University Of Wisconsin-Madison

NIH Research Projects · FY 2024 · 2021-09

ABSTRACT Aging is the single largest risk factor for many common diseases that burden public health. This is especially true in the prostate. The prostate is a male sex accessory gland that is important in reproduction. However, as men age the prostate undergoes a prototypical aging change, fibrosis. The aged fibrotic prostate causes urinary symptoms which will afflict nearly every man if they live long enough. Our team has led an effort to define the aged prostate and its associated urinary symptoms in overall health. To date aging mechanisms have not been thoroughly tested or targeted for the nonmalignant prostate. Rather androgen regulated pathways and alpha adrenergic activity have dominated the field. The long-term goal of this application is to better understand how mitochondrial dysfunction and related molecular and cellular mechanisms promote prostate aging and fibrosis, ultimately leading to prostate dysfunction, urinary symptoms and overall poor health. Mitochondrial dysfunction has become an accepted mechanism of aging. However, the role of mitochondrial dysfunction in the prostate has not been thoroughly tested. In part this is because there is little understanding of the role of mitochondria in prostate function and no models have been identified to test it. To better understand the role of mitochondrial dysfunction in the aging prostate, we will perform 4 Aims. Aim 1 will assess the gain of prostatic mitochondrial dysfunction using chemical inhibitors of mitochondrial complex I of the electron transport chain and determine if prostatic aging is accelerated ultimately leading to a dysfunctional prostate. Aim 2 will determine the molecular mechanism by which mitochondrial dysfunction induces aging and fibrosis. Aim 3 identifies the localization of mitochondrial dysfunction in specific cells and anatomical areas of the prostate of men, including differences in race as well as in the lower urinary tract of mice. Aim 4 tests the effectiveness of pro-mitochondrial health drugs in reversing mitochondrial dysfunction, prostate aging, and urinary dysfunction in human and mouse models of aging. Identifying pharmacological age related interventions in novel prostate aging animal models to improve mitochondrial homeostasis would be highly desirable towards the goal of prolonging healthspan. The potential translational impact of this approach is high, as the proposed senolytics are already FDA approved and can be rapidly included into clinical trials. Upon the completion of this work, we will better understand the role of mitochondrial dysfunction in the aging prostate and how to target this pathway for better urinary and overall health. Furthermore new aging models will be developed and better characterized for future aging and urological related research.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY The goal of this grant is to optimize hepatic histotripsy to create safe and effective ablation in any location in a large animal, human-scale model. Liver cancer is a leading cause of death with ablation one of the limited curative options in select patients. Unfortunately, currently available ablation procedures have a variable local failure rate of ~10-40%. Also, tumors located near critical structures, such as bile ducts and bowel, often do not receive curative treatment as thermal ablation is associated with increased risk of injury. Histotripsy is the first non-invasive, non- thermal, and non-ionizing ablation modality, using focused ultrasound energy to create cavitation, resulting in mechanical tissue disruption. In preliminary studies, histotripsy has shown an ability to cause tissue disruption that spares certain structures with collagenous architecture, including bile ducts and bowel, and to create ablation zones with a thin margin between treated and normal tissues. To catalyze the clinical translation of histotripsy and potentially increase the number of patients eligible for curative treatment, a key question needs to be answered: Can we leverage the potential safety advantages of histotripsy while maintaining efficacy such that more tumors will be eligible for curative treatment? First, strategies to mitigate the effects of respiratory motion by decreasing liver motion with high-frequency jet ventilation or using in-suite cone-beam CT to model liver motion and modify prescriptions will be trialed in Aim 1. In Aim 2 we will determine dose thresholds to treat excised HCC while sparing critical structures to identify a safe, effective treatment dose for tumors of any location and then validate this dose in a survival, in vivo swine liver model. Finally, in Aim 3 we will advance a SCID-like HCC porcine liver tumor model, which will allow us to apply these strategies to tumors located within specific high-risk locations of the liver to confirm safety and efficacy, ultimately, proving our hypothesis that histotripsy can treat tumors in any liver location safely. The three Specific Aims are the following. Aim 1: Determine the best strategy to mitigate the effects of respiratory motion to increase the precision and safety of histotripsy ablation. Aim 2: To determine dose thresholds for liver cancer and critical structures ex vivo, allowing a trial of safe, effective treatment parameters for in vivo treatment in critical locations. Aim 3: Advance a highly relevant large animal liver HCC model for medical devices and confirm safety and efficacy in this large animal model. This project will yield critical preclinical data which will be necessary before the widespread adoption of histotripsy to treat patients with non-surgical hepatocellular carcinoma.

NIH Research Projects · FY 2024 · 2021-09

Project Summary/Abstract: Cancer is the second leading cause of death in the United States. In some patients, cancer can be cured with surgery and/or radiation. Many patients will develop advanced disease that must be managed with various systemic medications and treatments. Unfortunately, the majority of patients in this group will eventually develop treatment resistant cancer, which is often lethal. Despite its importance, our understanding of how this resistance develops and evolves is limited. The primary challenge is that the study of treatment resistance requires obtaining tumor samples before, during, and after it develops. However, obtaining these samples involves surgical or other invasive procedures that carry some risk of causing a complication which could harm the patient. Repeatedly obtaining tissue samples for research is not feasible for the majority of patients. We propose to use a new “liquid” biopsy technique in which molecular information about the tumor is collected from serial blood samples, which patients with cancer are frequently providing for a variety of laboratory tests already. This information can then be used to understand how treatment resistance develops and how it evolves over time. This will allow us to identify potential strategies to overcome this resistance, as well as create tests to pick it up early so that treatment can be adjusted before the cancer grows and the patient gets sicker. This strategy could be used across cancers and treatments and change the paradigm in how we understand cancer progression as well as change how we monitor and treat patients.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY / ABSTRACT Atypical and delayed oromotor development is a well-known clinical aspect of Down syndrome (DS) and contributes to devastating challenges in speech, feeding, and swallowing. These challenges can affect the majority of individuals with DS, with profound consequences for quality of life and health. The tongue and brainstem are both complex systems that undergo rapid changes during early postnatal development and are critical for speech and swallowing. However, the central and peripheral changes occurring in early childhood that permit postnatal expansion in movement and function of the tongue are poorly understood in typical development and in DS. Because early childhood is a time of rapid development during which the neuromuscular system is plastic, altered tongue activity during this time may also alter the postnatal maturation of the tongue neuromuscular system. However, the impact of altered lingual activity on intrinsic tongue and brainstem maturation in early post-natal development has rarely been studied and is therefore unknown. We hypothesize that DS is associated with developmental delays in maturation of the tongue neuromuscular system. The proposed work is highly significant in using mouse models to advance understanding of a developmental disorder in which atypical tongue function contributes to compromise of speech intelligibility and health. Aim 1 will generate normative data for the study of tongue and brainstem maturation with reference to three consecutive early postnatal ages and will determine how DS impacts lingual development. This will be achieved through behavioral, immunofluorescence, and gene expression studies of tongue muscles and brainstem in the Ts65Dn mouse model of DS in comparison to typical sibling controls. Aim 2 will determine whether lingual activity levels after weaning impact maturation of the tongue neuromuscular system. This aim will be achieved through analysis of tongue and brainstem before weaning and after 2 weeks of an ecologically valid post-weaning condition in which all mice naturally refrain from licking due to a liquid consistency modification. This aim will clarify the extent to which shifts in tongue activity imposed by environmental modifications elicit changes in postnatal maturation of the tongue and brainstem in Ts65Dn mice and in typical sibling controls. Collectively, these aims will further the science underlying both typical and delayed lingual maturation. This work will also shed light on basic biological implications of feeding interventions used with children with DS that alter oromotor activity. As such, this work will provide basic knowledge for future efforts to develop biologically based approaches for successful resolution of pediatric oromotor disorders. These goals will establish an experimental framework to advance biologically informed treatments for developmental speech, feeding, and swallowing disorders.

