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NIA - National Institute on Aging

PROJECT SUMMARY/ABSTRACT Epidemiological evidence links peripheral inflammation to an increased risk of dementia, yet the mechanisms underlying this association remain unclear. Although peripheral immune challenges can amplify neuroinflammation and accelerate cognitive decline, we still do not understand the thresholds required to elicit neuroinflammatory responses that alter neuronal activity, their underlying cellular mechanisms, or how these thresholds and mechanisms change with age. This gap stems from viewing neurons as a passive recipient of neuroinflammatory signals, but also from the use of models with limited relevance. Our long-term goal is to understand how peripheral inflammation interacts with aging to increase the risk of dementia. Prior studies showed that aging sensitizes microglia, making them highly responsive to immune signals and driving exaggerated responses that disrupt synaptic circuits and lead to cognitive deficits. Furthermore, increasing evidence-including our preliminary data-indicates that peripheral inflammation can also directly alter neuronal activity and connectivity. Our proposal builds on this foundation and advances a novel hypothesis: while chronic inflammation directly activates microglia, in acute inflammation, the flow of events begins with neurons. Our preliminary data show that acute inflammation initially alters the activity of inhibitory neurons in key cortical regions. This change may then be detected by microglia, which respond according to their current, age-dependent state by further altering inhibitory synapses and the excitation-inhibition balance. To test this hypothesis, we will use mouse models that mimic common human inflammatory conditions: house dust mite (HDM}-induced respiratory allergy and dextran sulfate sodium (DSS}-induced colitis. Aim 1 will define microglia responses to acute and chronic inflammation as a function of age and will assess whether T cells contribute to increased responses of microglia to acute inflammation in aged mice. Aim 2 will test whether changes in inhibitory activity following acute inflammation trigger microglia activation in aged mice and will define the associated microglial molecular responses. Aim 3 will examine if microglia respond to changes in inhibitory activity by further altering cortical circuits in an age-specific manner. With expertise in molecular, cellular, and circuit neuroscience, inflammation, and imaging, our team is uniquely positioned to carry out this interdisciplinary project. The Pl's past discovery of specific microglia-inhibitory neuron interactions is an additional strength. We will use an innovative approach that combines relevant mouse models, advanced immunological techniques (e.g., adoptive transfer, immune cell depletion), and state-of-the-art neuroscience methods (e.g., calcium imaging, chemogenetics) to test our hypothesis. This research addresses a significant biomedical challenge-understanding how peripheral inflammation affects the aging brain-and has the potential to transform our understanding of neuroimmune interactions in dementia. We will identify key features of microglia-PV neuron interactions following peripheral inflammation and define how they shift with aging. Ultimately, our findings could reveal age-specific therapeutic strategies to reduce the risk of dementia.

NIAID - National Institute of Allergy and Infectious Diseases

Accidental or deliberate radiation exposure of humans remains a major health concern, due to the paucity of medical countermeasures (MCMs) to ameliorate radiation-induced damage. While high dose radiation exposure is generally fatal, even low dose whole body (WBI) or partial radiation exposure can have acute- and/or delayed- negative impacts that appear to act through disruption of the immune system. The cytoreductive effects of WBI have long been exploited in conjunction with chemotherapy as a preparative regimen prior to hematopoietic stem cell transplant in patients with blood cancer to deplete malignant cells and suppress the immune system. While there is strong evidence that radiation kills rapidly dividing cells, a hallmark of the immune system, and induces inflammation that can mediate tissue destruction, the precise nature of radiation induced immune-dysfunction is not well understood. This knowledge gap is a key impediment to development of MCMs to treat radiation exposure. For one example, memory CD8 T cells provide enhanced resistance to re-infection and malignancies. However, most studies in the literature examine the impact of radiation exposure on the capacity of the host’s naïve CD8 T cells to mount a new (primary) immune response and just a few reports have looked at how radiation exposure influences the longevity and protective capacity of pre-existing pathogen or vaccine-induced CD8 T cell memory. Memory CD8 T cell populations have the job of surveying the entire body for signs of re-infection. They accomplish this task using two complimentary and interactive strategies. This first strategy involves populations of memory CD8 T cells that survey the body by using the circulatory system (circulating memory CD8 T cells - Tcircm). The second strategy involves the generation of a population of non-circulating memory CD8 T cells (called T resident memory, Trm), generally in the tissue of pathogen entry. These cells, which persist long-term in tissues, provide rapid detection of re-invading pathogens and then send out mediators to recruit other cells of the immune system to the site of infection. Importantly, our recent data obtained after WBI or partial (targeted) thorax radiation suggest that sublethal ionizing radiation inflicted numerical and functional damage to Tcircm and Trm cells that diminished their ability to provide protection to pathogen-re-encounter. Our long-term goal is to precisely identify mechanisms that govern maintenance, differentiation and function of infection and/or vaccine- induced memory CD8 T cell subsets and explore modalities to recover memory CD8 T cell responses in radiation survivors. We will address our long-term goal through the following specific aims: SA1 - Delineate the tissue-specific impact of WBI on pathogen-specific Trm and evaluate targeted vaccine strategies to restore memory CD8 T cell numbers and function after irradiation. SA 2 - Define mechanisms underlying WBI-induced numerical and functional diminishment of Tcircm and exhausted (Tex) CD8 T cells generated after acute or chronic viral infections.

NIA - National Institute on Aging

Project Summary Aging is a degenerative process resulting in the functional decline across organs. How organs interact to coordinate the aging process is largely unknown, but this knowledge is important in understanding the increasing prevalence of dysfunctions in multiple organs and multi-morbidities with aging. Recent human studies have shown that somatic mutations accumulate in hematopoietic stem cells (HSCs) over time, resulting in expansion of mutated blood cells and a higher risk for not only blood diseases but also myocardial infarctions, strokes, vascular complications of type 2 diabetes, and earlier mortality. These observations suggest that changes in HSCs may impact the functions of distant tissues. In this proposal, we will test the hypothesis that because the blood system supports all tissues, HSC aging can manifest in their progeny and therefore affect distant tissues and organismal aging. We have established a mouse model that reverses HSC aging. We will characterize this mouse model for healthspan and lifespan and decipher the molecular and cellular changes that underlie the alteration in healthspan and lifespan. This proposal is significant because it will address whether and how HSC aging impacts the functions of distant tissues and organismal aging, and improve our understanding of how organs interact to coordinate the aging process. The unique mouse models we have generated provide an opportunity to address this question. Clinic ready compounds will be tested for reversing the effects of HSC aging on tissue functions and organismal aging.

