Utah State Higher Education System--University Of Utah

NIH Research Projects · FY 2026 · 2024-09

PROJECT SUMMARY/ABSTRACT Although venous thromboembolism (VTE) is a disease of aging, the current evidence base neglects older adults’ priorities, which prevents patients and clinicians from making individualized VTE treatment decisions. VTE and its treatment are associated with substantial morbidity and mortality for older adults, yet existing data offer few insights into real-world VTE outcomes in older adults, and the current age-agnostic decision framework does not incorporate their unique experiences or values. Aging-focused evidence on VTE that expands beyond disease-focused predictors and outcomes would guide a new paradigm for treatment and improved quality of care. My overarching goal is to build a backbone of data to support individualized treatment decisions among older adults with VTE using qualitative methods to elucidate core decision-making priorities, high-quality existing data to detail how VTE is associated with aging-related characteristics and outcomes, and risk prediction modeling to estimate bleeding risk specific to older adults on long-term anticoagulants to prevent recurrent VTE. These insights will inform subsequent interventions to align VTE treatment with current best practices from geriatrics and older adults’ values. We propose the following Aims: Aim 1) Engage stakeholders to identify core components of individualized VTE treatment decision-making for older adults, Aim 2) Use two powerful and complementary existing data sources to describe the presentation, treatment, and outcomes of VTE in two large cohorts of older adults with VTE, and Aim 3) Develop and externally validate a clinical risk model incorporating geriatric syndromes to predict anticoagulation-related bleeding in older adults after VTE. This proposal will have a significant impact because it will produce evidence to guide a paradigm for VTE treatment that is founded on older adults’ experiences and priorities and will result in improved care. Through this award, I will obtain advanced training in stakeholder engagement, user-centered design and clinical trials of design aids, experience building a real-world cohort and advanced causal inference methods, and risk prediction modeling, along with mentorship from national leaders in the field. This research and training will provide a foundation for my long-term goal of transitioning to an independent researcher to develop interventions to improve the health and well-being of older adults with non-malignant hematologic diseases.

NIH Research Projects · FY 2025 · 2024-09

Summary Diet-induced obesity affects about 40 percent of US women and increases the incidence, morbidity, and mortality of postmenopausal breast cancer (BC). Obesity also increases the risk of large, high-grade tumors, metastasis, and recurrence regardless of menopausal status. Our long-term goal is to contribute to the development of new therapeutic approaches for the treatment of obesity-associated human BC. Our research proposal addresses this by interrogating the mechanisms by which dietary lipids accelerate BC tumor growth, and whether BC in patients with obesity have unique metabolic vulnerabilities that can be leveraged therapeutically. Supported by published evidence and our own preliminary data, our central hypothesis is that, in settings of chronic dietary lipid overabundance such as obesity, BC cells are wired to utilize free fatty acids (FFA) over glucose to support cancer lipid anabolism, resulting in accelerated tumor growth. The insulin sensitivity and health of the adipose microenvironment dictate whether tumors source these lipids locally or from systemic metabolism. We will test our central hypothesis by pursuing three specific aims: 1) Test if dietary lipids, rather than glucose, are preferentially utilized by BC cells in lipid-rich environments, 2) Determine the metabolic fate of absorbed fatty acids in breast tumors and 3) Assess the translational implications of an altered metabolic program to the treatment of BC in patients with obesity. In aim 1, we will use different dietary and genetic mouse models that can accelerate BC growth to quantify the relative uptake of dietary fuels and their source in lean versus obese BC. In aim 2, we will use stable isotope infusions to trace the fates of dietary- derived FFAs and establish their biochemical contributions to tumor growth. In aim 3, we will use pharmacological inhibitors of lipolysis and circulating FFA-lowering agents to test the therapeutic potential of restricting FFA supply for inhibiting tumor growth. We will also analyze the expression of lipid metabolism genes in human BC stratified by body mass index as a measure of obesity status. Our approach, which collectively addresses physiology, adipose biology, and tumor metabolism, is enabled by our combined expertise in nutrition and metabolic status (Dr. Chaix), adipose tissue biology (Dr. Hilgendorf), and in vivo stable isotope tracing to study tumor metabolism (Dr. Ducker). Together, we have established a system in which BC tumor growth can be accelerated solely by the manipulation of circulating levels of lipids, independent of adiposity and associated metabolic syndrome. This lipid-centric view of tumor metabolism generates strong testable hypotheses for future therapeutic interventions. Specifically, we propose that pharmacological and dietary interventions targeting cancer metabolism need to be optimized for the lipid metabolic program of the tumors which is determined by the metabolic health of the patient.

NIH Research Projects · FY 2025 · 2024-09

Project summary Viruses and the organisms they infect impose strong reciprocal selective pressure on each other. This is particularly pronounced at protein-protein interfaces between viruses and their hosts, such as in the case of antiviral proteins and the virus-encoded proteins that they target. Studying the biology of infection therefore provides insight into infectious disease as well as into the underlying mechanisms of protein evolution. Host- virus interactions have been extensively studied in mammals and to a lesser extent other vertebrates, yet protein-based immunity has been studied less in other metazoans. Studying protein-based immunity in divergent species will provide an important comparative point to better understand how antiviral proteins evolve. It additionally presents an opportunity to characterize unique ways by which other species combat viral infection, with potential implications for our own struggles with viral diseases. This Pathway to Independence proposal will support the development of a research program focused on the use of structural homology as a means of uncovering and studying independently evolved effector proteins, both in understudied, biodiverse species and in the viruses that infect them. Throughout the proposal, structural modeling is used to close the gap in our understanding of the structural and functional diversity present in the proteomes of model organisms and viruses and those that have been less studied. In Aim 1, I will perform extensive structural homology searches for viruses and diverse animals. The goals of these searches will be to 1) define patterns of gene capture in diverse viruses, with focus on unique domain organizations, and 2) define structural homologs of antiviral proteins in diverse metazoans. Aim 2 investigates the apparent independent evolution of an antiviral zinc finger-containing protein in mollusks and vertebrates. This aim will provide insight into how domains adapt to serve unique functions. It integrates virological and biochemical approaches to understand the relationship between RNA binding properties and antiviral potential of proteins that include this domain. Aim 3 involves the use of yeast as a heterologous system to study the functional plasticity of antiviral EIF2a kinases and virus-encoded proteins that inhibit them. This aim will provide insight into the rules of pathogen sensing by kinases and expand the study of translational shutoff during viral infection beyond vertebrates and model organisms. Aims 2 and 3 of this proposal will establish a foundation for the future study of other independently evolved effector proteins, such as those found in the searches proposed in Aim 1. This proposal will provide me with extensive training to attain my career goals. I already have robust experience in molecular biology and virology techniques, as well as a developing skillset in computational biology. By completing the Aims of this proposal, I will learn new techniques in computational biology, biochemistry, and yeast genetics from my outstanding mentor and advisory committee that will supplement my skillset and diversify the research paradigms in my future independent career.