NIH Research Projects · FY 2024 · 2021-09

SUMMARY The last step in cell division, abscission, relies on a transient structure called the midbody, which resides inside the intercellular bridge between newly forming daughter cells. It consists of overlapping spindle midzone microtubules which are coated with electron dense material called the midbody matrix. Long conceptualized as a structural remnant subject to degradation following cytokinesis, emerging data suggest that midbodies play instructive post-mitotic roles in establishing cell fate, proliferation state, tissue polarity, cilia formation, neuron function, and oncogenesis. However, very little is known about the functional significance of the electron dense material, since it was first actively pursued by Michael Mullins and Dick McIntosh in the 1970s, and then by Ryoko Kuriyama in the 1980s. My lab has uncovered a surprising novel function for this electron dense material in that it is a site of RNA storage and is a novel actively translating RNP granule with a uniquely complex life cycle comprised of both membrane-less and membrane-bound phases, that we are calling the MB-granule (for Midbody-granule). Employing quantitative, super-resolution approaches in live and fixed cells, coupled with genomics and genetic manipulations to address our questions, we discovered that translation occurs in a compartment surrounding the midbody RNP granule, as well as in post-mitotic midbody remnants (or MBRs), and internalized MBRs (or MBsomes). RNA-seq data of isolated mammalian midbodies revealed an enrichment of both oncogenic and stem cell transcription factors that have no described function in cell division, but presumably act post-mitotically. Midbody-enriched transcripts initiate translation immediately before abscission, a step that we have shown occurs in early G1, just after the nuclear envelope is fully reassembled. Treatments commonly used to determine RNP phase condensates revealed that the midbody matrix behaves as a novel type of RNP granule, and that the critical cytokinesis kinesin motor, Kif23/MKLP1, may serve as a novel RNP scaffold. The MB-granule is a very novel class of RNP granule in that it’s translationally active, has membrane- less and membrane-bound phases, and functions post-mitotically in cell fate and proliferative decisions. Here, we will focus our efforts to determine the cell-type specific components of MBRs, the spatiotemporal regulation of MBsome structure, and function, and if MB-granule RNAs are being liberated in cells that engulf them. Our proposed studies will uncover unique insights into conserved and divergent MBsome structure and function, offering insight into how this unique RNP condensate and organelle behaves as novel form of intercellular communication.

NIH Research Projects · FY 2025 · 2021-09

ABSTRACT In the final six months of life older adults often receive invasive treatments despite their preferences to avoid burdensome interventions with limited efficacy. Strategies to reduce overtreatment at the end of life have focused on improving communication and decision making, yet systems-level practice patterns have a strong influence on the delivery of patient care. My patient-oriented research program focuses on improving major treatment decisions for older adults with serious illness. As a sought after mentor for early-career investigators, I now wish to expand my research program to include the human factors and systems-level forces that lead to these decisions and build a robust pipeline of researchers focused on improving care for older adults. Use of systems engineering to evaluate the initiation of life-supporting treatments in older adults with life-limiting illness is a five-year K24 Midcareer Investigator's Award in patient-oriented and aging research responding to PA-20-186. Our research team has previously recognized systems-level practice patterns leading to overtreatment and developed a conceptual model to describe this phenomenon that we call clinical momentum. We theorize that clinical momentum is a major contributor to overtreatment for older adults with life-limiting illness and is an important barrier to the success of communication interventions designed to improve care at the end of life. The objective of this proposal is to use a systems engineering approach to characterize the systems in which decisions about life-supporting treatments occur and to employ user- centered design to generate interventions to improve patient, clinician and organizational outcomes. In this observational study we will perform a comparative analysis of the initiation of life-supporting treatments, specifically dialysis, feeding tube placement, and prolonged mechanical ventilation, which will provide a rich laboratory for a variety of mentored projects. For aim 1, we will use a systems engineering approach to characterize patterns of care leading to initiation of life-supporting treatments. For aim 2, we will develop interventions to disrupt clinical momentum for older adults with life-limiting illness. This award will allow me to (1) build a new direction of research and investigative skills and (2) expand my capacity and skill as a mentor and to increase the number of young investigators who aim to develop a career in patient-oriented and aging research. This research is innovative because it uses a novel empirical strategy to identify practice patterns that may play a critical role in the provision of overtreatment for older adults with life-limiting illness. This research is significant because characterizing the role of clinical momentum in the initiation of life-supporting treatments has the potential to unlock the pathway to care truly driven by patient preferences instead of systems-level incentives and forces. With my strong mentorship team, career development plan, and the resources of existing studies I am well-positioned to achieve these objectives.