Imperial Oil

Supports STEM education, Indigenous community development, and environmental programs across Canada.

NHLBI - National Heart Lung and Blood Institute

Project Summary Adult human hearts cannot regenerate cardiomyocytes (CMs) to repair the damaged myocardium following injury. Instead, the injured heart undergoes extensive remodeling which may eventually lead to heart failure. Implantation of CMs derived from stem cells into the damaged myocardium has shown promising therapeutic results. One strategy is implanting the human induced pluripotent stem cell (hiPSC) derived cardiac tissue to repair the myocardium. The implanted tissue engrafts with the host heart and reconstructs the damaged muscular tissue. Electrical integration between the implanted graft tissue and the host heart is an important consideration. Proper electrical integration ensures that implanted graft can contract in synchrony with host heart and will not become a source of arrhythmia. A prerequisite for investigating the electrical interaction between the graft and host myocardium is that a substantial number of implanted CMs must survive for a sufficient period in the heart of a clinically relevant large animal model. Additionally, there must be a technical platform to detect the electrical activity of implanted CMs located deep inside the host myocardium. Recently, all these technical prerequisites have been resolved in our laboratory. In our prior study, we found that the implanted hiPSC-CM spheroids can survive in a porcine myocardial infarction model for at least 7 days. With our newly developed technical platform, our prior study highlights two major challenges in host-graft electrical integration: 1, electrical coupling along the host-graft interface is spatially sparse; 2, the in-graft electrical conduction is slow. Poor electrical integration not only impedes functional remuscularization, but also highlights a long-standing concern regarding the pro-arrhythmic effect associated with cardiac cell therapy. In this project, our first goal is to investigate the effects of connexin-43 (Cx43) over-expression to the host-graft electrical coupling. We expect that Cx43 over-expression will promote electrical coupling along the host-graft interface. Our second goal is to improve the compatibility of electrical conduction between the host and graft. We expect that the hiPSC graft with enhanced electrical conduction will be less arrhythmogenic than its wild-type counterpart. To our knowledge, this is the first attempt to directly intervene in the process of electrical integration between engineered cardiac tissue and the host heart in a large animal model. The results of the proposed project will guide a critical translational step toward the future clinical application of cardiac cell therapy.

NCI - National Cancer Institute

PROJECT SUMMARY Our overall objective is to identify the best strategies for lung cancer screening (LCS) in a representative group of people with HIV (PWH). Lung cancer (LC) is now the leading source of cancer mortality among PWH. Unfortunately, most LCs in PWH are diagnosed at a late stage and have very poor survival. Thus, LCS among PWH is needed to stem this growing source of preventable mortality. Two large trials demonstrated that LCS with low-dose chest computed tomography (LDCT) reduced LC mortality among heavy smokers without HIV (PWoH). We have confirmed the benefits of LCS in well-controlled PWH who have a high-risk smoking history and guidelines recommend LCS for PWH. Many issues regarding the optimal indications for LCS in PWH remain unclear, however. Research in PWoH has shown that LC risk prediction models, such as the PLCOm2012 score, are superior to current eligibility criteria for LCS. PWH develop LC with less tobacco exposure and at earlier ages and existing LC risk models have not been developed or tested in PWH, a population for which several unique LC risk factors (e.g., low CD4/CD8 ratio values) exist. Additionally, false positive lung nodules are common in LCS. Robust algorithms to work-up these nodules are critical to minimize the harms of LCS. However, current nodule follow-up protocols do not consider several important factors affecting PWH like an increased rate of false positive screens, follow-up testing complications and competing risks of death. While LCS is recommended for PWH with well-controlled HIV, several other factors such as increased comorbidities and other HIV-related factors that affect life expectancy and quality of life may impact the optimal regimen for LCS in PWH. Therefore, the VACS index, a validated HIV mortality risk index, may be a convenient tool for further improving the screening decision-making process. Our overall goal is to use simulation modeling to improve LCS regimens for PWH. Our Aims are to: 1) Derive and validate an HIV- specific LC risk prediction model; 2) Compare the impact of LCS eligibility criteria based on USPSTF guidelines, existing risk prediction models for PWoH, and a novel HIV-specific LC risk prediction model on LC mortality reduction in PWH; 3) Identify optimal recommendations for management of screen-detected nodules in PWH; and 4) Determine personalized indications and LCS regimens according to HIV-related prognosis (based on the VACS index) and major comorbidities common among PWH (chronic obstructive pulmonary disease, cardiovascular disease and liver disease) that maximize benefits and minimize harms. In Aim 1, we will apply machine learning methods to data from several of the largest US HIV cohorts to derive and validate an HIV-specific LC risk prediction model. For Aims 2 to 4, we will update and use a well-established simulation modeling framework previously developed by our group. Using the updated model, we will evaluate the best criteria for eligibility for LDCT screening in PWH, identify the most effective strategies to work-up screen- detected nodules and assess personalized LCS indications that consider HIV-related prognosis.

