microPET/CT small animal imaging scanner for the University of Wisconsin Small Animal Imaging and Radiotherapy Facility (SAIRF), which will function as a long-term shared resource for NIH-funded investigators at the UW School of Medicine and Public Health (UW SMPH). Specific aims include: Aim 1: To improve the productivity of small animal imaging research at the UW SMPH by making a state-of-the-art microPET/CT scanner accessible to federally-funded investigators, Aim 2: To enhance the ability of these investigators to perform high resolution PET and CT scanning to determine cancer treatment efficacy, biological basis of disease and using-imaging based dosimetry to provide more accurate radiotherapy dosing, and Aim 3: To foster the development of new small animal imaging resources that efficiently use the personnel and shared facility resources at the UW SMPH and UWCCC. The SAIRF provides support to faculty and trainees working on small animal imaging research projects. The laboratory offers high- quality multimodality image acquisition and analyses and consultative services on a fee-for-service basis available to the campus community and beyond. Our Siemens Inveon microPET/CT is at the end of its life and will not be supported past 2024. With this S10 grant application, we seek to replace the Inveon with a high resolution, sensitivity, and uniformity system with a compact footprint that will yield accurate quantitative data and allow seamless continuation of research for our cancer center members and University researchers. An acquisition of the Molecubes β-CUBE/X-CUBE small animal scanner meets all of these needs. This will facilitate and enhance the scientific quality and productivity of numerous NIH-funded research projects. The research programs that will use the new shared instrument seek to better understand cancer biology, the effects of external beam radiation and targeted radionuclide therapy (TRT) on tumor microenvironment, to combine radiation, including TRT, with immunotherapies with the intent of affording durable curative cancer responses accompanied with immune memory induction. The Major Users group consists of RO1, PO1, UO1, and DOD-funded investigators, while the Minor Users group also includes U54, P01, RO1 and DOD-funded investigators who request this instrument to achieve their specific aims. Exceptional departmental and institutional support (providing 41% of the purchase price) and outstanding technical expertise assure that the requested equipment will be operable immediately and highly productive at UW for many years to come.

NIH Research Projects · FY 2025 · 2024-09

Minimally invasive liquid biopsies have revolutionized our understanding of cancer biology and emerged as biomarkers for disease monitoring and drug development, but have been limited to a few commercial entities or academic laboratories with the requisite technological capacity. The Circulating Biomarker Core (CBC) at the University of Wisconsin Carbone Cancer Center (UWCCC) was established in 2017 to leverage innovative technologies and clinical research infrastructure, to expand access to these biospecimens and assays for UW faculty and NCI Cancer Centers across the country. Custom UW-developed liquid biopsy technology arises from a decade-long collaboration between bioengineering and biomarker researchers at UW and offers unparalleled sensitivity for rare target analytes. Dr. Jennifer Schehr, who played an integral role in developing and refining custom liquid biopsy technologies since joining the lab of the founding director, Dr. Joshua Lang, in 2015, was successfully recruited as facility manager for the CBC during its inception and continues to spearhead its trajectory. The CBC supports NCI-funded research programs both directly through services provided to specific NCI grants or trials, as well as indirectly as a shared resource facility pursuing the aims of the NCI cancer center support grant (CCSG) to advance scientific partnerships, precision medicine research and education. Dr. Schehr delivers high levels of scientific innovation and achievement in biology and biomarker discovery by providing expert scientific oversight, investment in developing increasingly more powerful computational tools for rapid data handling, and particular attention to thorough and continuous education and engagement of undergraduate and entry-level staff. The CBC has now supported 64 different projects involving 34 different protein and nucleic acid biomarkers, 9 NCI grants and 29 clinical trials from NCI cooperative groups, pharmaceutical companies and Universities. Dr. Schehr leads the development of new methods for new cancer types, new liquid biopsy biomarkers, and new clinical applications, as well as the setup, data management and biomarker utility evaluation for ongoing clinical trials. Dr. Schehr is also actively engaged in developing process controls and demonstrating analytical validity of custom technologies in pursuit of obtaining regulatory approval for implementation into routine clinical use. With the recent successful execution of a UH2 analytical validation for an mRNA panel in prostate cancer circulating tumor cells, the CBC has now gained approval for a UH3 regulatory-approved clinical trial, which will result in the first clinically actionable liquid biopsy developed by the CBC under Dr. Schehr. Future directions include the development of automated workflows for circulating tumor DNA (ctDNA) extraction and library preparation from >5,000 plasma samples over the next 5 years for a custom ctDNA assay that evaluates 821 targeted mutations and high-sensitivity fragmentomic patterning to differentiate tumor origin. Leveraging innovative problem-solving, computational tools for high efficiency, and an extensive collaborative network, Dr. Schehr will develop and implement novel liquid biopsy biomarkers into clinical use.