NIH Research Projects · FY 2025 · 2021-09

ABSTRACT Down syndrome (DS, trisomy 21, T21), a complex multigene disorder and the most common genetic cause of intellectual disability. However, surprisingly little is known about the underlying mechanisms that lead to cognitive impairment in DS. Reduced neurogenesis and synaptogenesis have been implicated as features of DS development. Yet, what and how specific neurons and synaptic contacts are affected at which period of development and what molecular pathways underlie these defects that lead to intellectual disability remain unclear. This supplement application requests funding to expand the goals of the parent award to carry out bulk whole transcriptomics to identify diverse types of RNA species that cannot be captured using the single cell approaches in the parent award. These results will complement the single cell results generated from the parent award and potentially identify new gene regulatory mechanisms in DS brain development. The supplement proposal is relevant to Component 1 of the NIH INCLUDE project: Targeted high risk - high reward basic science studies in areas highly relevant to Down syndrome. Data generated from this award will be shared as a resource through the INCLUDE Data Coordinating Center (DCC) to maximize and accelerated research in Down syndrome.

NIH Research Projects · FY 2025 · 2021-09

Project Summary & Abstract Individuals with brain injuries or disorders that affect movement (such as Parkinson’s disease, cerebral palsy, amyotrophic lateral sclerosis, and many others) often have difficulties in being understood when they speak. While treatments exist, they often require substantial conscious attention to the way speech is produced, or require increased breath support to speak louder. Many individuals with speech disorders have cognitive or respiratory difficulty that renders these treatments ineffective. These individuals will benefit from alternative strategies that promote motor learning: the ability to alter motor actions through practice. One type of motor learning, sensorimotor adaptation, is a particularly promising pathway for alternative rehabilitation. In this paradigm, the auditory feedback people receive while speaking is externally perturbed, causing them to quickly change their speech to oppose these perturbations. Because of its ability to rapidly induce changes in speech production without conscious control, sensorimotor adaptation holds unique promise for rehabilitation. However, its potential clinical applicability is limited by poor understanding of key clinically-relevant features. First, existing sensorimotor adaptation paradigms do not affect speech in a way that facilitates communication. To improve rehabilitation outcomes, sensorimotor learning must target clinically-relevant speech parameters such as intelligibility. We address this barrier through a novel auditory perturbation that artificially decreases the perceived space between vowels, causing speakers to produce more vowel contrast. Critically, reduced vowel contrast is a hallmark of motor speech disorders and significantly contributes to decreased intelligibility. We determine the effectiveness of this paradigm to increase intelligibility and test how these increases are retained across multiple training sessions, how they generalize to untrained words, and how they can be elicited in complex sentences—characteristics which are key for potential clinical applications. Second, while sensorimotor adaptation is a robust effect on average, not all individuals learn to the same degree. This variability limits the potential impact to only those who show a large degree of learning. This proposal uses behavioral interventions and brain stimulation that target the hypothesized causes of this variability. By directly manipulating these factors, we can determine, for the first time, the mechanisms that underlie speech motor learning. Additionally, establishing how these factors can be modulated to increase learning would allow treatment to benefit a wider range of individuals. Although sensorimotor adaptation can quickly induce changes in speech, its current clinical applicability is limited by substantial gaps in our understanding of its mechanisms. By establishing the capacity of sensorimotor adaptation to increase speech intelligibility, characterizing retention and transfer of learning, and identifying the mechanisms underlying variability between individuals, this work lays a critical foundation for future treatments that optimize the clinical impact of motor learning.

NIH Research Projects · FY 2024 · 2021-09

Inguinal hernia repair – the most common general surgery operation in the U.S. – provides a unique opportunity to improve outcomes for older adults by changing surgical practice. Nearly 80% of inguinal hernia operations are performed under general anesthesia versus 15%-20% using local anesthesia. Although some studies suggest that exposure to general anesthesia can cause cognitive and physical decline in older adults, the evidence for choosing an anesthesia technique for inguinal hernia repair in older adults is inconclusive. Several studies demonstrated that using local anesthesia for hernia repair reduced morbidity by one-third, unplanned admissions by 20%, and operative time and costs by 15%, while other studies showed no significant differences. Unfortunately, these studies have significant shortcomings that limit their applicability for older adults, and our preliminary data suggest that the benefits of local anesthesia increase with age. The applicant is an assistant professor in surgery whose long-term career goal is to use expertise in implementation science and clinical trials to promote patient-centered outcomes for older adults before, during, and after surgery. The project goal is to obtain preliminary data to support a multisite trial comparing general versus local anesthesia for inguinal hernia repair in adults aged 65 years and older. We hypothesize that using local rather than general anesthesia for inguinal hernia repair in older adults will reduce morbidity and enhance quality of life. We propose the following specific aims: (1) Identify the optimal target population for a pilot study of general versus local anesthesia among patients aged 65 and older who are undergoing inguinal hernia repair. We will use a national database of operations in the Veterans Affairs system to determine which subsets of older patients (age, comorbidity, and functional status) are most likely to have complications or prolonged operative and recovery time with general anesthesia. (2) Determine which outcomes of inguinal hernia repair are most relevant to patients, caregivers, providers, and hospital administrators for a pilot trial of local versus general anesthesia for hernia repair in older adults. We will interview stakeholders to identify outcomes valued by each group. (3) Conduct a pilot study to assess and refine study procedures and determine feasibility of recruitment, randomization, and retention for a multisite randomized trial of local versus general anesthesia in older adults having inguinal hernia surgery. We will conduct a pilot randomized trial of local versus general anesthesia (30 patients/arm) targeting the population identified in aim 1 and assessing outcomes from aim 2. We will measure rates of enrollment among eligible patients, assess acceptability of study instruments, and verify our ability to follow patients and measure outcomes at each time point. Expected outcomes of the study are (1) crucial preliminary data for planning and executing a multisite trial comparing general versus local anesthesia for hernia repair in older adults, and (2) training and knowledge necessary for the applicant to become a leader in surgical research.