NIH Research Projects · FY 2024 · 2024-09

Project Summary Abstract Older patients with carotid artery atherosclerotic disease are at risk of stroke, and some evidence suggests that people are affected by their carotid artery stenosis even in the absence of a stroke. These non-stroke outcomes are poorly studied, but may include cognitive decline, sleep disturbances, and mood abnormalities. Whether medication or surgery for carotid artery stenosis improves these non-stroke symptoms is unclear. Therefore, it is necessary to identify the best way to measure these non-stroke patient-reported outcomes to be able to study how carotid artery stenosis treatment affects these symptoms. A reliable and accurate measurement of patient-reported outcomes in carotid artery stenosis will enable identification and tracking of these symptoms throughout the treatment continuum. Research Aim 1 of this project will use instruments developed by the National Institutes of Health to measure quality-of-life and function across diseases, as well as a robust, multidimensional assessment of cognition (NIH Patient-Reported Outcomes Measurement Information System; NIH Toolbox-Cognitive Battery). These will be collected on people with a diagnosis of carotid artery stenosis, including those with prior medical or surgical treatment, and newly diagnosed carotid artery disease requiring surgery. Patients will have at least two timepoints 6 months apart, with more frequent assessments directly after surgery in patients undergoing surgery during this study period. Research Aim 2 of this project will use interviews and focus groups to gain patient and caregiver perspectives about non-stroke changes that may have occurred after revascularization for carotid artery stenosis. This data will help select the best measures of non-stroke outcomes for carotid artery stenosis to be used in large scale trials evaluating which treatment is best for which patients. For older patients with carotid artery disease, this research will ensure better alignment of treatment with the 4M Geriatric Framework of Age-Friendly Health Systems. With this lens, we will better understand how to align treatment of carotid artery stenosis with 1) what matters most to patients, 2) how medication treatment effects older patients, 3) how treatment can improve mentation, and 4) how to promote mobility and independence in this complex patient population.

NIH Research Projects · FY 2025 · 2024-09

PROJECT ABSTRACT Cell identity, crucially controlled by transcription factors (TFs), is perturbed in cancer, contributing to highly aggressive and metastatic tumors, such as pancreatic ductal adenocarcinoma (PDAC). PDAC represents a formidable challenge with an alarmingly low 5-year survival rate of less than 10%. Predominantly driven by mutations in KRAS and subsequent loss of tumor suppressor genes, PDAC is poised to become the second leading cause of cancer-related deaths by 2030. Integrated genomic, transcriptomic, and proteomic analyses have identified two distinct PDAC subtypes: classical and basal. The critical difference between these subtypes lies in the expression of endodermal lineage specifiers, with the classical subtype expressing FOXA1, FOXA2 (FOXA1/2), and HNF4⍺, critical for pancreatic cell-fate determination, while the basal subtype downregulates these genes, leading to the loss of endodermal identity. The clinical significance of these subtypes is evident as the basal subtype confers shorter median survival and exhibits differential responses to first-line chemotherapies. We reason that endodermal lineage-specific TFs not only serve as a biomarker for the classical subtype but are essential regulators of PDAC subtype differentiation. Understanding the molecular regulators of the classical subtype is crucial as they may hold the key to developing effective targeted therapies and improving patient outcomes. Furthermore, the emergence of targeted therapies has highlighted the role of changes in cancer cell identity as a resistance mechanism. Here we focus on the pivotal transcription factors, FOXA1/2 and HNF4α, that play critical roles in pancreatic development. Despite their relevance in other cancers, their specific functions in PDAC remain largely unexplored. In this study, we aim to define the functional roles of FOXA1/2 and HNF4⍺ in the classical PDAC subtype, exploring their regulation of growth and cellular identity. Additionally, we will investigate how MEK/ERK signaling influences FOXA1/2 and HNF4⍺'s transcriptional activity in PDAC, shedding light on the mechanisms underlying lineage switching upon MEK/ERK inhibition. Overall, we will test the central hypothesis that FOXA1/2 and HNF4⍺ are critical regulators of the transcriptional network governing the cellular identity of classical PDAC and that MEK/ERK signaling modulates the activity of these TFs. To test this hypothesis, we will be reconstituting and modulating the expression of these factors in human and murine PDAC cell and organoid lines and assessing gene expression changes and genomic localization of these TFs through ChIP-seq. This proposal will show how oncogenic signaling and lineage- defining TFs regulate cancer cell identity.