NINDS - National Institute of Neurological Disorders and Stroke

ABSTRACT Mild traumatic brain injury (mTBI) or “concussive” injuries are a major societal issue and are associated with activities such as sports, motor vehicle crashes, and falls. Sports-related concussions in children and adolescents (5-18 years) account for between 30-60% of all pediatric concussions. There currently exists no available technology to provide accurate measurement of head impacts in concussive or sub-concussive environments. While a number of head impact exposure devices are on the market or are in development, few of these devices have undergone baseline validation studies to assess the accuracy of their results in biofidelic environments. When events are detected using these systems, there is little support as to whether the data is of a relevant impact or spurious in nature when device deployment is unsupervised. Most existing systems rely on simple acceleration thresholds as a trigger to begin data collection. While such methods are easy to implement and interpret, the trade-off is collection of spurious events above the threshold, and loss of data for events below the threshold. We propose utilizing the Data Acquisition System for Head Response (DASHR) to better understand patterns in head kinematic behaviors leading to and characteristic of head impact in youth football as a mechanism by which relevant and spurious wearable sensor data can be distinguished. We propose leveraging existing DASHR head impact exposure data and video data from prior seasons in concert with prospective data acquired from the DASHR in two upcoming seasons alongside newly acquired high-definition video data. This study benefits from extensive leveraging of existing work stemming from an on-going longitudinal study that the investigators and community collaborators are already engaged in, allowing for additional resources to be devoted to high-definition video acquisition coupled with an overall reduction in the total-price point for comparable studies due to the existing and parallel data sources. These data will be utilized to develop and assess post-processing algorithms using machine learning methods to develop an improved data acquisition pipeline for the DASHR and similar systems more accurately distinguishing relevant impacts from non-relevant events. DASHR data and auxiliary sensor input from the prior four years and the first prospective year will be utilized to train (learning dataset) for the algorithm. Year two of the prospective study will be utilized as a validation dataset to assess the effectiveness of the post-processing algorithm on correctly identifying relevant and non-relevant head impact exposure. The proposed study would be the first to design and develop an algorithm capable of effectively identifying relevant impacts from continuous time-series head kinematic data, using pre-impact behavioral patterns and impact characteristics, with video data as ground truth for validation and assessment.

NIH

Significance to VA: There are few treatment options for Veterans with spinal cord injuries (SCI). Recently the Tuszynski lab has developed an approach where neuronal stem cells are implanted into the injury site. These grafted cells differentiate into neurons which extend axons caudally to form synapses with the host; simultaneously, host axons enter the graft and form synapses with graft neurons. This system restores connectivity across the lesion site and improves functional recovery in rodent and primate models. However, recovery is incomplete, in part because of only partial growth of host axons into and within the graft. Innovation and Impact: This CDA-1 proposal will use a new path to enhance the graft by exploiting the existing biology of the graft to enhance its functionality. Specifically, it will explore the role of axonal guidance cues (secreted molecules that attract or repel growing axons) in the graft and manipulate these cues to increase host axon growth into the graft and improve connectivity across the injury site. The Tuszynski lab is currently beginning the process of clinical implementation of our graft system. Success in this project and follow-up work in a CDA-2 award will lead to approaches which can be used to improve the functionality of grafts to improve recovery for SCI patients including Veterans. Specific Aims: This proposal will test the hypothesis that a mismatch of secreted guidance cues may limit host axon regeneration into the graft. This proposal will target mechanisms associated with axon growth into stem cell grafts and test whether modifying guidance cues will increase host axon regeneration into the graft. Aim 1 will focus on reducing the inhibitory effects of the injury site. Injury sites express Wnts which inhibit the growth of corticospinal tract (CST) axons via binding to the Ryk receptor. This aim will test the hypothesis that neutralization of the inhibitory effect of Wnts will increase CST axon growth into the graft. Aim 2 will focus on increasing the attractive environment of the graft. Axons that enter the graft grow towards appropriate interneuronal targets, indicating that some attractive cue exists; however, the relatively short distance of growth within the graft (1-2 mm) suggests that the effects of this cue are limited. A viral labeling and sequencing approach will be used to identify and validate these attractive cues released by the graft. Methodology: Both Aims will be performed in mice using a C4 contusion model of spinal cord injury. Regeneration of host CST axons into the graft will be assessed with histology (N=12 per group). Functional recovery following SCI will be assessed with behavioral performance on a skilled reaching task (N=30 per group). Treated animals will be compared to our current grafting paradigm to determine if these treatments improve the efficacy of the graft in recovery following SCI. Path to Translation/Implementation: Treatments for spinal cord injury are currently limited, and success of this proposal may increase the effectiveness and therapeutic potential of stem cell grafts. While work in this proposal is limited to mouse grafts, future work in a CDA-2 award would test any treatments identified here in human cell grafts which could then be implemented as part of a clinical product to treat Veterans with SCI. The proposed project will provide excellent research training for the applicant including systems neuroscience, spinal cord injury, and human disease. Additionally, he will learn multiple techniques including rodent models of SCI, mouse behavioral assessment, and RNA sequencing. The research environment of the Tuszynski lab is highly collaborative so he will gain exposure to many techniques and subject areas beyond his own research, refine his scientific presentation skills, mentor younger scientists, and network with leaders in the field. Finally, he will directly engage with Veterans by shadowing doctors at the VA San Diego Medical Center while they treat Veterans recovering from SCI. Overall, this CDA-1 grant will provide new insight into novel therapeutic avenues for spinal cord repair and allow the applicant to transition into a career as an independent investigator at the VA.