NIH Research Projects · FY 2025 · 2024-09

Pneumonia results from uncontrolled lung inflammation and injury often triggered by viral/bacterial pathogen insults. Pneumococci, instigating agents of bacterial pneumonia, are independently pathogenic causing lower respiratory tract infections and hospitalizations in adults, including those with chronic pulmonary conditions like asthma. Pneumococci are also opportunistic pathogens particularly synergizing with respiratory viruses, like influenza A virus (IAV), to cause severe morbidity and excess mortality. Our prior work established that IAV infection during heightened eosinophilic allergic inflammation was host protective, recapitulating clinical data from the 2009 Swine Flu pandemic. Using a laboratory model we developed to investigate mechanisms by which this protection occurred, we identified novel functions for eosinophils as direct mediators of antiviral immunity during early and late phases of IAV infection. Importantly, eosinophilic asthma was also host protective during co-infection with IAV and Streptococcus pneumoniae (Spn), an outcome that was lost in eosinophil deficient mice. Further preliminary data show that eosinophils, a) internalize Spn in large numbers, b) kill intracellular and extracellular Spn, c) undergo physiologic and phenotypic alterations in response to Spn uptake. These data led to our central hypothesis that eosinophils in allergic airways promote anti-bacterial immunity against Spn through direct and indirect mechanisms to reduce the bacterial load and safeguard the host. The two overlapping aims to be investigated in this project are: (1) To determine mechanisms and outcomes of interactions between eosinophils and Spn, and (2) To elucidate pathways by which eosinophil-Spn interactions impact surrounding leukocytes important in mucosal host defense during co-infection. This project is significant because we propose to identify basic immune mechanisms in pulmonary host defense against a prominent human pathogen with an innovative approach of investigating eosinophils as a regulator of local innate immunity and mediator of host protection rather than as an end-stage effector cell. These studies will have a broad impact on eosinophil biology, on our appreciation of host-pathogen interactions in allergic asthma and may offer novel therapeutic targets to treat bacterial co-infections during influenza in allergic hosts.

NSF Awards · FY 2024 · 2024-09

Extreme phenomena throughout the Universe can produce photons trillions of times more energetic than the human eye can detect. Gamma-ray astrophysics is an essential component of time domain and multi-messenger astrophysics, providing the most important link from neutrinos and gravitational waves to the electromagnetic spectrum and thereby unlocking the scientific potential of the new messengers. Gamma rays enable robust identification of the sources of these multi-messenger signals. The Cherenkov Telescope Array Observatory (CTAO) is an international project in development to detect very-high-energy gamma rays with excellent sensitivity. An innovative telescope and camera design led by United States CTAO groups, the Schwarzschild-Couder Telescope (SCT), promises excellent performance in measuring these very-high-energy gamma rays. The prototype SCT located at the Fred Lawrence Whipple Observatory in Arizona is currently being upgraded. The present project will develop data acquisition and analysis procedures to exploit the full scientific capabilities of the SCT to measure astrophysical particle accelerators that are likely sources of neutrinos and gravitational waves. The team leads the Distributed Electronic Cosmic-ray Observatory (DECO), a project that enables citizen scientists around the world to use their cell phones to detect cosmic rays and other energetic particles. DECO users span 46 states, 80 countries, and seven continents. This research takes full advantage of the newly upgraded prototype SCT, a dual-mirror imaging atmospheric Cherenkov Telescope located next to the VERITAS array of four traditional single-mirror very-high-energy gamma-ray telescopes. The PI’s team and their collaborators will realize the full potential of the Schwarzschild-Couder concept, developing a path for US contributions to the CTAO. Work to be accomplished includes (1) developing optimized waveform analysis algorithms, (2) developing optimized camera image and video analysis algorithms, (3) applying these algorithms in concert with VERITAS data analysis to understand the newly discovered ultra-high-energy Galactic particle, (4) observing and analyzing the upcoming outburst by nova T Coronae Borealis and (5) leading DECO (described above). 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 2024 · 2024-09