NIH Research Projects · FY 2025 · 2024-09

Ultrasound neuromodulation promises to revolutionize treatment for neurological and mental disorders by providing pre- cise, non-invasive treatment of the neural circuits involved in disease. Ultrasound’s strength lies in its capacity to focus energy through the intact skull to grain of rice size regions deep in the brain. At these target regions, the ultrasound interacts with the neural tissue resulting in modulation of the neural activity. Transcranial ultrasound neuromodula- tion treatments are emerging in both pre-clinical and clinical studies as a promising approach to treat diseases from depression to Alzheimer’s and epilepsy. The effect of ultrasound on the target tissue depends on the sonication parameters—the amplitude, duration, duty cy- cle, and pulse repetition frequency of the ultrasound pulse. Studies show that, depending on the selected parameters, ultrasound can both excite and inhibit the target tissue. However, this flexibility is not yet utilized clinically because the relationship between the acoustic parameters and the neural response remains elusive. This study will develop a nonhuman primate (NHP) model capable of measuring real-time changes in neural activity after ultrasound neuro- modulation. Thus, the study aims to deliver clinic-ready protocols capable of optimally exciting or inhibiting the target region. To achieve this goal we will combine two existing technologies. Remus is a remote ultrasound system capable of flexibly delivering arbitrary ultrasound pulses to deep brain regions in an awake, behaving NHP. In.Tra is a cranial implant that is transparent to ultrasound and thus enables functional ultrasound imaging. Combined, the two technologies enable real-time monitoring of the awake brain’s response to ultrasound neuromodulation. Our two aims will validate this approach by measuring the response of the awake visual system to ultrasound neuro- modulation of the lateral geniculate nucleus (LGN). In Aim 1 we will measure the neural response of the targeted LGN and the ipsilateral primary visual cortex. In Aim 2 we will measure changes in the correlation coefficient (a marker of functional connectivity) between the same two regions. Both experiments will include systematic variation of the am- plitude, duration, duty cycle, and pulse repetition frequency of the neuromodulatory sonication, including parameters expected to excite and inhibit the targeted anatomy. Thus, validation of our platform will produce clinic-ready protocols to suppress or excite neural activity in the targeted circuit.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY / ABSTRACT Hereditary deficiency of galactose-1-phosphate uridylyltransferase (GALT, E.C. 2.7.7.12) activity in humans can lead to a potentially lethal disease called Classic Galactosemia (OMIM 230400). Despite the life-saving consequences of newborn screening, early diagnosis, and a galactose-restricted diet, affected women invariably show ovarian damage and fertility impairment representing the greatest burden of their disease. There are currently no satisfactory treatments available to prevent this complication. Recently, insights into the underlying pathophysiology and innovative technological advancements have become available, and options for curative treatment have emerged. Using this momentum, we aim to develop a treatment to prevent fertility impairments. We aim to 1) develop a non-viral nucleic acid therapy approach that targets the ovary and 2) determine the optimal timing to rescue the ovarian function. Folliculogenesis is driven by the cross-talk between oocytes and granulosa cells. Restoration of GALT activity in these cells could possibly rescue the ovarian damage. In this pilot grant application, we will explore a new modality of gene therapy using nanoparticles encapsulating episomal GALT cDNA within a non-viral expression vector. This will include determination of the optimal cationic polymer layer for delivery of episomal DNA plasmids expressing GFP or GALT to granulosa cell lines and the addition of ligands to encourage uptake and promote specificity. In addition, we will determine the optimal window of opportunity for this treatment. A prenatal origin has been considered for decades whereas the data currently available, albeit scarce, favor a postnatal origin. There is undoubtedly early damage, but whether treatments aimed to prevent ovarian damage needs to be started in the neonatal period, or treating in infancy or adolescence would suffice, is not clear. This will be studied using the zebrafish model for classic galactosemia that mimics the fertility impairments and is suitable for studies through development. Zebrafish reproduction is regulated by the brain-pituitary-gonadal axis, comparable to the human situation. For this purpose, RNA-seq, histology/immunohistochemistry of follicole development and single cell RNA-seq of oocytes and granulosa cells at 4 developmental stages will be studied. These studies will uncover developmental stage and cell-specific alterations in the affected ovaries. Distinctive patterns at the different stages are expected to reveal at which stage(s) damage can be prevented/halted using ovary targeted gene therapy.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY (PI: YU) Since bones and cartilage (B&C) are common sites of serious degenerative diseases (e.g. cancer, arthritis, osteoporosis), a strategy to localize therapeutic agents to skeletal tissue (for high efficacy) with minimal distribution to other sites (for low side effects) could lead to significant improvement in treating a wide range of debilitating conditions. Recent advances in antibody therapy have produced promising drugs for rheumatoid arthritis (e.g. infliximab, abatacept); however they have off-site, target related side effects due to systemic immune suppression. Due to these side effects, mainly serious infection, patients need to be screened for therapy, and co- or concurrent administration of two types of immune modulatory drugs is not practiced although such approach may treat RA symptoms better. Based on a new understanding of RA biology and our recent findings that collagen hybridizing peptide (CHP) can bind to degraded collagen in skeletal tissues undergoing pathologic resorption, we propose to develop joint targeted antibody therapy that can seek and bind to collagens degraded by rheumatoid arthritis (RA). In aim 1, we will synthesize new CHP structures that have high affinity to denatured collagen. In aim 2, we plan to develop RA joint-targeted anti-TNF-a therapy by conjugating CHP to Fab that can neutralize mouse TNF-a. In aim 3, we will study the pharmacological properties, efficacy, and systemic immune suppression of the Fab-CHP conjugates in RA mouse models. Latest understanding of RA disease mechanism teaches that immune activations in RA take place locally at the disease site and most of TNF-a are produced by the inflamed tissue. Since off-site side effects are the major limitation of antibody therapy, the ability to localize immunomodulatory drugs could lead to high efficacy and low side effects. The success of this work may lead to an entirely new platform for antibody therapy for RA and other autoimmune diseases.