NIH

Rotator cuff tearing, a pervasive age-related shoulder injury, imposes a substantial burden on millions of patients in the United States, particularly within our aging Veteran population. Up to 20% of individuals over 50 exhibit symptomatic rotator cuff tears, and nearly half of those aged 70 or older are grappling with this condition. Shoulder pain and dysfunction emerge as the major symptoms for patients with rotator cuff tears. While non-surgical treatments prove effective for smaller tears, the management of larger or massive rotator cuff tears demands surgical repair. Poor muscle quality stands out as a critical contributor to the failure of rotator cuff tendon repairs, emphasizing the pivotal role of enhancing muscle quality for advancing clinical outcomes in patients with rotator cuff repairs. In the past decade, our laboratory has been at the forefront of unraveling the complexities of rotator cuff muscle degeneration and regeneration. Our groundbreaking studies have elucidated the role of muscle stem cells, specifically fibro/adipogenic progenitors (FAPs), in this context. Notably, our findings in both mice and humans have demonstrated the transformative potential of inducing FAP brown/beige fat (BAT) differentiation and horizontal mitochondria transfer toward myocytes. These mechanisms effectively reduce muscle degeneration and promote shoulder function post-rotator cuff tears. Though the detailed mechanism remains unknown, blood flow restriction (BFR) therapy, a method that temporarily limits blood flow in limbs, emerges as a promising intervention in reducing muscle atrophy and musculoskeletal pain. Our recent endeavors to unlock this mystery have uncovered the potential benefits of BFR in stimulating FAP BAT differentiation and horizontal mitochondria transfer during muscle regeneration. Adding to our arsenal of innovation, we've developed a low-cost tool employing machine learning techniques to quantitatively assess shoulder function. This tool, analyzing hand-over-hand string-pulling motions, provides a reliable means of evaluating shoulder health in both animal models and human subjects with rotator cuff tears. Additionally, our novel machine-learning approach utilizes the Blackbox® system to measure mechanical pain in mice following rotator cuff tears, offering a nuanced understanding of pain dynamics. Looking ahead, our proposed study aims to push the boundaries of innovation further. In this proposed study, we aim to define the role of BFR in a preclinical rotator cuff tears and repair model to evaluate the effectiveness of BFR in stimulating FAP BAT differentiation and mitochondria transfer, reducing muscle atrophy and degeneration, enhancing shoulder function, and alleviating pain. This groundbreaking research aligns with our vision of translating innovative findings from the laboratory to future clinical trials, promising impactful outcomes for patients with rotator cuff tears, particularly within the aging veteran population.

NIH

Significance to VA: Every year, nearly 2 million Veterans undergo prostate-specific antigen (PSA) screening for prostate cancer within VHA. Despite widespread use, current screening practices are inconsistent and inefficient, leading to unnecessary biopsies, overtreatment, and missed opportunities for early intervention. These inefficiencies stem from the uncoordinated nature of the screening care cascade—a series of complex, multistep decisions involving screening timing, follow-up imaging, biopsies, and treatment choices. Prior attempts to improve PSA screening in VHA have focused on isolated steps within the cascade, missing critical interdependencies and failing to identify where improvement is most needed. To optimize outcomes, a comprehensive understanding of the entire care cascade is essential. One promising alternative approach is microsimulation, which simulates millions of patients as they undergo screening, diagnosis, and treatment for prostate cancer (i.e., the entire care cascade), allowing analysis of complex care decisions in an integrated, system-wide context. This approach is widely used to inform national cancer screening guidelines for this very reason. The overall objective of this proposal is to develop a VHA-specific microsimulation model of prostate cancer care, enabling rigorous identification of potential improvement opportunities, development of high-impact strategies tailored to VHA, and a detailed accounting of benefits and harms. This work is significant because it would be an enormous leap forward in VHA's ability to identify, analyze, and address opportunities to improve complex, multi-step cancer care pathways through microsimulation. This would result in a methodological toolbox that could be applied to other cancer care pathways and produce concrete benefits for the millions of Veterans undergoing PSA screening each year. Innovation and Impact: The research in this CDA is innovative because it would be the first use of microsimulation to identify opportunities for improvement in a VHA cancer care pathway and develop evidence- backed strategies to address them. This work has the potential to revolutionize how VHA develops and prioritizes cancer screening quality improvement initiatives by enabling VHA to identify the highest-impact strategies and allocate scarce resources accordingly. Specific Aims: Aim 1: Describe facility-level variation and potential improvement opportunities in PSA screening care cascades. Aim 2: Adapt an established microsimulation model to reflect current VHA prostate cancer care. Aim 3: Develop and refine high-impact strategies to improve PSA screening cascades. Methodology: Aim 1 will explore facility-level variation of key steps in contemporary VHA screening cascades, assessing drivers of this variation and focusing on patterns indicating potential overscreening of low-benefit Veterans, underscreening of higher-benefit Veterans, and inefficiencies in biopsy and treatment practices. This will identify potential opportunities for improvement and direct Aim 3 intervention assessments. Aim 2 will adapt an established, NCI-funded microsimulation model to reflect VHA-specific prostate cancer care, incorporating facility-level differences and unique Veteran risk factors and enabling simulation of improvement strategies. Aim 3 will use the VHA-specific microsimulation model to test and refine strategies, such as adjusting screening intensity by age and risk level or using pre-biopsy MRI. To ensure they are impactful and feasible, the most promising strategies will then be refined through a modified Delphi expert panel of multidisciplinary stakeholders, Path to Translation/Implementation: The project will yield a set of evidence-based strategies for improving screening efficiency and patient outcomes, tailored to address the specific inefficiencies in current VHA care cascades. These insights will be disseminated through professional channels, including through multiple research publications and presentations, seeding an effort to establish a VHA prostate cancer screening learning community focused on implementation and iterative refinement of model-informed interventions.

U.S. National Science Foundation

The Improving Undergraduate STEM Education:Computing in Undergraduate Education (IUSE: CUE) program aims to better prepare a wider, more diverse range of students to collaboratively use computation across a range of contexts and challenging problems. With this solicitation, the National Science Foundation focuses onre-envisioninghow to teach computing effectivelyto a broad group of students,in a scalable manner, with an emphasis on broadening participation of groups who are underrepresented andunderservedby traditional computing courses and careers.

