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NIA - National Institute on Aging

ABSTRACT Our broad research goal is to understand chromatin regulatory mechanisms in nuclear and epigenetic programs and how these mechanisms are deregulated in aging and disease. A fundamental mechanism for regulating chromatin involves the reversible modification of histones by chemical moieties such as acetyl-, methyl-, and phospho- groups. These different histone marks are linked to discrete chromatin states and regulate the accessibility of DNA to transacting factors. In budding yeast, histone deacetylation by the chromatin silencing factor Sir2 prevents genomic instability and aging, and in mammals, de-regulation of histone acetylation is linked to cellular senescence and aging-related pathologies from neurodegeneration to cancer. Here, we focus on the mammalian Sir2 family member SIRT7, a chromatin regulatory, highly selective, lysine deacetylase enzyme. Previous studies reported that loss of SIRT7 function in mice leads to genomic instability, shortened lifespan and aging-related phenotypes including fatty liver, cardiac disease, and hematopoietic stem cell dysfunction. This project will study new roles of SIRT7-dependent histone deacetylation in chromatin regulatory mechanisms that are deregulated in aging-associated metabolic pathologies. It employs biochemical, cellular, and genomic approaches, and leverages SIRT7 knockout (SIRT7-KO) mice and new mouse models in which SIRT7 is overexpressed (SIRT7-OE). A central hypothesis is that SIRT7 protects against aging and metabolic disease processes and attenuates metabolic pathologies when overexpressed in mice. The project also hypothesizes that a novel histone substrate of SIRT7, H3K36, contributes to functions of SIRT7 in aging and metabolic pathways. Little is known about acetylation of H3K36, but di-methylation of H3K36 (a histone modification linked to gene regulation) is implicated in many human cancers, developmental disorders, and recently, metabolic disease. We hypothesize that deacetylation of H3K36 by SIRT7 is coupled to methylation by lysine methyltransferase (KMT) enzymes. We will test the model that a key mechanistic function of SIRT7 is to clear H3K36 acetylation from large swaths of DNA across the genome to enable methylation by KMTs, and that such a H3K36 acetyl-methyl switch mechanism is essential for preventing aging-associated gene expression reprograming in metabolic tissues.

NIH

Significance to VA: Type 2 diabetes (T2D) is a chronic, adult-onset metabolic disease with no cure to date. Alarmingly 1 in 4 (25%) Veterans are diabetic, significantly higher percent compared to civilians. Diabetes is the leading cause of renal and cardiovascular diseases, blindness, and amputations in Veterans. The annual mortality rate of Veterans with diabetes is nearly twice the rate compared to Veterans without diabetes (VA Fact Sheet 2019). The predominant risk factors for T2D advent in Veterans are military exposures and PTSD. Relevance to VA Military Exposures Research Program Mission: Vietnam War (VW) Veterans were exposed to Agent Orange (AO). Evaluating the effects of military exposures, it is established that tetra- chloro-dibenzo-p-dioxin (TCDD), contained in AO caused T2D pathology. T2D is a presumptive condition in VW Veterans. In the recent Global War on Terrorism (GWOT) conflicts, 85% of military personnel were exposed to open burn pits which emitted large amounts of TCDD. Measuring TCDD levels in the blood involves a long, cumbersome procedure requiring specific equipment and highly trained personnel, thereby deterring routine evaluation of TCDD exposures. Further, little is known about the chronic metabolic outcomes, specifically T2D, in GWOT Veterans. There is an immediate and dire need to identify Veterans with increased susceptibility to advent of T2D due to service-related TCDD exposures, independent of their genetic makeup, aging, or obesity. The proposal fills this gap with our overarching goal to establish a rapid, blood genetic test to identify Veterans vulnerable to chronic health sequelae of T2D, years after TCDD exposures. Innovation and Impact: We have established that low GAS5 levels are causal to T2D (US Patent Nos. 10,724,097; 11,214,835, 11,278,521. All with VA-asserted rights). The data demonstrates that GAS5, a noncoding regulatory RNA, is the genetic target of TCDD in humans, which unknown thus far. The project will establish GAS5 as a surrogate biomarker of TCDD-exposure related advent of T2D in Veterans. Importantly, to integrate into clinic, we developed a rapid blood droplet test for reproducible, consistent measurements of GAS5 levels requiring minimal technical expertise. Successful completion of the proposal will establish GAS5 as a surrogate biomarker of TCDD-exposure related advent of T2D in Veterans. This determination will significantly reduce the advent of T2D as the most preventable cause of death in US Veterans. Specific Aims: Our compelling data shows TCDD decreases GAS5. We hypothesize that low GAS5 levels in the blood correlate with past military associated TCDD exposures and the advent of T2D in Veterans. Specific Aim 1: Longitudinal study evaluating the correlation of blood GAS5 with TCDD levels in Veterans. Specific Aim 2: Determine the TCDD-regulated molecular mechanisms affecting GAS5 in human adipocytes. Methodology: For SA1, we will leverage our existing JAHVA Research Biospecimen Repository and obtain de-identified blood samples (IRB determination: Not Human Subject Research). The levels of TCDD, GAS5 will be measured and correlated to T2D by a sample-blinded biostatistician. For SA2, we will use human adipose stem cells differentiated to adipocytes. We will elucidate the underlying molecular and cellular mechanisms to understand TCDD-regulation of GAS5 levels, thereby providing unequivocable support complementary to SA1. NPC86, a therapeutic which increases GAS5, will be used as a molecular tool. Path to Translation/Implementation: We have developed a minimally invasive, minimal technical expertise requirement and ease-of-use, rapid (2-hour turn around) blood droplet test to measure GAS5 levels that can be easily incorporated into clinic. The results can be evaluated along with the Veterans’ TCDD exposure history to implement a personalized, time-sensitive treatment plan to prevent the advent of T2D.