Despite the importance of addressing climate change, existing K-12 curricula struggle to make the urgency of the situation personally relevant to students. To help students learn about climate change and empower them to take action in their own communities, educational interventions need to help them understand the scientific process of climate change and strategies for mitigation and adaptation, the social and economic impacts of those strategies on people and communities, and the fact that young people have agency to effect meaningful change. This project will thus address the most significant challenge in climate change education: making the abstract, global, and seemingly intractable problem of climate change concrete, local, and actionable for young people. The goal of this project is to develop and test actLocal, an online platform for K–12 teachers, students, and the public to easily create localized climate change adaptation simulations for any location in the contiguous United States. These simulations will enable high school students and others to implement and evaluate strategies to address the impacts of climate change in their own communities. This project will build a new educational technology that simulates the future impacts of climate change adaptations made now across a range of ecological and socioeconomic issues and related civic processes in a specific local context. actLocal is unique because students will be able to simulate the scientific and civic processes of land-use planning in their own communities and see the future impact on climate resilience. The project team hypothesizes that this localized, community-based focus will improve student learning about climate change and motivate students to take action in their own communities. Researchers will test the extent to which this occurs using a convergent mixed-methods design. The simulation itself, as well as curricular supports and other pedagogical materials, will be co-designed with both teachers and students as active participants in the design process. Researchers will conduct both efficacy and effectiveness testing in a variety of educational contexts nationwide. By providing teachers with the ability to construct localized climate change adaptation simulations, researchers will be able to study whether, how, and to what extent making climate change more personally relevant to students improves STEM and civic learning, including knowledge of and disposition toward climate change adaptation/ mitigation, self-efficacy, and civic engagement. This research will inform climate change education and improve understanding of how place-based simulations can best be used to make complex or abstract problems more concrete to students. Thus, this project will identify best practices for designing and implementing STEM learning technologies that localize complex global problems, including pressing challenges in agriculture, energy, transportation, and public health. The Discovery Research preK-12 program (DRK-12) seeks to significantly enhance the learning and teaching of science, technology, engineering and mathematics (STEM) by preK-12 students and teachers, through research and development of innovative resources, models and tools. Projects in the DRK-12 program build on fundamental research in STEM education and prior research and development efforts that provide theoretical and empirical justification for proposed projects. 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 · 2024-09

Project Summary/Abstract To meet national needs of the future, the United States must increase the production of biomedical college graduates and draw on a broader range of talent, particularly among historically excluded communities (HECs). Yet an alarming proportion of college students who declare STEM majors switch to other majors before graduating. Moreover, students who belong to certain HECs enter STEM at the same rates as their white peers but leave far more frequently: 44% of white students leave STEM before graduation, whereas 58% of Latine and 66% of Black students leave. A seminal study of the reasons students leave STEM found that students frequently cite a fear of failure as important, but failure is rarely included as a topic in STEM coursework or as a focus for interventions. Therefore, a better understanding of the impact of failure and approaches that de-stigmatize and normalize failure is needed to assure greater success and retention of diverse students in the biomedical sciences. Scientists are affected by two types of failure that are natural parts of a career in science—personal setbacks and scientific failures—which influence advancement in academic and professional paths. But many students interpret a failure in college due to academic or personal struggles or due to failed experiments as an indication that they lack the ability to succeed in the biomedical sciences. In reality, when students encounter learning challenges, personal roadblocks, or wrong hypotheses and failed experiments, they must tap into productive failure responses to identify support structures, figure out what went wrong, adjust their approach, and try again. Productive responses to failures can be personal (e.g., a growth mindset; scientific self-efficacy, fear mitigation tools) or actionable, scientific approaches such as troubleshooting an experiment. By learning productive failure responses, students develop problem-solving skills, reasoning, and resilience, which strengthen a sense of belonging and lead to persistence in science. This study hypothesizes that if students are taught about failures experienced by successful scientists or engage in a structured research experience, they will be less discouraged when they experience difficulties or failures. This research will study the effects of an intervention on student failure responses and STEM persistence. The first experiment will test the effect of videos about personal and scientific failures on students’ behaviors and attitudes about failure and STEM persistence. The second will test these videos in two educational contexts, one containing a course-based undergraduate research experience (CURE), which may have synergistic effects with the intervention. To assess their failure responses, students will complete a survey and attempt an impossible scientific task—a biology video game. The analysis will seek to understand the interactions between the video intervention and participation in a CURE, student demographics, and course characteristics such as class size and placement in the curriculum.