Indiana Department of Education

STEM education initiative grants for IN to expand science, technology, engineering, and mathematics programs in K-12 and postsecondary institutions.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Project Summary/Abstract For patients with neuropathic bladder from spina bifida or spinal cord injury, the current surgery of using intestine for bladder augmentation causes high morbidity, as well as short- and long-term complications. A recent clinical trial using bioengineered bladder wall showed the feasibility and relative safety of bioengineering bladder wall but failed due to dehiscence and graft contraction from ischemia. While these grafts were engineered from synthetic matrices and autologous urothelium and muscle, they had no blood vessels. Angiogenesis from the patient’s bladder is not fast enough to prevent large graft necrosis since early imbibition and perfusion are limited to the outer perimeter of the graft. As shown in murine and porcine models, bladder vessels will connect (inosculate) with graft vessels within a few days after transplantation to the bladder and facilitate blood flow to the entire graft. Thus, engineering vessels in a large animal bladder graft and evaluating these grafts are the next and final steps before development of grafts for clinical testing. To vascularize matrix grafts, others are trying to “endothelize” grafts by soaking them with stem cells and growth factors in vitro, which creates capillary-like structures rather than organized vessels with lumens. This proposal employs a different strategy where grafts are cellularized and vascularized in vivo on the rectus muscle bed. This ensures optimum graft maturity and a healthy and functional vasculature prior to bladder transplantation. The current proposal is to build upon successes in the rodent and porcine models to design and test endothelial cell ligands to enhance endothelial adhesion and angiogenesis (Aim 1), to evaluate a novel strategy to create long, coronally-directed vessels in large grafts (Aim 2) and to then transplant these matured grafts to the bladder after partial cystectomy in pigs (Aim 3). Grafts will be analyzed grossly to determine size and histologically to determine vessel density, length, perfusion, endothelial/vascular maturity, and epithelial and stromal differentiation. Graft vessel function will be analyzed via perfusion of dyes into the blood stream. Graft function will be assessed by urodynamics to measure bladder capacity and compliance, and by standard biomechanical testing for material and viscoelastic properties. The long-term, translationally directed goals for this project are to produce and evaluate a vascularized graft in a large animal model and to develop vascularized grafts for patients with spinal anomalies or injury. Since bioengineering human bladder wall has proven feasible but not safe or efficacious due to insufficient blood supply, this project has the potential to make bioengineered bladder a realistic treatment option. The directed vascularization technologies developed in this project could be used to improve engineering of other organ tissue.

NCI - National Cancer Institute

ABSTRACT Glioblastomas (GBMs) lack critical innate immune context for productive T cell immune surveillance. Our team developed a live-attenuated recombinant poliovirus, PVSRIPO, that induces MDA5-mediated, sustained type-I interferon (IFN-I) responses in tumor-infiltrating myeloid cells to elicit productive antitumor T cell immunity. I.t. PVSRIPO infusion yielded long-term survival in a subset of recurrent (r)GBM patients (~20%, vs 4% in criterion- matched controls at 3 years) in two independent clinical trials. Long-term survival after PVSRIPO was associated with higher pre-treatment intratumor myeloid and MHC-class II (MHC-II) signatures, baseline inflammation (IL- 1 , TNF) and MHC-II+ monocytes in blood, and IFN-I induction after PVSRIPO infusion. Similarly, IFN-I responsiveness to PVSRIPO in patient-derived GBM ex vivo cultures associated with myeloid inflammatory signatures at baseline. Thus, the induction of IFN-I responses to virotherapy is linked to baseline myeloid inflammation and may determine virotherapy efficacy in patients with rGBM. Environmentally sculpted bone marrow (BM)-resident hematopoietic stem & progenitor cells (HSPCs) have been shown to predetermine antiviral responsiveness of their progeny myeloid cells. In rGBM, intra-patient myeloid profiles are maintained in tumor and blood across multiple time points, implying such durable mechanisms may control systemic myeloid biology. Serendipitously, we discovered that intramuscular (i.m.) vaccination against antigens not expressed by the tumor alters HSPC phenotype and rescues the antitumor efficacy of i.t. immunotherapy (PVSRIPO and STING agonist) in otherwise resistant models. I.m. vaccination caused vaccine-specific CD4+ T cell accumulation, sustained (>1 month) HSPC proliferation and IFN-I signaling, and dendritic cell (DC) progenitor expansion in the BM. These changes were accompanied by higher MHC-II and IFN-I signaling at baseline and stronger IFN-I responses to PVSRIPO therapy in glioma infiltrating DCs. Antitumor effects of i.t. immunotherapy after i.m. vaccination depended on IFN-I, T cells, and MHC-II epitope, and were not reproduced by -glucan—a canonical inducer of trained immunity. Thus, modulating HSPCs may induce antitumor myeloid functions and improve virotherapy sensitivity in gliomas. We hypothesize that IFN-I induction predicts survival after virotherapy, associates with baseline myeloid and HSPC status, and is improved through peripheral vaccine-mediated HSPC modulation. We will test this hypothesis by defining the relationships between IFN-I induction, baseline innate inflammation, HSPC phenotype, and survival after virotherapy in patients with rGBM; determining how HPSC modulation after i.m. vaccination occurs and defining its role in promoting glioma i.t. immunotherapy; and testing whether i.m. vaccination may serve as a novel route to engage cDC1 functions. These studies will define determinants of effective rGBM virotherapy, elucidate the impact of HSPC imprinting on glioma infiltrating myeloid cells, and will test HSPC modulation as a route to engage antitumor myeloid functions.

U.S. National Science Foundation

The Innovations in Graduate Education (IGE) Program is designed to encourage development and implementation of bold, new, and potentially transformative approaches to STEM graduate education training. The program seeks proposals that a) explore ways forgraduate students in STEM master s and doctoral degree programs to develop the skills, knowledge, and competencies needed to pursue a range of STEM careers, or b) support research on the graduate education system and outcomes of systemic interventions and policies. IGE projects are intendedto generate the knowledge required for the customization, implementation, and broader adoption of potentially transformative approaches to graduate education. The program supports piloting, testing, and validating novel models or activities and examining systemic innovations with high potential to enrich and extend the knowledge base on effective graduate education approaches. The program addresses both workforce development, emphasizing broad participation, and institutional capacity-building needs in graduate education. Strategic collaborations with the private sector, non-governmental organizations (NGOs), government agencies, national laboratories, field stations, teaching and learning centers, informal science organizations, and academic partners are encouraged.