NIH Research Projects · FY 2025 · 2024-08

Major depressive disorder (MDD) and anxiety are linked to brain deficits in the bioenergetic molecules creatine (CR) and acetyl-L carnitine (ALC), nutritional supplements which show potential as antidepressants. MDD and anxiety are often comorbid, and affect 20% of US adults. Moreover, cognitive dysfunction contributes markedly to MDD-linked functional disability. Classical antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are ineffective in ~50% of patients, and mostly do not improve cognitive symptoms. Unlike classical antidepressants, bioenergetic compounds show promise for improving multiple aspects of MDD symptomology, including cognitive function and comorbid anxiety. We now plan to explore the bioenergetic compounds CR, cyclocreatine (CyCR, a CR analog) and ALC as therapeutics in a model for treatment resistant depression (TRD). We established a sex-based animal model to study etiology of the high rates of MDD and anxiety in people at altitude (hypobaric hypoxia). At moderate altitude (4500ft), rats of both sexes exhibit symptoms of depression, anxiety and cognitive dysfunction vs. those at sea level, and a sustained lack of response to most SSRIs. Hypo- baric hypoxia induces brain bioenergetic deficits, and CR, CyCR and ALC can reduce the deficit to show sex- based antidepressant-like or anxiolytic-like efficacy in this model. Brain bioenergetic deficits are directly linked to MDD, but can further promote onset of MDD by causing inflammation and oxidative stress. Hypoxia-inducible transcription factors (HIFs) interact with the oxidative stress system to mediate cellular response to hypoxia, and CR can alter HIF activation. Our central hypothesis is that bioenergetic compounds will improve status of de- pression, anxiety and cognitive function by reducing inflammation and oxidative stress at altitude. In Aim 1, we will identify impact of CR, CyCR and ALC vs. SSRI on behavioral symptoms. Efficacy in reducing symptoms of depression (in forced swim, sucrose preference tests), anxiety (e.g., marble burying, elevated T-maze tests) and cognitive dysfunction (e.g., novelty object, radial arm tests) will be tested. In Aim 2, we will study the mode of action by which bioenergetic compounds reduce MDD-linked biomarkers. The impact of CR, CyCR and ALC on biomarkers of inflammation (e.g., the nonspecific inflammatory marker CRF, inflammatory cytokines TNFα, IL6, IL1β), HIF1a activation and oxidative stress (e.g., reactive oxygen species, antioxidants) will be assessed. In Aim 3, we will test molecular mechanisms via which bioenergetic compounds protect against TRD. In our model, bioenergetic drugs may protect against TRD by activating HIFs. CR and ALC can also activate mTOR, PI3K or NfκB pathways. We will now use inhibitors of the signaling pathways likely involved (HIF1a, mTOR, PI3K, NfκB) to block behavioral and biomarker impacts of bioenergetic drugs. Data from studies in this model will further be confirmed using the chronic restraint stress rodent model. These studies are designed to have translational value towards improving multiple aspects of TRD symptomology, including cognitive dysfunction and anxiety, and to investigate novel therapeutic mechanisms as targets for TRD.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Cardiometabolic diseases are the leading cause of death in the United States. With rates of these diseases rising, there is an urgent need to identify modifiable risk factors that contribute to cardiometabolic diseases. A growing literature has shown that circadian disruption, including disturbances in the regularity of circadian activity and misalignment of sleep to circadian activity, increases cardiometabolic disease risk. However, there is a critical gap in our understanding of the sleep-related behaviors which lead to circadian disruption and subsequent disease risk. Bedtime procrastination refers to the tendency to delay bedtime in the absence of external obligations. Bedtime procrastinators often have late and irregular sleep timing and engage in behaviors that increase evening light exposure, potentially serving to misalign and destabilize circadian rhythms. Through circadian disruption and insufficient sleep, bedtime procrastination poses a risk to cardiometabolic health. However, no research has investigated the role of bedtime procrastination in circadian disruption or cardiometabolic health. Furthermore, to date, research on the mechanisms underlying bedtime procrastination has centered on a single construct: self-regulation. However, emerging research suggests that there are two distinct pathways leading to bedtime procrastination. The first pathway involves delaying bedtime due to difficulties with disengaging from rewarding pre-sleep activities, and second involves delaying bedtime to avoid pre-sleep anxiety. As intervention on the reward- and avoidance-driven pathways would require different strategies, this lack of research represents a significant barrier to future research and treatment. Together, the primary objective of this project is to advance a biopsychosocial model of bedtime procrastination. To accomplish this objective, two studies will be conducted. The first study will evaluate the impact of bedtime procrastination on circadian disruption (Aim 1) and the risk of bedtime procrastination to cardiometabolic health (Aim 2). Aims 1 and 2 will be evaluated in a sample of overweight individuals using innovative multidimensional assessment of circadian disruption and cardiometabolic health over the course of a year. The second study seeks to elucidate the roles of anxiety, reward, and self-regulation in the development of daily bedtime procrastination (Aim 3) using an intensive longitudinal design in a large sample of young adults. This project will advance an integrated model of bedtime procrastination. Given that nearly 75% of individuals report procrastinating their bedtime at least once per week, and the extensive impact of this behavior on sleep health, bedtime procrastination likely has a substantial impact on public health. Accordingly, this project will evaluate the impact of this behavior on circadian disruption and cardiometabolic health. Furthermore, by elucidating the mechanisms that underly bedtime procrastination, this project will lay the foundation for future research identifying treatment targets and developing novel interventions for bedtime procrastination and circadian-sleep disturbances.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT I am seeking a Mentored Research Scientist Development Award (K01) in order to acquire the necessary training, practical experience, and knowledge to become a leading independent investigator focused on improving the value of rehabilitation after stroke through an understanding of person and system level variability. This award will provide the necessary support to achieve my Career Development Aims related to 1) health services research, 2) the application of machine learning approaches, 3) scientific communication, and 4) leadership and management skills. To achieve these goals, I have assembled a Mentoring Committee comprised of: Dr. Amit Kumar (primary mentor), a health services researcher and expert in Medicare data; Dr. Julio Facelli (co-mentor), a biomedical informatician and recognized expert in the application of machine learning clustering approaches to healthcare data; Dr. Angela Presson (co-mentor), an epidemiologist with expertise in predictive modeling wit machine learning approaches. I have also created an Advisory Committee of individuals with expertise in stroke care, rehabilitation, and health services research. Individuals with stroke experience multiple care transitions from acute hospitals to post-acute settings and between post-acute settings. Post-acute rehabilitation (PAR) is essential to recovery after stroke, yet many individuals receive inadequate and interrupted PAR, which contributes to poor continuity of care, inefficient care, and poor outcomes. To improve PAR utilization, we must transformation our healthcare system to improve the value of PAR after stroke. However, because past work has only focused on PAR utilization cross sectionally, we lack the foundational understanding of longitudinal PAR utilization that is needed to reshape post-acute stroke care. My Scientific Aims directly address this gap and are to: 1A) identify subgroups of longitudinal PAR utilization patterns during the first year after stroke, 1B) characterize subgroups of PAR utilization with patient-, facility-, and community-level factors, and 2) determine the predictive strength of PAR utilization on one-year outcomes after stroke. The proposed work is significant because it will provide the required understanding of PAR utilization after stroke that is needed to improve the continuity of care and the value of rehabilitative care. The proposed work is innovative because it focuses on longitudinal PAR and long-term outcomes, uses cutting edge approaches to access and analyze Medicare data, and incorporates nationally representative data sources. The expected outcome will 1) lay the groundwork for subsequent R01 submissions examining the impact of PAR utilization on functional outcomes and validating models of PAR utilization and outcomes and 2) facilitate my transition to independence.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY The number of individuals with Alzheimer’s disease or Alzheimer’s disease-related dementias (AD/ADRD) in the U.S. is projected to increase to 9 million by 2030 (from 6.7 million in 2023). A diagnosis of AD/ADRD can not only be emotionally devastating for persons living with dementia (PLWD) and their care contributors, but also financially devastating, as AD/ADRD is often cited as the most expensive disease in the world, with the majority of the financial burden falling to PLWD and their care contributors. As financial hardship is associated with worse mental and physical health outcomes and lower health-related quality of life, both PLWD and their care contributors are at risk for adverse consequences. PLWD and their care contributors may represent a previously overlooked group who are especially vulnerable to greater financial hardship and subsequent negative health outcomes compared to individuals diagnosed with other chronic diseases, indicating the need to screen and prioritize interventions for this group. However, no validated measures exist to assess financial hardship in the context of AD/ADRD. Measures of financial hardship for the general public do not include care contributors, and those in the context of cancer are not appropriate for a disease such as AD/ADRD that has a longer trajectory and often results in a PLWD turning over their financial responsibilities to a care contributor. Furthermore, as the diversity of US older adults increases, many PLWD may have unique support networks involving families of choice. This project will address the need for an inclusive measure of AD/ADRD-related financial hardship (Inclusive Screener for AD/ADRD Financial Expenses or I-SAFE) for use by PLWD and their care contributors. Developing and psychometrically validating an inclusive measure of financial hardship in the context of AD/ADRD will lay the groundwork for future intervention studies designed to reduce financial and health inequities among PLWD and their care contributors. By incorporating one or more care contributors—which attends to the specific disease trajectory of AD/ADRD—and expanding the concept of family to include non-kin care contributors, I-SAFE will further the current measurement of financial hardship and be inclusive enough to capture the unique needs of a diverse population of PLWD and their care contributors. With projections regarding increasing numbers of older adults with AD/ADRD, growing diversity of the population, and rising costs of healthcare, this study has the potential to make a significant impact on the lives of all PLWD and their care contributors.