NIH Research Projects · FY 2025 · 2021-09

Project Summary Metalloenzymes are ubiquitous throughout biology and implicated in a variety of human diseases. A gap in our understanding of metalloenzymes lies in their maturation. Biogenesis intermediates precede formation of the mature enzyme and must be tightly regulated to correctly assemble the metallocofactor in the active site. Despite the wealth of knowledge on mature metalloenzymes, their biogenesis, especially active site assembly, is not well understood. Photosystem II (PSII) is a light-driven oxidoreductase whose active site contains a metallocofactor that is assembled through a series of step-wise ion binding and photooxidation events called photoactivation. Photoactivation provides a convenient model for understanding metallocofactor assembly because it is facile; in vitro assembly may be achieved by simply adding the required ions in solution and assembly is advanced by providing light quanta. Furthermore, recent advances in structural investigation of PSII have developed a platform for routinely solving high-resolution structures of PSII assembly intermediates. We propose to characterize biogenesis intermediates of PSII that may reveal generalized rules for metalloenzyme assembly. The long-term goals of this project are to provide structural and functional bases for assembly of the metallocofactor in PSII (training phase), and reveal how PSII biogenesis intermediates maintain precursor structures important for active site maintenance (independent phase). We will use structural approaches, biochemical techniques, and computational modeling to achieve the following three specific objectives: (1) to reveal how the oxygen evolving complex of PSII is assembled, (2) to uncover precursor structures of PSII that are integral for assembling its active site, and (3) to understand the role of transiently-bound subunits during PSII biogenesis. Gaining such insight may allow for the development of new therapeutics and design principles for de novo metalloenzyme engineering.

NIH Research Projects · FY 2025 · 2021-09

Project Summary The ability to accurately predict the effect of genetic variation on phenotypes at multiple scales would radically transform our ability to apply genomic technologies in order to understand human health and disease. This predictive ability would significantly improve the effectiveness of a broad spectrum of genomic analyses ranging from genome-wide association studies for common diseases to diagnostic odysseys searching for genetic causes of rare diseases. To address this challenge, we propose to develop a trainable approach for predicting the phenotypic impact of genetic variants. This approach will support predictions for a broad range of genetic variations, phenotypes, and biological contexts. It will incorporate and exploit mechanistic knowledge of pathways where available, but augment this pathway knowledge with learned models where it is not. This approach will consist of a synthesis of (i) methods that link genomic variants to their effect on expression or function of individual gene products, (ii) methods that link those relationships into the subnetworks involved in cellular responses of interest, (iii) machine-learning approaches that infer models pertaining to a variety of genotype-phenotype relations from large training sets. We will also develop and apply active learning algorithms to identify the most informative experiments for subsequent analysis by IGVF Consortium. Additionally, we will develop and apply a statistical framework for elucidating genetic modifiers, through probabilistic, network-informed inference of common variants identified in GWAS that modify the impact of rare variants implicated in sequencing-based association studies. Throughout the project, we will work closely with other IGVF Centers to guide experimental data collection, benchmark methods from across Centers, and contribute to the variant-element-phenotype catalog which will have broad applications by the community.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY/ABSTRACT Not applicable to the application.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY/ABSTRACT Given significant, structural changes in the labor market, mothers' employment experiences differ markedly today than in previous decades. As mothers dramatically increased their labor force participation over the past 50 years, the growth of the service sector and rise of the “24/7 economy” led to an increase in jobs with nonstandard schedules outside of the traditional Monday to Friday, 9am to 5pm work week. The current high prevalence of maternal nonstandard work schedules raises concerns about the potential adverse effects on children's health and development. Yet, prior research on mothers' work schedules and child outcomes is outdated, relying predominantly on samples of families from the 1980s to early 2000s. Increases in precarious jobs and public investments in child care and early education since then suggest that the effects of mothers' work schedules on mothers' time with children and child care arrangements, and ultimately on child well-being, have also changed. The proposed research aims to further knowledge on how maternal employment has changed in recent decades and its implications for children and families by: (1) documenting and explaining trends in mothers' work hours and schedules over the past 30 years; (2) assessing how the associations between mothers' work schedules, mothers' time with children, and child care arrangements have changed over time and as a result of increased public spending on child care and early education programs; and (3) examining how mothers' work schedules are associated with children's health and development outcomes in a contemporary, nationally-representative sample of U.S. households, as well as testing multiple, key mediators of these associations. The project will generate novel findings on how mothers' employment matters for child health and development that are necessary for making informed policy decisions about how to best intervene and support children and families to improve health and well-being over the life course. This K01 award would provide Dr. Alejandra Ros Pilarz with the training required to become an independent researcher and leading expert in how parental employment matters for child health and development. The extensive research infrastructure and support for early career investigators, rich, intellectual environment at the Center for Demography and Ecology and Institute for Research on Poverty, and a committed mentoring team of experts in their respective fields make the University of Wisconsin-Madison an ideal environment to complete the proposed research and training activities. The proposed training plan would allow Dr. Pilarz to receive instruction and mentorship toward meeting the following career goals: (1) increasing substantive knowledge in demography and demographic methods; (2) increasing substantive knowledge of family processes, child health, and middle childhood development; and (3) gaining proficiency in advanced quantitative methods. The K01 award will lead to an R01 proposal that builds on Dr. Pilarz's newly-acquired substantive knowledge and methodological skills and will help launch Dr. Pilarz's career as an independent researcher.

NIH Research Projects · FY 2024 · 2021-08

Cardiac toxicity is a devastating complication of cancer treatment and occurs during, shortly after, or even many years after treatment. Long-term follow up of patients undergoing thoracic radiation, such as lymphoma, lung, and esophageal cancers, has shown that in particular, radiation therapy (RT) can lead to major radiation-induced cardiac toxicities like congestive heart failure and coronary artery disease. Typically, the standard of care for cardiac dose assessment involves simple heart dose/volume metrics. However, mounting evidence suggests that cardiac substructures contained within the heart are highly radiosensitive and dose to substructures are more strongly associated with overall survival than assessing whole-heart dose/volume metrics. Nevertheless, precise characterization of cardiac substructure dose in routine clinical practice is currently limited because substructures are not visible on CT simulation scans used for RT planning, cardiac MRI are not widely available for cancer patients, and manual delineation is cumbersome, taking 6-10 hours per case. Further, precise localization is complicated by both cardiac and respiratory motion. Our long-term goal is to develop and validate clinically viable novel technologies to localize cardiac substructures for novel cancer therapies and interventions. The rationale for the proposed research is that by developing a robust and efficient clinical framework for cardiac substructure dose assessment, more effective cardiac sparing strategies can be achieved. Our expertise in deep learning coupled with experience in MR-guided RT has laid the groundwork for this paradigm-changing proposal with the long-term goal of optimal cardiac sparing to ultimately reduce radiation- induced cardiac toxicity. To attain the overall objectives, we propose the following specific aims: (i) develop high quality, efficient cardiac substructure segmentation and accurate synthetic CT generation via deep learning, (ii) quantify respiratory and cardiac-induced cardiac substructure motion using a novel 5D-MRI approach and inter-fraction uncertainties to derive margins and planning strategies for robust cardiac sparing, and (iii) evaluate the clinical efficacy of these emerging technologies in a randomized clinical trial for lung cancer evaluating longitudinal changes in cardiac function from MRI, quality of life, echocardiogram, and blood biomarkers between MR-guided adaptive radiation therapy with sparing and standard x-ray based treatment with whole-heart dose metrics. This multi-disciplinary (oncology, cardiology, radiology, and computer science) proposal integrates state of the art technologies while challenging the standard of care of using whole-heart dose evaluations. The research proposed is innovative as it challenges the current, oversimplified classic model of whole-heart dose estimates via several cutting-edge techniques. The research is significant because of its widespread application in other thoracic cancers including lung, breast, lymphoma, esophageal, and future pediatric cancer trials. Ultimately, the overall positive impact is that our pipeline will yield highly effective cardiac substructure sparing to reduce radiation-related cardiac toxicities and maximize therapeutic gains.