NCI - National Cancer Institute

SUMMARY/ABSTRACT The Problem: Cancer cells often reside in environments deprived of growth factors and nutrients. Yet they thrive by rewiring their signaling through autocrine and paracrine “secrete-and-sense” circuits, enabling self- sustaining growth. This phenomenon, known as growth signaling autonomy, is one of the earliest recognized hallmarks of cancer and central to cancer stemness, tumor progression, and treatment resistance. However, the core molecular mechanisms driving these circuits remain poorly defined, limiting therapeutic progress. Central premise: Our data identify GIV (Gα-interacting vesicle-associated protein) as a master regulator of cancer cell signaling autonomy. GIV is a multimodular scaffold protein that integrates signaling across monomeric and heterotrimeric G proteins—elements typically studied in isolation—into a coherent, feed-forward signaling circuit that sustains EGF/EGFR-dependent growth. Endogenously expressed in many breast cancers, particularly triple-negative breast cancers (TNBCs), GIV enables cells to sustain tumor progression under nutrient- and growth factor-limiting conditions. In contrast, ER+ BCs, which often lack endogenous GIV, acquire it via intercellular transfer from stromal neighbors, highlighting a novel mode of proteomic exchange. We hypothesize that GIV promotes cancer stem cell-like states, tumor growth, and drug resistance under nutrient- and growth factor-limited conditions. GIV-dependent cancer cell signaling autonomy may also extend to neighboring GIV-deficient cancer cells via paracrine signaling, enhancing cooperative growth among heterogeneous cancer cell populations. Our team—experts in breast cancer biology, GIV signaling, and in the use of both animal and non-animal models (patient-derived organoids and tissue microarrays) alongside synthetic biology tools (cells with engineered circuits) and quantitative live-cell imaging—is uniquely positioned to test this model through integrated experimental and computational approaches. Our aims are to discover how GIV’s modular domains orchestrate key states of cancer cells driving tumor progression in the setting of: (1) intrinsic autonomy in GIV-expressing TNBCs or (2) intercellular transfer- dependent acquired autonomy in ER+BCs; and 3) establish the cooperative dynamics by which GIV-expressing autonomous cells support non-autonomous GIV-deficient neighbors in heterogeneous tumors. We leverage human organoids and tissue microarrays to preserve translational potential and ensure clinical relevance. Impact: This work will redefine cancer signaling by identifying the first mechanistic framework of secrete- and-sense growth factor autonomy within the EGF/EGFR pathway. It will also chart how a single intracellular hub (GIV) coordinates autocrine and paracrine signaling across diverse cell populations to drive tumor progression. By mechanistically linking cancer growth signaling autonomy to stemness, plasticity, tumor heterogeneity and therapeutic resistance, our findings will uncover new intervention points and provide a transformative conceptual advance in targeting signaling rewiring in breast cancer and beyond.

NHLBI - National Heart Lung and Blood Institute

Project Summary: Genetic heart disease is associated with heart failure and arrhythmias, which can lead to significant morbidity and mortality. Small animal models of genetic heart disease often fail to capture the clinically relevant features of the disease. Patient- and gene-specific therapies, such gene therapy, gene editing, and exon skipping are making their way into the clinic and are in development. In many cases, genetics has provided a clear understanding of underlying patient-specific disease mechanisms by linking a patient’s disease to a specific gene variant. However, individualized therapeutic strategies lag behind this understanding. Recognizing the limitations of animal models, the FDA Modernization Act 2.0 (2022) and subsequent FDA regulatory guidance (2024) now allow for the use of non-animal models including cell- and organoid-based models to assess therapeutic and efficacy. Patient-specific human induced pluripotent stem cells (hiPSCs) can now be readily created from patient cells such as those obtained via a standard blood draw. These cells can then be differentiated in heart-like cells to created hiPSC-derived cardiomyocytes (hiPSC-CMs), offering an platform to test personalized, genotype-specific therapies for heart disease in vitro. HiPSC-CM models can be further improved by using them to create heart-like tissues in the dish, known as engineered heart tissues (EHTs). Commercial platforms now support the creation of these tissues, and contractility measurements can be obtained non-invasively, enabling therapeutic assessment. However, arrhythmia assessments in EHTs remain limited due to the need for specialized optical equipment, the use of toxic contraction inhibitors such as blebbistatin, the need for voltage-sensitive dyes, and the terminal nature of current experimental protocols, which restrict the ability to track therapeutic effects over time. We have recently developed an electromechanically monitored EHT (emEHT) platform that enables simultaneous measurement of contractility and field potentials. This platform leverages flexible electronics technology to noninvasively and concurrently detect electrical signals and assess tissue forces. We have previously demonstrated the ability to simulate arrhythmias using electrophysiology protocols adapted from the clinic with this system. This proposal aims to develop a next-generation emEHT platform capable of simultaneously assessing action potentials and calcium transients in a non-invasive, non-terminal format through the integration of flexible electronics embedded with optical microsensors. Additionally, we aim to develop the molecular tools necessary to leverage this emEHT platform, including the stable expression of genetically encoded voltage and calcium sensors. The platform will be validated against traditional optical mapping techniques and tested using hiPSC-CMs derived from an arrhythmic form of cardiomyopathy. The development of this platform holds transformative potential for assessing arrhythmia propensity in EHTs, ultimately enabling the evaluation of the functional consequences of genotype-specific cardiovascular therapeutics in the dish.

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY/ABSTRACT The three-dimensional organization of eukaryotic genomes plays a crucial role in transcriptional regulation and cellular functions. However, current genome structure models, primarily derived from genomic data, have significant limitations. They lack precise physical dimensions, fail to capture nuclear morphologies accurately, and are constrained by a resolution limit of approximately 200 kb—insufficient for studying interactions between regulatory control regions. These shortcomings hinder the use of 3D genome structures in understanding gene regulation and cellular processes. Recent advances in imaging technologies have provided powerful tools to explore 3D genome organization. In this project, we will develop a probabilistic approach to integrate genomic and imaging data to reconstruct 3D genome structures from thousands of imaged nuclei. We have three aims: (1) Develop integrative methods for inferring high-resolution single cell genome structures from sparse imaging and multi-omics data. This integration minimizes experimental biases and improves resolution and coverage by 100-fold compared to imaging alone. Our approach will offer unprecedented insights into the structural basis of gene regulation, enhancer networks, and the role of chromatin architecture in epigenetic memory formation—insights unattainable through single-cell genome-wide imaging or genomics data alone. (2) Structure-Function Mapping by analyzing the 3D regulatory architecture. We will analyze the 3D regulatory environment of genes in mouse embryonic stem cells and the reorganization of the microenvironment surrounding cell-type-specific long genes in the mouse brain cortex. For the first time, we will systematically classify genes based on their 3D regulatory microenvironment and investigate its role in gene expression. (3) We will expand our Integrative Genome Modeling (IGM) platform to incorporate imaging- based features. The platform generates a population of genome structures to reproduce the input experimental data. We will dedicate significant effort to improve user experience and enhance computational efficiency.