NIH Research Projects · FY 2025 · 2024-08

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. To effectively address the nation's biomedical, behavioral, and clinical pain research needs, it is imperative to prepare an interdisciplinary pool of well-trained clinical pain research scientists. To accomplish this charge, the University of Utah Program to Provide Pain Research Knowledge (UP3RK) mission is to impart the science knowledge, skills, and core competencies needed by post-graduate, interdisciplinary Scholars to address the nation’s scientific needs in clinical pain research. UP3RK is situated at the University of Utah (UU), a rich environment to train interdisciplinary Scholars on clinical pain research across multiple settings. UP3RK training focuses on our institutional strengths of: 1) nonpharmacologic pain treatment; 2) effective interventions for pain and co-morbidities, particularly substance use disorders; 3) implementation science, and 4) research with varied populations of persons who experience chronic pain. Annually, UP3RK supports five Scholars—within a two- year training duration—through dedicated UP3RK Mentors within an innovative, multi-level mentor model (Mentor Matrix Model) that has proven extremely successful in developing independently-funded investigators who remain in academic research careers. The UP3RK trains our Scholars in: 1) in our four focus areas, 2) career development and programmatic skills, and 3) interdisciplinary research skills. UP3RK’s emphasis on communication, grant writing, and team science at all levels equip our Scholars with key knowledge, skills, and abilities to advance innovations to improve health for persons with chronic pain and enable a multi-disciplinary approach to team science. To accomplish our mission, we leverage new and existing local training curricula and national trainings available from the HEAL PAIN Cohort Program. We evaluate UP3RK training activities through a dedicated evaluation process. UP3RK program objectives are: 1) Recruit and support an interdisciplinary group of clinical pain research Scholars with particular emphasis on those with different career paths and clinical backgrounds, 2) Provide a state-of-the-art training environment and curriculum to develop the next generation of clinical pain researchers with emphasis on the UP3RK focus areas; nonpharmacological pain treatments; effective interventions for pain and co- morbidities, particularly SUDs; implementation science; and research within various populations of persons with chronic pain, 3) Provide Scholars with opportunities to improve the impact of their clinical pain research careers and achieve independent research support within 5 years of completing the UP3RK program by developing career development and programmatic skills (e.g., technical, operational, professionalism, communication skills) and interdisciplinary research skills (e.g., working with an interdisciplinary research team). The research environment and novel training opportunities available through the UP3RK will facilitate achieving these objectives and ensure the program develops Scholars with the characteristics of successful, independent clinical pain researchers.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY The vision of The ASCENT Research Training Program in Sexual and Reproductive Health (SRH) is to strategically develop an innovative, interdisciplinary, and multi-level national research training experience that enhances the future of SRH-related biomedical, behavioral, clinical, and translational research. The program will achieve this through foundational research curricula, advanced training in community-engaged research (CER), hands-on simulation training, mini-immersion experiences, and mentoring, utilizing the Matrix Mentor Model. Currently, research curricula and mentorship specific to SRH and CER lack consistency across academic institutions, disciplines, and training levels. Strategic efforts are necessary to progress academic and community partnerships that can lead to critical innovations and interventions through CER. To address this gap, we have designed a unique research training program with community-, institutional-, and national support open to Scholars from upper undergraduate to professional levels. The program goals include, (1) Establishing The ASCENT Research Training Program, creating administrative excellence and a research training toolkit focused on advanced SRH topics and CER methods, (2) Providing 10 weeks of focused hands-on research experiences, mentoring, and funding for a multi-level cohort of 8 nationally recruited SRH Scholars; and (3) Develop regional and national opportunities for scholar advancement through partnerships with professional societies. These national partners will support recruitment and provide a wide pool of mentors and research opportunities, showcasing specialized research techniques. ASCENT Research Training Program Scholars will gain SRH knowledge, confidence, and essential hands-on CER experience. The program will support Scholars in attending and presenting at regional and national scientific conferences to enhance their professional networks and career trajectories. Successful completion of these activities will establish a multi-level interdisciplinary SRH Scholar training program, unlike any existing program. Ultimately, this program and toolkit will equip participants with advanced CER techniques, enhance the training experiences of SRH biomedical scholars, and train a new generation of reproductive health scholars trained in CER and advanced research approaches

NIH Research Projects · FY 2025 · 2024-08

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. To effectively address the nation's biomedical, behavioral, and clinical pain research needs, it is imperative to prepare an interdisciplinary pool of well-trained clinical pain research scientists. To accomplish this charge, the University of Utah Program to Provide Pain Research Knowledge (UP3RK) mission is to impart the science knowledge, skills, and core competencies needed by post-graduate, interdisciplinary Scholars to address the nation’s scientific needs in clinical pain research. UP3RK is situated at the University of Utah (UU), a rich environment to train interdisciplinary Scholars on clinical pain research across multiple settings. UP3RK training focuses on our institutional strengths of: 1) nonpharmacologic pain treatment; 2) effective interventions for pain and co-morbidities, particularly substance use disorders; 3) implementation science, and 4) research with varied populations of persons who experience chronic pain. Annually, UP3RK supports five Scholars—within a two- year training duration—through dedicated UP3RK Mentors within an innovative, multi-level mentor model (Mentor Matrix Model) that has proven extremely successful in developing independently-funded investigators who remain in academic research careers. The UP3RK trains our Scholars in: 1) in our four focus areas, 2) career development and programmatic skills, and 3) interdisciplinary research skills. UP3RK’s emphasis on communication, grant writing, and team science at all levels equip our Scholars with key knowledge, skills, and abilities to advance innovations to improve health for persons with chronic pain and enable a multi-disciplinary approach to team science. To accomplish our mission, we leverage new and existing local training curricula and national trainings available from the HEAL PAIN Cohort Program. We evaluate UP3RK training activities through a dedicated evaluation process. UP3RK program objectives are: 1) Recruit and support an interdisciplinary group of clinical pain research Scholars with particular emphasis on those with different career paths and clinical backgrounds, 2) Provide a state-of-the-art training environment and curriculum to develop the next generation of clinical pain researchers with emphasis on the UP3RK focus areas; nonpharmacological pain treatments; effective interventions for pain and co- morbidities, particularly SUDs; implementation science; and research within various populations of persons with chronic pain, 3) Provide Scholars with opportunities to improve the impact of their clinical pain research careers and achieve independent research support within 5 years of completing the UP3RK program by developing career development and programmatic skills (e.g., technical, operational, professionalism, communication skills) and interdisciplinary research skills (e.g., working with an interdisciplinary research team). The research environment and novel training opportunities available through the UP3RK will facilitate achieving these objectives and ensure the program develops Scholars with the characteristics of successful, independent clinical pain researchers.