NSF Awards · FY 2024 · 2024-09

Compared to traditional manufacturing processes such as machining, laser powder bed fusion (LPBF)-based metal additive manufacturing (AM) offers an opportunity for making complex metal components with design freedom, short development time, and environmental sustainability. However, the LPBF fabricated components often suffer from severe fatigue scattering problems, that is, the fatigue life of a component produced by LPBF under similar process conditions exhibits a very large variation. Fatigue scattering imposes a significant challenge to using an LPBF process for fabricating load-bearing and highly reliable components. This significantly limits the applicability of metal AM processes. To address this limitation, the objective of this project is to establish a physics-informed machine learning (PIML) framework, which integrates the physical knowledge of fatigue and the measured data to enable accurate and transparent predictions of fatigue life and its variation. Based on the PIML framework, process design optimization can be achieved to mitigate the fatigue scattering. The new knowledge and modeling methods obtained from this project will bring disruptive impacts on the AM industry by providing an enabling predictive tool for the fatigue life and scattering of printed materials. The scattering mitigation strategy facilitates printing consistent high-quality components in batch or mass production. This project will also contribute to workforce training by promoting interdisciplinary research at the intersection of AM, fatigue mechanics, and machine learning and provide unique training opportunities and learning testbeds for students. To achieve the project objective, baseline fatigue samples as-printed via LPBF, and the post-processed (i.e., hot isotropic pressing) alloys, including SS316L and Ti-6Al-4V alloys will be fabricated. The sample quality including surface finish, geometrical defects, residual stress, and microstructure will be characterized. Then high-frequency and load-varying resonance-based fatigue testing (up to 20 million cycles/day) will be conducted to obtain the data of fatigue initiation, development, and fracture behaviors. With the experimentally obtained fatigue data, the PIML framework is established to integrate the governing phenomenological laws or physics-driven fatigue laws and uncertainty quantification with data-driven deep neural networks to enable the accurate, data-efficient, and interpretable prediction of fatigue life, scattering band, and dynamic fatigue behavior. A scattering mitigation strategy will be established as well using Bayesian optimization based on the established process-quality-fatigue (P-Q-F) model. If successful, this project can generate new understanding in the P-Q-F relationship of LPBF, which will advance the metal AM industry. 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 · 2024-09