NIMHD - National Institute on Minority Health and Health Disparities

MODIFIED PROJECT SUMMARY/ABSTRACT SECTION As a result of effective HIV therapy, the proportion of people with HIV (PWH) living to at least 50 years of age increased from 27% in 2006 to 58% in 2020. An unintended consequence of this aging is that chronic diseases such as cancer are now increasingly common. In the US, PWH with cancer are over twice as likely to die due to cancer compared to cancer patients without HIV, with a disproportionate impact of the US HIV epidemic in the Southeastern US. Herein, we posit that HIV-associated cancer outcomes differences are driven in part by biological changes resulting from exposure to individual-level (e.g., perceived job stress) and neighborhood-level (e.g., proportion of residents below national poverty line) factors (referred to collectively as multi-level stressors). Recent data from our study team demonstrate that, compared to cancer patients without HIV, PWH with cancer have epigenetic (DNA methylation) patterns indicative of accelerated aging and a higher prevalence of somatic mutations that clonally expand in the hematopoietic compartment as individuals age (clonal hematopoiesis). Importantly, each of these genomic aging biomarkers have been associated with inferior survival among PWH with cancer, but their association with multi-level stressors remains unexplored among PWH. We propose to address this research gap, specifically the lack of empirical evidence testing the hypothesis that accelerated aging, stemming from exposure to multi-level stressors, is a mediator of poor cancer outcomes among PWH and cancer in the US. To accomplish this, we will leverage existing infrastructure to prospectively identify 500 cancer patients (250 PWH, 250 people without HIV [PWoH]) from Moffitt Cancer Center and 250 PWH without cancer from an existing partnership with the HIV FIGHTER registry at the University of South Florida. The inclusion of PWH without cancer from FIGHTER, as well as cancer patients without HIV from Moffitt, will help elucidate whether the impact of multi-level social stressors on the genomic aging process is uniquely exacerbated by the presence of both chronic HIV infection and a cancer diagnosis. Our aims are: Aim 1. Examine the association between multi-level stressors and epigenetic age acceleration in the presence of HIV and cancer; Aim 2. Examine the association between multi-level stressors and the prevalence of age-related clonal hematopoiesis in the presence of HIV and cancer; and Aim 3. Estimate direct and indirect effects of multi-level stressors on mortality among PWH and cancer, accounting for the mediating role of accelerated aging. The successful completion of our project will: (1) provide descriptions of the magnitude of the association between multi-level stressors and mortality among PWH with cancer in the US Southeast, which is currently unavailable; (2) elucidate biological mechanisms (accelerated genomic aging) through which multi-level stressors contribute to poor cancer outcomes among PWH; and (3) create a clinic-based cohort with biological specimens, augmented with contextual individual and neighborhood-level data, to support studies on cancer and aging among PWH.

NIA - National Institute on Aging

PROJECT SUMMARY Alzheimer’s disease (AD) is an aging-related incurable neurodegenerative disorder, which a slow but irreversible cognitive decline leaves patients unable to take care of themselves and eventually leads to death in 5-10 years after the diagnosis. About 40 million people worldwide have developed AD and this number is expected to double in the next 20 years. it is imperative that novel solutions are found for the prevention and treatment of AD. Although the disease mechanism remains unknown, through large cellular atlases and the single cell molecular profiling, several types of disease associated cell subtypes, such as disease associated microglia and astrocytes have been found to contribute to the disease etiology or progression. However, despite all these years of research, there is still no effective treatment for AD. With the advance of real-world data (RWD) analysis from large databases of electronic medical records, drug repurposing has become a viable option to address this urgent need for AD drugs. Our project addresses these needs by combining all three of these approaches into a single proposal so that the molecular profiles of high-risk cellular subpopulations, drug repurposing studies, and cell line based mechanistic studies can be leveraged together to find repurposable drug(s) on targetable cell populations in the brain. Specifically, we will apply deep transfer learning models developed by our group to identify the most high-risk subpopulations of cells that are related to clinical and pathological features of AD and use these subpopulations to pick the most similar induced pluripotent stem cell (iPSC)-derived neural cell lines for validation. Simultaneously, based on large RWD cohorts of AD patients, repurposable drug candidates will be identified and tested on human iPSC-derived neural cell lines to validate their causal effects. Specifically, by using the most high-risk cell types and drug candidates identified in this study, these combinations will be tested using cell culture and co-culture assays to detect the effects of these drugs on identified cell types and their effects on neuron loss. When an effect is found, these cultures will be sequenced at single cell resolution to phenotype the cellular response and further pinpoint the cell subtypes that are responsible for the phenotype. Finally, the results of the iPSC culture assays will be used to inform our deep reinforcement transfer learning models of single cell data and our drug repurposing algorithms of RWD via hidden confounder debiasing, resulting in improved future predictions. With this feedback architecture of the reinforcement learning approach, we will be able to develop predictive deep learning models with higher accuracy on cell subtypes that are tightly associated to AD-related clinical and pathological features, while at the same time identify repurposable drugs with direct effect on brain cell subtypes that are linked to AD.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY/ABSTRACT The global population is aging rapidly, with the number of people over 65 expected to double by 2050. Aging alters hematopoietic stem cells (HSCs), leading to increased inflammation, immune dysfunction, and clonal hematopoiesis. These changes have been linked to hematological disorders, cardiovascular disease, and other age-related conditions. Dissecting the contribution of human HSC heterogeneity to these disorders has been accelerated by single-cell RNA-sequencing and the development of new algorithms to derive of biologically meaningful insights. These algorithms include consensus non-negative matrix factorization (cNMF) and CellAnnoTator (*CAT), which aim to identify consensus gene expression programs that shape cellular heterogeneity across datasets. However, these algorithms have not been applied to human HSC aging, and the circuitry that controls their role in aging and disease remains poorly understood. There is a here is a critical need to identify the molecular programs that drive age-associated changes in human HSCs. The long-term goal is to mitigate age-related immune dysfunction and its associated diseases. The central hypothesis is that inflammatory signaling is a principal driver of human HSC heterogeneity and that AP-1 factors define an HSC subset that expands with age. To test this hypothesis, the investigators will pursue two specific aims: 1) Identify age-associated changes in HSCs across eleven existing datasets, and 2) Determine how consensus gene expression programs shape HSC heterogeneity and relate to aging. For Aim 1, the working hypothesis is that aging HSCs exhibit consistent gene expression changes, including AP-1 activation in a subset that expands with age. Using publicly available datasets, the investigators will identify conserved gene expression and transcription factor activity changes and leverage single-cell data to quantify an aging-associated subset of inflammatory HSCs. For Aim 2, the working hypothesis is that applying cNMF and *CAT within a unified analytical framework will identify biologically meaningful gene expression programs that underlie HSC heterogeneity, including inflammatory pathways linked to aging. The investigators will identify consensus gene expression programs in HSCs, assess their association with age and inflammation, and develop an R-based computational pipeline for broader community use. The expected outcome is the discovery of programs and genes, led by AP-1, that shape heterogeneity of human HSC aging across datasets. The proposed research is innovative because it shifts from evaluating the human HSC compartment as a whole to linking a distinct HSC subset to aging and because it applies an advanced analytical framework to identify consensus gene expression programs shaping HSC heterogeneity. The significance of this research is that it will establish a foundation for predicting how HSC aging impacts immune fitness, systemic inflammation, and cardiovascular risk.