NIH Research Projects · FY 2025 · 2024-08

Ventricular tachycardia can be a life-threatening arrhythmia that requires effective and timely treatment. This treatment often takes the form of catheter based ablation; however, the success rates are modest. Moreover, the ablation procedure is invasive, done under general anesthesia, and can take many hours in patients who already have compromised cardiac function, putting them at risk for more complications. Recently, radiation therapy, like that used in oncology has been used to ablate cardiac arrhythmias. Initially performed in patients who had run out of other options, the success in a few patients has opened the possibility of wider use. However, despite this promising success, the biophysics of how radiation affects the cardiac tissue, the timeline of scar formation, the acute and more chronic effect on the electrical propagation and the dose response are all unknown. The time to response in radiation ablation in the reported studies is also highly variable, ranging from immediate to more than 6 weeks for any results. More importantly, although radiation ablation is non-invasive, it often requires an invasive electrophysiology study to identify the target site(s), an essential step that determines the success or failure of the procedure. We propose to address both these limitations by using our proven expertise in the fields of imaging, electrophysiology, computational modeling, and radiation oncology to advance the use of radiation as a noninvasive means of ablation with the following aims: (1) Determine the dose response and structural and functional effects of radiation on the cardiac tissue; (2) Create radiation targeting strategies using personalized computational models of ventricular arrhythmias in a pre-clinical VT model and patients; (3) Carry out non-invasive radiation ablation treatment in a pre-clinical infarct model with ventricular tachycardia. In aim 1 we will address the biophysics of ablation by performing electrophysiology studies at different time points after ablation with different doses to understand the effects of radiation on electrical propagation. We will be doing serial MRIs to create a dose response and to evaluate the heart for structural remodeling like edema, fibrosis, and scar. To provide a physiological basis for the effects, we will do histology, protein expression analysis and confocal microscopy. In aim 2 we will use MRI to assess patients with pre-existing ventricular scar and make personalized simulation models to determine the VT circuit and the critical part of the circuit to target with radiation. Our existing database of VT patients, with MR images and ECGs with VT and detailed map of the VT will provide the opportunity for validation of these models along with a pre-clinical VT model. Finally, in aim 3 we will treat suitable VT pre-clinical model with radiation instead of the traditional radiofrequency to further understand the mechanism underlying ablation with radiation. Improving our understanding of the effects of radiation treatment for cardiac arrhythmias will fundamentally change the way that patients with VT are managed, shortening procedure times, and reducing the risks associated with invasive traditional ablation.

NIH Research Projects · FY 2025 · 2024-08

Project Summary: Our long-term goal is to gain a molecular understanding of the machinery that regulates the assembly, release, and maturation of infectious HIV virions. Newly released HIV virions are immature and have a lattice of proteins (mainly the Gag polyprotein) that underpins their viral membrane. Through proteolysis, HIV enzymes help transform this lattice into a conical mature core, after which the virus becomes infectious. Maturation Inhibitors, a new class of antiviral drugs, are designed to bind to the immature lattice and interfere with this transformation. During the previous award period, we showed that the stability of the immature lattice is dependent on other HIV components aside from the Gag polyprotein. The small size of HIV virions makes studying their lattice dynamics challenging, therefore, we developed biophysical, imaging, and computational methods to enable these measurements. We have two main aims for this award period. Our first aim is to investigate the specific effects of different non-Gag components on the stability of the immature lattice and determine the nature of biomolecular forces stabilizing it. Our second aim is to determine how dynamics within the lattice drive the activation of HIV enzymes and kick start the maturation process. By advancing our understanding of the biomechanical principles governing the immature lattice of HIV and its maturation, our studies will inform both the design of next- generation antivirals as well as future lentiviral systems.

NIH Research Projects · FY 2025 · 2024-08

––– PROJECT SUMMARY ––––––– R21/R33: Alcohol Tolerance as a Driver of Self-Administration ––– PI: Rothenfluh ––– Alcohol use disorder (AUD) is still highly prevalent in the US, and the recent pandemic has made it even more pervasive. Risk factors for the development of AUD include initial resistance to the intoxicating effects of alcohol, as well as tolerance, where individuals require increasingly larger doses to attain the same behavioral outcomes. Yet, how the initial reaction to alcohol is related to the development of tolerance, and how both of them drive alcohol self-administration is not well understood. This R21/33 application responds to NIAAA PAR- 21-250 “Mechanisms of Alcohol Tolerance”, which aims to ”build a framework for the systematic analysis of the factors that contribute to alcohol sensitivity and tolerance and the mechanisms that regulate tolerance and transition to AUD”. We use Drosophila as a model organism because they show many alcohol-related behaviors also observed in mammals that involved conserved molecular, genetic, and even neuronal mechanisms. Analyzing over 120 distinct genetic manipulations, we recently showed that initial alcohol resistance is correlated with the development of less tolerance with repeat alcohol exposures. In Aim1, we propose to similarly, and systematically analyze 49 genes that affect initial resistance/sensitivity and/or tolerance for their development of experience-dependent alcohol self-administration preference. While tolerance to alcohol is mostly determined by reduced effects on the motor system with repeat alcohol exposure, the ‘reward system’ is also blunted by repeat alcohol. This hedonic tolerance is characterized in humans by experiencing less ‘pleasure’ with various rewards than before drug experience, while rodents become less responsive to normally reinforcing stimuli with hedonic tolerance. Based on our promising preliminary data, we will develop a robust and convincing assay for hedonic tolerance in Drosophila (Aim2). In order to progress to the R33 phase of the proposal, our MILESTONE is to successfully accomplish Aim2 by clearly defined metrics. Upon achieving this milestone, we aim to investigate genetic, molecular, and neural mechanisms of hedonic tolerance in Drosophila. In Aim3 we will investigate how the mechanisms and neuronal circuits affecting motor tolerance overlap with hedonic tolerance. Lastly, Aim4 proposes to investigate the molecular and neuronal mechanisms of hedonic tolerance, with both these Aims testing our overarching hypothesis that molecular mechanisms are (partially) overlapping between motor and hedonic tolerance, but the circuits mediating them are distinct. We will also test how mechanisms of hedonic tolerance affect experience-dependent alcohol preference. Together, these Aims yield much needed insight into the relevance of tolerance in AUD, especially hedonic tolerance, which has been labeled “key” to understanding AUD.