NIH Research Projects · FY 2025 · 2021-08

ABSTRACT Informed by the Eunice Kennedy Shriver National Institute on Child Health and Human Development mission “to ensure the health, productivity, independence, and well-being of all people,” demographic research provides key insights into the population processes that shape health and well-being. Students trained in population science are well-equipped to pursue careers across academic, government, and applied research settings and contribute to advancements in human health and development. There remains, however, a striking lack of racial and ethnic diversity among our PhD programs, researchers, and professional associations that limits the potential of the field. We propose to address this critical challenge with a research education program, NextGenPop, that draws undergraduates from underrepresented backgrounds into population science. This is important both for providing opportunities to students who have been historically marginalized and for generating a body of demographic knowledge that fully reflects the diversity of human populations today. Our proposed program will use the pressing growth of inequality as a lens for studying population composition and change, and our training approach will be structured to support the learning and career advancement of diverse students. It is a collaborative initiative across five universities and will be coordinated by the Population Association of America, guided by an external Advisory Committee and regional partners, and supported by a consortium of population centers within the Association of Population Centers. The broad aim of NextGenPop is to significantly increase the pipeline of scholars from underrepresented backgrounds entering the field of population science. It has three specific aims: Aim 1) to introduce advanced undergraduate students from underrepresented backgrounds to foundational demographic concepts and tools; Aim 2) to integrate students’ training in research and professional development; Aim 3) to foster ongoing engagement of program participants in population research and allied fields. These specific aims will be met through an intensive nine-day summer residential program and an infrastructure for ongoing engagement of program participants. The summer program will be hosted in turn by Wisconsin, Cornell, Duke, UC-Irvine, and Minnesota. It will be governed by a strong central coordinating core and share a common curriculum. Unique signature themes each summer will leverage key research strengths of individual population centers. NextGenPop has extensive institutional commitments from its host institutions, other key contributors in the population profession, and wide-ranging organizations that serve underrepresented students. It promises to have significant and sustained impact on the population field by broadening the pipeline and ultimately expanding the kinds of questions, tools, and conceptual frameworks engaged to advance the science, providing a richer perspective on human health, well-being and development.

NIH Research Projects · FY 2025 · 2021-08

PROJECT SUMMARY Tissue stem cell lineages maintain organ function and respond to dietary and physiological factors, and they also experience intrinsic metabolic shifts as cells differentiate Metabolic/physiological alterations are also linked to a number of diseases, including obesity and cancer. The mechanisms associated with intrinsic metabolic shifts in stem cell lineages and how physiological factors affect them remain largely underexplored. The Drosophila melanogaster ovary is ideal for the study of metabolic changes and their systemic control. Oogenesis is an energy/nutrient-intensive process that precisely links oocyte development through the germline stem cell (GSC) lineage with accumulation of lipids, carbohydrates, and other macromolecules. Developmentally-controlled metabolic changes occur along differentiation of the GSC lineage. Over the past ~18 years, our work has shed light on a multi-organ network that tightly coordinates oogenesis with whole- body physiology. GSCs and their progeny grow and divide faster on nutrient-rich rather than poor diets, and brain insulin-like peptides, Target of Rapamycin, AMP-dependent kinase, the steroid hormone ecdysone, and other factors mediate this response. Other organs also support the nutritional demands of oogenesis. For example, adipocyte lipophorin-mediated transport of lipids is crucial for oocyte yolk uptake, and several other adipocyte metabolic pathways have specific effects in oogenesis. The coordination of hormones, nutrients, metabolism, and highly regulated transitions in the GSC lineage thus integrates information from the diet and other organs. It remains unclear, however, how diet-dependent pathways affect cellular metabolism as cells differentiate along stem cell lineages, and how metabolic disorders (e.g. obesity) alter this complex process. Cellular metabolism is closely tied to nutrient fuel availability and utilization. Major cellular fuels include sugars, fatty acids, amino acids, and ketone bodies, and their availability varies depending on the overall physiological and metabolic state of the organism. Over the next 5 years, we will focus on two major questions in the Drosophila model: 1) How does fuel preference shift as GSC daughters develop through various stages of differentiation and in response to diet-dependent physiological input? 2) How does obesity impact the development of the GSC lineage, its fuel preference, and response to physiological signals? These projects will provide fundamental new knowledge to significantly advance our understanding of the integration between metabolism and physiology in the control of stem cell lineages in vivo, with the potential to inform future research additional stem cell systems and how their metabolic deregulation is tied to diseased states.