Intel Foundation

Funds STEM education programs for K-12 students, with emphasis on increasing access for underrepresented groups in technology.

NIGMS - National Institute of General Medical Sciences

Tulane University was started as the Medical College of Louisiana in 1834 and has a long track record of training physician scientist leaders in US Medicine including Dr. Michael DeBakey, Dr. Ruth L. Kirschstein, past Director of NIGMS and NIH, and Dr. Clyde Yancy, Chief of Cardiology at Northwestern University. Recognizing the need to train the next generation of physician scientists, the Dean established the Physician Scientist Program in 2002 that provides tuition support for 2 trainees per year from the Dean’s office. Over 90% of these trainees have stayed in academic research and some of the trainees have been awarded independent research grants already. Tulane has made a strong commitment to research with establishing the American Association of University (AAU) recruitment program that has led to the recruitment of several AAU scholars that have increased Tulane’s investigator initiated R01 funding by over 70% in the last five years. Moreover, President Fitts has established the Presidential Chairs of which two reside in the School of Medicine. This strategic investment has greatly increased the training opportunities for MD-PhD students. Recognizing the need to expand this program, Tulane has developed this MSTP application to take advantage of the exceptional training faculty in the School of Medicine, the School of Public Health, and the School of Science and Engineering. This program takes advantage of several pipeline programs already established at Tulane to target STEM based students in clinical and bench research and provide these undergraduates, the skillset to be competitive applicants to the MSTP program. Moreover, this program will complement the NHLBI funded R38 that focuses on the resident pipeline. The goal of TuLEAD is to train a cohort of MSTP students in innovative research in the areas of infectious disease, immunology, cardiovascular and renal physiology, and pharmacology. Aim 1: Tulane MSTP will develop a highly innovative national and local campaign to identify and encourage meritorious students to train as physician scientists and provide them with rigorous dual degree training in clinical medicine and in wet-lab or dry-lab (or both) research. Aim 2: We will train clinician-scientists with the necessary qualifications to conduct rigorous scientific research and engage in clinical and translational research across the spectrum of human disease. Training will be a through a combination of didactics, simulation, and state of the art rigorous research training. Aim 3: A key component of physician scientist development is not only learning and conducting rigorous research but to also serve as educators for the next generation. With the interaction of this program with Tulane’s undergraduate programs we well our summer research programs, MSTP trainees will also have the opportunity to serve as mentors. We have strong relationships with several undergraduate universities in New Orleans (such as Dillard University), and an established summer program for their undergraduates to work in Tulane laboratories, with current MD/PhD students mentoring one on one.

U.S. National Science Foundation

The International Research Experiences for Students (IRES) program supports international research and research-related activities for U.S. science and engineering students. The IRES program contributes to development of a diverse, globally engaged workforce with world-class skills. IRES focuses on active research participation by undergraduate and/or graduate students in high quality international research, education and professional development experiences in NSF-funded research areas. The overarching, long-term goals of the IRES program are to enhance U.S. leadership in science and engineering research and education and to strengthen economic competitiveness through training the next generation of science research leaders. IRES focuses on the development of a world-class U.S. STEM workforce through international research experiences for cohorts of U.S. students. Student participants supported by IRES funds must be citizens, nationals, or permanent residents of the United States. Students do not apply directly to NSF to participate in IRES activities. Students apply to NSF-funded investigators who receive IRES awards. To identify appropriate IRES projects, students should consult the directory of active IRES awards. All PIs, co-PIs and Senior Personnel on IRES proposals must be from U.S. based organizations. Personnel from international partners should be listed as "non-NSF funded collaborators." Guidance on information to provide for "non-NSF funded collaborators" is found in Section V.A. IRES projects engage a group of undergraduate and/or graduate students in active high-quality collaborative research, in principle at an international site with mentorship from international researchers. IRES projects must be organized around a coherent overarching intellectual theme that may involve a single discipline or multiple disciplines funded by NSF. For all IRES proposals, PIs are strongly encouraged to outline a variety of virtual, hybrid or other alternative approaches to strengthen and maintain international collaboration in addition to travel. It is expected that these approaches will extend collaboration beyond the actual international trip and strengthen IRES proposals overall.