NIH Research Projects · FY 2024 · 2024-08

Project Summary In the face of increasing antimicrobial resistance, understanding the mechanism of virulence factor(s) characteristics in bacteria is critical for developing new therapeutics. For many pathogens, large multi-protein molecular machines called injectisomes (also known as type III secretion systems) are central to pathogenesis. Injectisomes are central to virulence by many human pathogens including Salmonella (gastroenteritis and typhoid fever), Shigella (dysentery), Vibrio (gastroenteritis) Pseudomonas (diverse systemic infections), Yersinia (plague), and Chlamydia (sexually transmitted diseases), presenting significant health burdens. By understanding the mechanisms of injectisome biogenesis, function and coupled gene regulatory mechanisms, we poise ourselves to develop novel antimicrobial therapeutics. Although these pathogens are common, a barrier to fighting infections by injectisome-utilizing organisms has been incomplete structural insights into core mechanisms of secretion. Understanding these core mechanisms is crucial to developing novel anti-pathogen strategies. We propose experiments that provide fundamental knowledge about injectisome mechanisms for use in combating these significant pathogens. Understanding the molecular mechanisms controlling effector secretion will provide crucial knowledge toward combating injectisome-deploying pathogens. Type III secretion (T3S) is arguably the most important route through which gram-negative plant and animal pathogens translocate effector proteins into host cells and is a key component in bacterial symbiosis with eukaryotic organisms. There are beautiful structures lacking mechanisms of assembly with superficial knowledge of coupled gene regulatory systems that we will uncover. Our track-record on the related flagellar systems leaves no doubt that we are most qualified to do this. For more than twenty years, the selectivity of substrates for specific secretion by the injectisome-associated T3S systems from thousands of proteins produced in the cell has been an unsolvable mystery until now. T3S is the only secretion system in Biology that undergoes a secretion- specificity switch from one class of secretion-substrates to a completely different class. Using newly devised genetic selections and screens we will determine how specific substrates are recognized and targeted for secretion by the Salmonella Pathogenicity Island 1 (SPI1) T3S systems in coordination with SPI1 injectisome assembly and the secretion-specificity switch.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT MicroRNAs (miRNAs) are essential regulators of the human transcriptome and play a central role in tissue development. As the hematopoietic system is composed of a multitude of mature cell types constantly produced from stem and progenitor cells, it is not surprising that correct miRNA biogenesis, function, and decay are essential for hematopoietic differentiation. We have recently identified U6 Biogenesis 1 (USB1) as being a novel 3·_ end miRNA deadenylase that regulates degradation of different miRNAs. As mutations in USB1 cause the bone marrow failure syndrome poikiloderma with neutropenia (PN), it becomes clear that the correct 3· - end processing of miRNAs by USB1 is critical for hematopoiesis. Due to a lack of adequate models and intrinsic difficulties in studying mi RNA processing, the pathways that control miRNA degradation remain largely unknown. A better understanding of the posttranscriptional regulation of miRNA processing, and how it relates to activation of different miRNA degradation pathways is essential to decipher the role of these non-coding RNAs during hematopoiesis. The focus of this proposal is to use the targeted hematopoietic differentiation of human pluripotent stem cells to decipher molecular pathways controlling posttranscriptional regulation and degradation routes of miRNAs. We have generated a large panel of human pluripotent stem cell lines harboring pathogenic mutations in USB1 and other miRNA 3'-end deadenylases, as well as mutations in different components of the exosome RNA decay complex. From these, we derive hematopoietic cells in vitro, following established protocols that recapitulate the in vivo formation of these cell types. Two specific aims are proposed that utilize this platform to identify novel regulators of miRNA processing and decay, and to determine their function in the hematopoietic system. Aim 1 will determine the mechanisms regulating target specificity and overlap of different deadenylases necessary for development, during several stages of hematopoiesis. We will complement these assays by determining which miRNA decay routes are activated in these cellular populations, focusing on exosome activation and target-directed miRNA degradation (TDMD). We will determine to which extent TDMD is modulated by incorrect miRNA 3'- end adenylation and deadenylation in WT and USB1 mutants. Aim 2 will investigate the specific mechanisms leading to impaired neutrophil development in USB 1 mutant cells, as PN causes severe non-cyclic neutropenia. We have identified potential targets of USB 1 that modulate neutrophil yield and will test their functional role in different processes, such as cellular replication and apoptosis, that could lead to a failure of myeloid progenitors to efficiently generate neutrophils. These studies will decipher novel effectors of miRNA degradation in the hematopoietic system, a tissue where miRNA-regulated gene expression plays a central role. Our unique molecular and cellular tools, combined with our expertise in DNA and RNA biology, as well as in hematopoiesis puts us in an ideal position to make a significant impact in this field.

NIH Research Projects · FY 2026 · 2024-08

This project seeks to comprehensively understand how gene regulatory elements within rapidly evolving areas of the human genome, segmental duplications, influence human evolution and disease. Despite their potential significance, these regions have historically been challenging to study due to technical limitations. The specific aims of this project are: 1. Characterize segmental duplications across the human population by constructing a pangenome graph using thousands of high-quality genome assemblies. 2. Establish a statistical and computational methodology for mapping regulatory DNA within SDs using long-read chromatin fiber sequencing (Fiber-seq). 3. Identify conserved regulatory and genomic elements within segmental duplication loci by mapping genetic and epigenetic haplotypes into the pangenome graph. 4. Uncover the regulatory fate of multi-copy gene families by analyzing segmental duplication para logs with Fiber-seq across tissues, determining if these para logs have undergone changes in regulatory function. Research Design and Methods: In this work, I will create a comprehensive SD pangenome graph by integrating thousands of long-read haplotypes from multiple consortia, which will significantly enhance our understanding of human variation within SDs. Next, I will use long-read Fiber-seq in conjunction with the development of a machine-learning framework to detect regulatory elements within SDs and use that information to impute the results of other short-read epigenetic assays. My approach will also involve a conservation analysis that prioritizes SD genes and regulatory elements. I will introduce a novel 'loss-of-paralog intolerance' (pLPI) score to rank these genes based on their conservation levels across populations. Additionally, the regulatory trajectories of SD genes will be determined using Fiber-seq conducted on a range of human tissues. This will help me identify distinct patterns such as neofunctionalization, subfunctionalization, or pseudofunctionalization. This investigative approach will deliver an in-depth understanding of the regulatory mechanisms in SDs using cutting-edge genomic tools. The insights gained have the potential to highlight human-specific regulatory adaptations and could pave the way for discovering new therapeutic avenues in personalized medicine.