NIH Research Projects · FY 2025 · 2021-08

PROJECT SUMMARY/ABSTRACT Language impairments in children have a persistent, lifelong impact on social communication, academic performance, and adaptive behaviors. Two clinical groups particularly impacted by language impairments include developmental language disorder (DLD) and fragile X syndrome (FXS). DLD affects 7-13% of school- age children, and is characterized by pervasive impairments in the grammatical system in the absence of an intellectual disability. Fragile X is the most common inherited form of intellectual disability and males with FXS have significant language impairments. Notably, there is a significant overlap in the language phenotype between DLD and FXS, in terms of grammatical production. This is striking given the difference in general cognitive abilities. Importantly, nothing is known regarding areas of overlap and distinction in grammatical comprehension between the two disorders. Additionally, although these two clinical groups have very different cognitive profiles in terms of IQ, there are overlaps in other aspects of cognition, namely executive function. This is particularly interesting, given evidence of a relationship between executive function and language skills during typical development as well as in children with DLD, however, this work is nonexistent in FXS. Comparative studies between disorders with known (FXS) and unknown (DLD) etiology have the potential to inform both theory and clinical practice. Thus, the proposed study has three specific aims designed to systematically investigate areas of overlap and distinction in terms of language with a focus on grammatical production and comprehension and the association with executive function in children with DLD and FXS in a developmental framework. Through careful investigations we will be able to determine the developmental trajectories of grammatical comprehension and production in addition to EF skills in DLD, FXS, and a language matched group of children with typical development. We will recruit children with DLD (n = 40), children with FXS (n = 40), and children with typical development (n = 60). Children will be matched on clause length to ensure similar language abilities. The proposed study will include a combination of standardized assessments, language samples, experimental tasks, and parent report measures taken at two time points in order to track growth and change during this critical period for grammatical development. The proposed study will yield key information regarding children's comprehension of grammar, change over time, best assessment methods, and critical information on the relationships between executive function and grammatical development. The data collected in this study will be used to inform treatment studies designed to maximize both the effectiveness and efficacy of language learning in DLD and FXS in targeted intervention studies.

NIH Research Projects · FY 2025 · 2021-08

Although hypertension diagnosis is relatively simple and there are cheap and effective medications for lowering blood pressure, less than 40% of patients with hypertension in low- and middle-income countries (LMIC) are aware of their diagnosis and less than 10% have good control of their blood pressure. Community health workers (CHWs) and mobile health (mHealth) technology are increasingly being used in LMIC to fill gaps in hypertension care, but current approaches are too dependent on physician direction. The long-term goal is to increase the number of patients living with hypertension in LMIC who are diagnosed and effectively treated through task sharing with CHWs equipped with mHealth technology. The overall objectives in this application are to 1) develop a mobile application to provide advanced clinical decision support (CDS) for CHWs in Guatemala, a middle-income country; 2) determine the accuracy of CHWs using this application in diagnosing hypertension; and 3) determine the effectiveness of these CHWs thus-equipped in managing hypertension compared to care provided by a physician. The central hypothesis is that CHWs using an mHealth application and remotely supervised can diagnose and manage hypertension with similar accuracy, efficacy, and safety to a physician. The rationale for this project is that demonstration of the efficacy of CHWs using mobile health technology for independent hypertension diagnosis and management would have broad implications for health service delivery in LMIC and the application and care model developed for this proposal could be easily adapted to other settings. The central hypothesis will be tested by pursuing three specific aims: 1) Test the accuracy of CHWs equipped with a mobile application to diagnose hypertension; 2) Assess the feasibility of CHW-led hypertension management enabled by a mobile application; and 3) Determine the efficacy of CHW-led hypertension management aided by a mobile application compared to physician care. Under the first aim, CHWs using the application developed for this proposal will screen patients for hypertension and their diagnostic accuracy compared with that of a physician. For the second aim, CHWs using the application will manage a small group of patients with hypertension to assess intervention feasibility and continue iterative application development. For aim three, a randomized, controlled, non-inferiority trial will be conducted to compare the safety and efficacy of hypertension management by CHWs equipped with the mobile application to physician care. The proposed research is innovative because it represents a substantive departure from the status quo by enabling CHWs to independently identify and treat hypertension with asynchronous physician supervision using a sophisticated mHealth CDS application providing guidance on titration of multiple medications and validated through a rigorous experimental design. This project is significant because it is expected to result in a model of care that would be widely adaptable to low-resource settings around the world, leading to increased diagnosis and treatment of hypertension and reduced cardiovascular disease and death.

NIH Research Projects · FY 2025 · 2021-08

Project Summary/Abstract Metagenomics sequencing is increasingly becoming important for human microbiome research. Human microbiomes comprise a rich ecosystem of beneficial and pathogenic microorganisms and bacteriophages that can influence human health. Yet, bacteriophages remain poorly studied because most bacteriophages cannot be isolated in a laboratory. As a result, cultivation-independent omics approaches such as metagenomics are emerging as important tools for studying bacteriophages directly from mixed communities. However, a significant challenge in virology is the relative absence of high-quality bioinformatics tools to enable the study of bacteriophages from metagenomics data compared to the abundance of such tools available for prokaryotes. We will develop several novel algorithms to enable the study of bacteriophages and their ecology from metagenomics data, including for the discovery of novel uncultivated phages, phage population genomics, phage taxonomy, phage:host and phage:metabolism interactions, and the dynamics of integrated phages. Our approaches will be formalized through the development and release of open access databases and software based on FAIR (Fair, Accessible, Interoperable, Reusable) data principles, which will enable investigation of fundamental questions in bacteriophage ecology governing human health. To demonstrate the utility and wide applicability of our methods to study bacteriophages, we will apply them on a diverse group of metagenome data sets from human microbiomes sourced from publicly available data and several existing collaborations. While our approaches are designed for the study of bacteriophages from metagenome data, they can also be applied broadly towards the study of all viruses including RNA phages from metatranscriptomic data and viruses infecting eukaryotes. Successfully accomplishing this project will provide scalable bioinformatics approaches that can be widely applied to the study of bacteriophages from metagenomics data.