PROJECT SUMMARY/ABSTRACT The goal of this research project is to develop optical redox imaging (ORI)-based medical instruments to guide surgical and therapeutic approaches in early cartilage damage. Osteoarthritis (OA), for which cartilage pathology is a central aspect, remains a challenging clinical problem without disease-modifying therapeutic strategies. This challenge is exacerbated by the inability of current diagnostic methods to accurately classify cartilage damage early in the OA disease process. Redox imbalance occurs in the OA disease process. Mitochondrial dysfunction is of particular importance, occurring in OA and after traumatic injury. Therapeutic strategies that target mitochondrial dysfunction and metabolic imbalance to treat OA show potential for modifying the disease trajectory. Therefore, measuring cartilage metabolic imbalance has strong potential for early OA diagnosis and for evaluating therapeutic strategies. This research program will use ORI as a diagnostic and evaluative tool for OA. ORI is a label-free, real-time method that captures the autofluorescence of electron donors and an electron acceptor, thereby providing insight into the metabolic balance of a tissue. ORI has been used in the cancer field to identify organoid responses to treatments and distinguish cell subgroups, thus suggesting its utility as a diagnostic and screening tool. Our preliminary data demonstrate that ORI metrics in cartilage are mechanoresponsive, oxygen sensitive, and are correlated with pathology. We will extend our preliminary data to further develop ORI as a tool to diagnose metabolic imbalances associated with pathology and evaluate emerging therapeutic strategies in cartilage. This proposal includes three aims. In Aim 1, we will develop a stress test that can be used to diagnose cartilage disease based on changes in ORI metrics following a mechanical stimulus. In Aim 2, we will develop an ex vivo test platform to rapidly evaluation emergent therapeutic strategies. In Aim 3, we will develop a medical instrument that captures ORI for staging cartilage disease. At the conclusion of this research, we will have developed ORI as an instrument to diagnose cartilage pathology, investigated ORI as a platform to test interventions, and generated a preliminary arthroscopy medical instrument ready for clinical translation.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Frontotemporal dementia (FTD) is an Alzheimer’s disease-related dementia and is the most frequent form of dementia in patients under 60 years old. Mutations in the MAPT gene encoding the neuronal protein tau, including the autosomal dominant MAPT R406W missense mutation, have been linked to FTD. Induced pluripotent stem cell (iPSC)-derived forebrain neuronal progenitor cells (NPCs) from MAPT R406W carriers have provided insight on FTD pathology in vitro. These cells display p-tau aggregation, fragmentation, impaired microtubule binding, and mitochondrial deficits. RNA sequencing of patient cells also revealed differentially expressed genes involved in calcium and synaptic signaling, lysosomal function, and neuronal development. Animal models that faithfully replicate FTD are needed to understand how neuronal cell tauopathy affects the organism, identify biomarkers, and test candidate new therapies. At the Wisconsin National Primate Research Center, 6 members of a family of rhesus macaques (aged 0.6 to 19 years) were identified as carriers of MAPT R406W. Preliminary evaluation of these animals identified behavioral and imaging features that resemble the human FTD phenotype. To take advantage of this resource, we generated iPSC lines from one male and one female mutation carrier. Based on the phenotype of the rhesus carriers and the 99% MAPT sequence homology between humans and rhesus, our overarching hypothesis is that rhesus iPSC-derived forebrain cortical NPCs will mirror the tau-related phenotype and transcriptomic signatures observed in cells from human MAPT R406W carriers. To test our hypothesis, we propose: Aim 1: To phenotypically characterize iPSC-derived forebrain cortical NPCs from MAPT R406W+/- rhesus macaques with direct comparison to human patient cells. Rhesus iPSCs will be CRISPR/Cas9-edited to correct the point mutation to serve as isogenic controls. Human MAPT R406W iPSCs and their isogenic controls will be obtained from collaborators at the Tau Consortium. Mutant and isogenic human and rhesus iPSCs will be patterned to forebrain cortical NPCs to study MAPT R406W-related pathology in vitro. Aim 2: To compare the gene expression profiles of iPSC-derived forebrain cortical NPCs from MAPT R406W+/- rhesus macaques and humans. Bulk cell RNA sequencing will be performed on mutant and isogenic forebrain cortical NPCs from both species to determine if there is a shared or divergent transcriptomic signature associated to MAPT R406W. Overall, these aims will establish the validity of the rhesus NPCs as an in vitro model of FTD. This study is highly translational as these cells could serve as an in vitro platform for screening novel therapies which will help reduce the number of monkeys used for in vivo preclinical testing before human clinical trials.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Commercial cigarette smoking is a modifiable risk factor implicated in one-third of all cancer deaths. Nicotine is the chief addictive agent causing sustained smoking, but diverse tobacco products (e.g., e-cigarettes, FDA- approved nicotine replacement) allow nicotine self-administration on a continuum of harm. Public health gains could be substantial if people who use the most harmful products (i.e., combusted cigarettes) switch to a less harmful nicotine product. Nicotine pouches – microfiber sachets containing powered nicotine but no tobacco leaf – are a new class of oral tobacco products rapidly growing in popularity. Switching from cigarettes to nicotine pouches is likely to be health-promoting because pouches are not combusted and contain fewer harmful and potentially harmful chemicals than other tobacco products. However, we currently know very little about how readily people who smoke will adopt nicotine pouches, how effectively pouches can substitute for cigarettes when smokers are trying to avoid smoking, the importance of nicotine dose in effective cigarette substitution, and the mechanisms that may promote or hinder product transition. To address these key gaps, we will enroll 284 adults who smoke daily and are not planning to quit in the next 30 days in a randomized controlled trial (RCT). Participants will be randomly assigned to receive: 1) 3-mg nicotine pouches; 2) 6-mg nicotine pouches; 3) nicotine mini-lozenges (2- or 4-mg); or 4) no study product. Participants receiving a study product (nicotine pouches or nicotine mini lozenges) will be asked to use them for 4 weeks, an initial experimentation week, and then for a 3-week switching trial where they will be asked not to smoke their usual cigarettes and instructed instead to use their study product (if assigned one). Before and after the switching trial, participants will come to the clinic following overnight abstinence and will use their assigned product (if any) during a 30-minute sampling test to assess the duration of product use, subjective evaluations of study products, and suppression of craving and withdrawal symptoms under controlled conditions. During the 4 weeks of the study, participants will use a smartphone app to record, in real-time, each time they use cigarettes (primary outcome) or a study product. For a random daily subset of use events, participants will answer additional questions about the context of their use (e.g., affect, any restrictions on smoking) and potential mechanisms driving use (e.g., withdrawal alleviation, satisfaction). Participants will also complete 3 daily prompted random assessments to characterize non-use contexts. This innovative, rigorous, and timely research will provide critical information regarding: (a) the potential impact of providing nicotine pouches on smokers’ use of combusted cigarettes, (b) whether nicotine dose influences the ability of pouches to replace cigarette use, (c) whether pouches substitute for cigarettes more effectively than FDA-approved nicotine mini lozenges, and (d) product usage patterns and effects that may promote or hinder cigarette substitution These data could inform regulatory policy decisions regarding the potential public health impact of nicotine pouches.