NIH Research Projects · FY 2025 · 2024-08

Abstract Malaria afflicted 247 million people in 2021, of which over 600,000 died. In the most severe cases, patients can develop organ-specific pathologies related to vascular leak, including cerebral malaria and malaria-associated acute respiratory distress syndrome (MA-ARDS). The mechanisms of pulmonary vascular leak are poorly understood, and the long-term goal of this work is to define the molecular mechanisms underlying pulmonary vascular leak in malaria to develop rationale therapeutics to treat this condition. It has been previously shown that CD8 T cells and platelets are activated by Plasmodium in humans and are required for vascular breakdown in mouse models, but specific mechanisms underlying how these cells incur damage is still unclear. The central hypothesis of this proposal is that platelets contribute both directly and indirectly to MA-ARDS by promoting CD8 cytotoxicity leading to barrier dysfunction. The rationale of this work is that identifying how platelets augment the pathogenicity of CD8 T cells will provide new avenues for chemotherapeutic targeting of MA-ARDS. Published work from the Lamb lab and preliminary data shown here demonstrate that mice deficient in platelet a-granules (Nbeal2-/-) survive Plasmodium berghei infection and fail to develop vascular leak in the lungs and brain. In intestinal colitis models, published work by the Petrey lab has demonstrated that platelet granule-derived hyaluronidase 2 (HYAL2) is responsible for driving degradation of hyaluronan (HA) in the endothelial glycocalyx (eGC), which serves as a key modulator of barrier integrity. Our preliminary data show that HA fragments in the plasma, an indicator of glycocalyx breakdown, are increased in infected wildtype mice but not in platelet a- granule-deficient mice. The literature shows that HA fragments can promote cellular activation and proliferation, and our preliminary data demonstrate that the Nbeal2-/-, which have low plasma HA, have low CD8 T cell accumulation in the lung during Plasmodium infection. The published literature and our preliminary data have led us to form the working hypothesis that platelet cleaves the endothelial glycocalyx, promoting CD8 T cell activation and recruitment via circulating HA fragments and exposing endothelial cells to CD8 effector molecules, resulting in barrier damage. We will test this hypothesis with the following specific aims: Aim 1: Demonstrate that platelet a-granule HYAL2 is required for eGC breakdown in MA-ARDS. Aim 2: Test the hypothesis that plasma HA promotes pathogenic CD8 trafficking via CD44 binding. We expect that the work proposed in Aim 1 will determine the mechanism by which platelet hyaluronidase causes pulmonary vascular leak during MA-ARDS, which has not previously been described in malaria, and demonstrate how the resulting plasma HA modulates CD8 T cell activation and trafficking. We anticipate that the findings from this work will provide a much-needed deeper understanding of the mechanisms of MA-ARDS, inform on potential mechanisms underlying vascular leak in other disease models, and give insight into potential pathways that could be targeted therapeutically to disrupt MA-ARDS in the clinic.

NIH Research Projects · FY 2025 · 2024-08

Project Summary The plasma membrane experiences many cellular and environmental changes in form of increasing or decreasing membrane tension. Events such as cytokinesis, cell differentiation, migration, and metabolic changes all affect volume to surface area ratios and thus plasma membrane tension. Therefore, an increasing number of studies identify changes in membrane tension as a common signal for the cellular status. This signal affects cytoskeleton, ion channels, and cell signaling and thus is able to coordinate cellular response pathways. A goal of cellular stress response is to reestablish normal membrane tension, which is important to maintain cell integrity and functionality of systems associated with the plasma membrane. How eukaryotic cells sense and maintain membrane tension is poorly understood. We started to address these questions by analyzing the response of yeast Saccharomyces cerevisiae to dramatic changes in osmolarity of the growth medium, a stress that is commonly encountered in the natural environment of this unicellular organism. Within seconds, osmotic stress can change the surface area of yeast by +/-20%, a change that suggests rapid addition or removal of membrane to/from the surface. Our data indicate that this rapid membrane flux is mediated by the ER-plasma membrane contact sites (EPCS). Current models implicate the EPCS in the shuttling of lipids between the two membranes, a transport activity that can explain our observations during cell shrinking. However, rapid cell expansion seems to require an additional mechanism, the fusion of the ER with the plasma membrane at contact sites. This proposed fusion allows not only for rapid membrane transport to the plasma membrane, but it also might be able to deliver within seconds stress-response proteins from the ER to the cell surface.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY Although static neck braces are prescribed to patients with head drop resulted from amyotrophic lateral sclerosis (ALS), many patients do not use these neck braces because they are uncomfortable and ineffective. As a result, patients leave their head drop condition untreated, which worsens their ability to breathe, swallow, speak, and perform other daily tasks. The long-term goal is to treat ALS head drop through an at-home assistive device. The overall objective in this application is to build a structurally suitable neck exoskeleton for ALS head drop, with comfortable and easy-to-wear attachments, as well as robust mechanical linkages and joints. The central hypothesis is that a structurally suitable neck exoskeleton will improve overall users’ satisfaction, increase head-neck range of motion, and enable social interactions. The rationale for this project is that once a structurally suitable neck exoskeleton becomes available, it will likely offer a feasible platform to support future clinical trials and facilitate its translation for domestic use. The central hypothesis will be tested by pursuing one specific aim: Determine mechanical factors of a suitable neck exoskeleton critical for ALS head drop. Under this aim, patients with ALS head drop will be involved in the design process and precisely made components will be used to build a structurally suitable neck exoskeleton. It will then be evaluated by patients with severe ALS head drop to determine the extent to which this neck exoskeleton increases head-neck range of motion, enables social interaction, enhances head-neck movement precision, and achieves overall satisfaction of these participants. The research proposed in this application is innovative, in the applicant’s opinion, because it focuses on achieving a structurally suitable neck exoskeleton to empower head-neck movements in patients with ALS head drop by incorporating patients’ feedback and utilizing advanced design and manufacturing methods. The proposed research is significant because it is the next fundamental step in the continuum of research that is expected to provide clinically available neck exoskeleton specifically targeted for ALS.

NIH Research Projects · FY 2025 · 2024-08

Project Summary My overarching goal is to become a biomedical engineer capable of advancing minimally invasive procedures through medical imaging and machine learning. To achieve this, I aim to develop a broad understanding of diagnostic and interventional radiology and robust technical skills in acquiring, reconstructing, and applying machine learning techniques to biomedical imaging data. This research focuses on addressing unsolved engineering problems in magnetic resonance imaging (MRI)-based evaluation of focused ultrasound for breast cancer treatment, providing a strong foundation for a successful career in interventional imaging. Traditionally, MRI has provided qualitative insights into biological tissues. Recent advances in image acquisition, reconstruction, and deep learning have created new opportunities for making quantitative measurements of physical and chemical properties using MRI. Deep learning techniques face technical challenges in quantitative MRI, such as the absence of large training datasets and their current inability to cope with variations across scanners and protocols, especially in the interventional context. This work investigates integrating physics knowledge into the architecture and training of deep learning models to mitigate these problems and enable reliable and clinically deployable quantitative MRI techniques for evaluating MR-guided focused ultrasound breast cancer treatments. Aim 1 uses physics-informed machine learning to develop an efficient technique for measuring MR relaxation times in the breast using configuration state imaging. A physics-informed neural network architecture and training paradigm will be methodically investigated using simulated data. The developed model will then be trained on sparse real data acquired using a multi-echo configuration state imaging sequence and rigorously evaluated on data from phantoms, healthy volunteers, and breast cancer patients across multiple MR scanners and time points. Aim 2 aims to develop a time-efficient technique for obtaining diffusion measurements in breast imaging with full 3D coverage, evaluating the relative performance of conventional model-based techniques and physics-informed neural networks in estimating diffusion parameters from the collected data. After developing the sequence and technique, diffusion parameter maps will be compared with gold-standard measurements in standardized diffusion phantoms, healthy volunteers, and breast cancer patients on multiple scanners. This research will advance the current understanding of how to create generalizable machine learning models for MRI and to design them for usability in a clinical context. Additionally, the developed MRI techniques will enable clinical and interventional use of quantitative MRI, supporting the development of biomarkers that provide real-time evaluation of MR-guided focused ultrasound breast cancer treatments.