NIH Research Projects · FY 2025 · 2021-08

PROJECT SUMMARY / ABSTRACT In addition to their debilitating impact on health and well-being, multiple chronic conditions (MCCs) account for 90% of Medicare spending. Among beneficiaries, 65% have 3 or more conditions such as diabetes and hypertension, and 23% have 5 or more. MCCs are often addressed in primary care, where time pressures prevent focusing on self-management—although such skills are crucial for living successfully with MCCs. Our long-term goal is to improve health and self-management for these patients, while reducing healthcare costs. An AHRQ-funded P50 supported our development of Elder Tree (ET). That eHealth system was shown in a randomized trial to improve quality of life and health factors among older adults with MCCs who were high users of primary care. ET provides tools, motivation, and support to help patients manage their health. Despite positive results, many did not use ET extensively, a very common problem with health apps. Our central question is whether adapting and delivering ET with voice-controlled technology can increase ET use, thereby improving quality of life and health outcomes even more than ET on a laptop. Smart speakers, used by talking and listening rather than typing and reading, offer the tantalizing but unproven promise of being easy to use, which may in part explain why the technology is being adopted faster than the internet or TV. Smart displays raise expectations even higher by adding a visual element that enables the system to "show" as well as "tell." We propose an R61/R33 project including a randomized clinical trial involving 282 (after attrition) patients age 65+ with 5 or more chronic conditions, 3 of which must be hypertension, hyperlipidemia, obesity, diabetes, or pre-diabetes. In the proposed 12-month trial plus 6-month follow-up, patients will be randomly assigned to receive ET via a laptop (ET-Text) or a smart display (ET-Voice). The project has the following specific aims: Aim 1: During the R61 phase, continue and complete development of the platform and operational procedures for delivering ET to the smart display group. Aim 2: During the R33 phase, conduct a balanced randomized clinical trial to test these hypotheses: Primary outcome: ET-Voice (vs. ET-Text) patients will have better functional health (a measure including physical function, pain, fatigue, sleep disturbance, anxiety, and depression) over time. Secondary outcomes: ET-Voice (vs. ET-Text) patients will have better outcomes for loneliness, number of symptoms, and healthcare use over time. In addition, amount of ET use, ease of use, and usefulness will be higher for the ET-Voice (vs. ET-Text) group. Mediators: Effects of study arm on outcomes will be mediated by ET use at 6 months and by Self-Determination Theory constructs of competence, social relatedness, and intrinsic motivation. Moderators: ET-Voice (vs. ET-Text) will show greater improvements in the primary outcome for: those age 65-74 vs. 75+ years old, women vs. men, those with 8+ vs. 5-7 chronic conditions, and those with more physical barriers to technology use (e.g. tremors). We will explore whether these moderation effects are also observed for the secondary outcomes.

NIH Research Projects · FY 2024 · 2021-08

PROJECT SUMMARY/ABSTRACT Finding novel therapies for treatment of radiation-induced toxicities is of value to not only patients who are receiving radiotherapy for different conditions, but also to national security due to risk of terrorism attacks. There is urgent need to develop therapies than can be administered quickly after exposure to minimize the effects of radiation and enhance immune recovery. Preclinical models have informed a great deal of our current clinical practice in managing acute radiation syndrome (ARS). These models can be used to test and develop new cellular therapies. Choosing the proper cell subset, engineering it to produce the necessary cytokines, and understanding how the cells interact with other hematopoietic and immune cells in vivo after infusion are all critical factors in developing a proper cell-based therapy for ARS. Our group has previously characterized an alternatively activated, high IL-6 producing human macrophage subset called mesenchymal stem cell (MSC)-educated macrophages that can enhance survival from lethal ARS using a xenogeneic mouse model as compared to infusions of MSCs or macrophages alone. We have simplified generation of these cells by using exosomes from lipopolysaccharide-stimulated MSCs to educate monocytes into a radioprotective cell subset. The long-term objectives of this proposal are to use MSC-exosomes to improve the generation and efficacy of radioprotective cells and define their mechanism of radioprotection in preclinical models of ARS. We will test the hypotheses that: (1) LPS-high exosome-educated monocytes (LPS-high EEMos) can mediate radioprotection as an allogeneic cell therapy through production of IL-6; (2) LPS-high EEMos protect the host from ARS by trafficking to radiosensitive organs, like bone marrow, and can be tracked by magnetic resonance imaging (MRI); and (3) LPS-mimetics can be used to stimulate MSC exosome production that generate EEMos through let-7b microRNA secretion. Success of any of the individual aims will be a major advance in understanding how monocytes impact blood cell development after ARS. Translation of the entire proposal will lead to an innovative, mechanistic understanding of a new cellular therapy for treating ARS.

NIH Research Projects · FY 2025 · 2021-08

Project Summary/Abstract Helminths (i.e., parasitic worms) infect all vertebrate taxa. Hosts generally evolve to block, purge, or limit the negative effects of infection, and parasites evolve to hide from or manipulate host physiology. Numerous molecules and cellular pathways are known to modulate interactions between vertebrate hosts and helminth parasites, but little is known about how the evolution of immunity and infectivity influences natural variation in parasite infections. Data on the particular genetic differences that underlie evolved differences in immunity are similarly limited. Over the next five years, my lab will describe the genetic mechanisms and evolutionary history of coevolution between a small fish with abundant ecological and genetic resources, the threespine stickleback (Gasterosteus aculeatus), and one of its cestode parasites. This work is facilitated by lab-based protocols to efficiently intercross cestodes, expose sticklebacks to controlled doses of these pathogens, co-culture host and immune cells in vitro, and assays of host immunity and parasite viability. We can not only identify and measure heritable traits that affect infection specificity and intensity, but also apply modern genetic approaches to dissect the molecular mechanisms underlying this naturally selected variation. Our preliminary data show that threespine sticklebacks repeatedly evolved to block the initial establishment and subsequent growth of cestodes, but that the mechanisms of resistance vary across populations. Cestodes also evolved to counteract the defenses of their local hosts, eventually leading to specialization on a subset of hosts. We will use forward genetics to map the chromosomal loci associated with pathogen-driven host evolution, while crossing diverged cestode populations will uncover loci evolving due to host-driven selection. This work will be complemented with pharmacological and transgenic manipulations of candidate genes and molecular pathways, as well as forays into natural settings where we will use both experimental transplants and time-series data to understand how coevolution varies due to ecological and spatial constraints. Perhaps most exciting, there are several closely related stickleback species and cestode species that, despite millions of years of divergence, remain interfertile, and which enable us to characterize the genetics of coevolution across both micro- and macroevolutionary timescales.

NIH Research Projects · FY 2025 · 2021-08

Breaking neuronal symmetry is a fundamental process in the formation of a polarized neuron. Neurons in the developing cerebral cortex are born as spherical cells that must extend leading and trailing processes to migrate to their destination in the developing cortical plate. Cortical neurons then extend long axons and dendrites from these processes to create functional circuits. Cortical neuron migration and process extension is critically dependent on the microtubule and actin cytoskeleton, but relatively little is known about how the actin cytoskeleton and plasma membrane are coordinated during these events. Membrane protrusion and invagination are fundamental cellular activities that require coordination of the plasma membrane and underlying actin cytoskeleton. However, there is a dearth of data on how membrane protrusion and invagination are integrated in process outgrowth and neuronal migration. The F-BAR superfamily of proteins are involved in membrane curvature sensing and deformation through their F-BAR domain, positioning them as potentially important players in both membrane invagination and protrusion. Structurally, they form a curved dimer that self-multimerizes around endocytic vesicles, causing their elongation into tubules. The CIP4 family of proteins (CIP4, FBP17 and TOCA1) is a group of F-BAR proteins that bind actin-associated proteins. Like other F-BAR proteins, the CIP4 family is thought to function primarily in membrane invagination and endocytosis, but our recent work has implicated CIP4 in neuronal membrane protrusion as well. Lamellipodial-like protrusions induced by CIP4 strongly inhibit neurite outgrowth in culture. Conversely, we find that a close family member, FBP17, forms endocytic tubules in developing cortical neurons and promotes prominent filopodia formation, resulting in precocious neurite outgrowth. In this proposal we will test the novel hypothesis that protrusion through CIP4 and invagination through FBP17 act in opposing manners to regulate cortical neuron migration and process formation in the developing cortex. Specifically, we will: 1) Determine how CIP4 induces membrane protrusions and FBP17 forms endocytic tubules, 2) Establish how membrane tubulation results in precocious filopodia formation and neurite outgrowth, 3) Reveal the spatial and temporal expression pattern of endogenously-labeled CIP4 and FBP17 in mouse lines and 4) Resolve CIP4 and FBP17 function in cortical development in vivo. This work will provide fundamental insights into how proteins that bridge the membrane and actin cytoskeleton function to regulate process outgrowth and cortical neuron migration in the early developing mammalian brain. CIP4 and FBP17 have been implicated in Huntington's disease and several forms of cancer, underscoring the importance of determining the function of these proteins in the developing cerebral cortex.

NIH Research Projects · FY 2024 · 2021-08

PROJECT SUMMARY Up to 5% of hospitalized adult patients on the medical-surgical wards develop clinical deterioration requiring intensive care. Medical errors are common before deterioration events, including delays and misjudgments in identification, diagnosis, and treatment, and these errors lead to increased morbidity and mortality. Therefore, it is critically important to improve the care of high-risk ward patients to decrease preventable in-hospital deaths. The current paradigm for attempting to decrease mortality from deterioration has several limitations. First, most early warning scores designed to identify high-risk patients are based only on vital signs and have limited accuracy. Clinical notes are an underutilized, rich source of information comprising nearly 80% of electronic health record (EHR) data. Natural language processing (NLP) can extract important risk factors from clinical notes for machine learning models to improve accuracy over existing tools. Second, current early warning scores only tell clinicians that a patient is at high risk but provide no information regarding what clinical condition is causing a patient’s deterioration. This leads to diagnostic and treatment errors, which results in worse patient outcomes. Developing tools to enhance diagnostic accuracy for high-risk ward patients could lead to fewer medical errors, decreased costs, and improved outcomes. Third, the initial treatment decisions for deteriorating patients are made by clinicians with limited experience caring for critically ill patients, which can result in delays of potentially life-saving therapies. By utilizing a large, granular, multicenter dataset, algorithms to predict the treatments a patient should receive can be developed, resulting in early, targeted, potentially life-saving therapy. The long-term goal is to develop and implement clinically useful decision support tools to decrease preventable death from deterioration. The overall objective of this project is to develop a clinical decision support tool for the identification, diagnosis, and treatment of patients at high risk of deterioration. This objective will be pursued in the following three specific aims: 1) Develop machine learning models to identify patients at high risk of deterioration using both structured data and unstructured clinical notes; 2) Develop models to predict the diagnosis that is causing the deterioration event and the potentially life-saving treatments that should be provided to high-risk patients; 3) Develop a clinical decision support tool with a graphical user interface incorporating the models from Aims 1 and 2 via user-centered design principles and then test its effectiveness, efficiency, and user satisfaction in a case-based simulation study. This research is innovative because it will utilize NLP, reinforcement learning, interpretable machine learning, and multi-task transfer learning approaches. The proposed research is significant because it will provide clinicians with powerful new tools that can be implemented in the EHR to identify, diagnose, and make treatment recommendations for high-risk patients. This will result in the delivery of early, personalized care to decrease preventable death from deterioration.

NIH Research Projects · FY 2025 · 2021-07

PROJECT ABSTRACT Colorectal cancer (CRC) is the second leading cause of cancer death among U.S. men and women. Racial disparities in CRC survival exist, where the CRC mortality rate for African Americans is 40% higher than the mortality rate for non-Hispanic white Americans. Evidence suggests there may be racial differences in intrinsic CRC tumor biology. We hypothesize that the molecular profile of CRC tumors is more aggressive on average for African Americans than white Americans, and that these tumor differences contribute to the racial disparity in survival. The overarching goal of the project is to define how the CRC survival disparity experienced by African Americans may be influenced by complex biologic differences in tumor characteristics, measured by molecular subtypes, driver gene status, and clinicopathologic markers. The research plan uses molecular epidemiologic and cancer biology approaches to achieve our study aims by leveraging resources from three established research studies, including CRC tumor tissue data from approximately 420 African American CRC patients and 404 non-Hispanic white CRC patients from the Southern Community Cohort Study, the Black Women’s Health Study, and The Cancer Genome Atlas (TCGA). To fulfill Aim 1, we will characterize CRC tumors from white and African American CRC patients for clinicopathologic markers (anatomic site, stage), microsatellite instability, driver gene status (BRAF, and RAS mutation status), and the recently-defined CRC consensus molecular subtypes. The proposed project will be the first study to define CRC consensus molecular subtypes in African Americans. Bioinformatics approaches will identify novel gene- expression molecular subtypes, measured using RNA-seq, to explore the possibility of detecting molecular subtypes that are more prevalent among African American tumors and that may be linked to CRC prognosis. (Aim 2). Lastly, to fulfill Aim 3, associations will be determined between the abovementioned tumor characteristics and CRC survival, and assessed for differences by race. The scientific impact of the proposed study will be to determine the biological mechanisms contributing to CRC survival disparities experienced by African Americans by uncovering the molecular attributes of the tumors themselves. The results of the study will establish the essential foundation for future interventional studies. Currently, CRC treatment is determined by a combination of molecular factors including stage and the presence of somatic mutations. Emerging CRC therapies may be guided by additional tumor factors such as tumor gene-expression or the presence of other targetable features. The existing limited knowledge of the biologic properties of African American CRCs reduces the prospect that precision medicine will be effective. The proposed study aims to provide data on African American CRC tumor molecular profiles to support subtype-specific treatments and precision health strategies to decrease mortality and reduce racial disparities.