NCI - National Cancer Institute

SUMMARY. Regulating the timing of meals and snacks to re-align the body’s circadian clock and improve metabolic health is emerging as a promising approach for cancer prevention in early animal and small clinical studies. Yet, a major barrier to studying meal timing and cancer is that large population studies rarely measure meal timing, which makes it impossible to conduct epidemiological studies of meal timing and cancer risk on a large-scale and across individuals with different biological and environmental characteristics and varied meal timing practices. Although obesity and its related metabolic dysregulation are important risk factors for at least 13 cancer types, weight management is notoriously difficult in the long-term. Behavioral strategies are needed that can improve metabolic risk factors for cancer but that do not necessarily rely on weight loss. Herein, we propose to discover and then externally validate novel objective biomarkers of meal timing practices, then test their relationship with incidence of breast (BC), endometrial (EC), and colorectal (CRC) cancers, three of the most prevalent obesity-linked cancers. Our central hypothesis is that meal timing is associated with perturbations in blood metabolomic profile, and with obesity-related cancer incidence in free-living humans. We will test our hypothesis with unique data from large-scale cohorts with validated measures of meal timing and sleep and longitudinal metabolomics data measured on the same metabolomics platform to facilitate data harmonization. In Aim 1, we will Identify biomarkers of meal timing patterns using a discovery and external validation design in the Cancer Prevention Study 3 Diet Assessment Sub-study (DAS) (n=750) and the Interactive Diet and Activity Tracking in AARP (IDATA) Study (n=718) and measure their association with risk of obesity-related cancer in the Cancer Prevention Study 2 (CPS-2, 782 BC matched sets; 517 CRC matched sets with 16-year follow-up time) and CPS-3 cohorts (1695 BC patients, 1983 controls, 3-year follow-up). In Aim 2, we will examine whether there is large-scale, real-world evidence that meal timing patterns are associated with obesity-related cancer risk among 185,000 US adults in the CPS-3 cohort. The proposed study will answer critical, outstanding questions about which meal timing practices are associated with cancer- relevant metabolic factors and risk of obesity-related cancers in a real-world scenario and identify objective biomarkers of meal timing behaviors that will facilitate large-scale investigations of meal timing and cancer risk at the population level. These meal timing biomarkers could also be used to assess response to meal timing interventions in clinical studies. Following successful completion of this project, we plan to apply the resulting biomarker profiles to study meal timing and cancer risk across international cohorts in the Consortium of Metabolomics Studies (COMETS). Epidemiological research stemming from our study findings will be vitally important prior to issuing public health guidance on meal timing for cancer prevention.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY/ABSTRACT (30 lines or less) The premise for the proposed research stems from precedence in other diseases, such as cancer, cardiovascular, neurodegenerative, and most relevant to the current proposal, autoimmune diseases, in which circulating extracellular vesicles (cEVs) play a role in pathophysiology and are important biomarkers for early detection. However, little is known concerning the role of cEVs in human type 1 diabetes (T1D). Our overall hypothesis is that cEVs have the potential to be used as biomarkers for early pre-disease detection of T1D, based on their distinct molecular and functional phenotype in T1D and pre-disease stages, compared to healthy or low risk individuals. Our specific aims are: 1) To identify the distinct protein and RNA cargo unique to cEVs at different stages of T1D disease development; and 2) To investigate the effect of cEVs from subjects at different stages of disease progression on immune and beta cell phenotypes and elucidate the functional relevance of their distinct molecular cargo. To address these aims, we have assembled a team of investigators with highly relevant expertise and techniques. We propose to use longitudinal samples from The Environmental Determinants of Diabetes in the Young (TEDDY) study of children with T1D associated genetic risk to identify critical timepoints and underlying mechanisms mediating, A) the earliest stages of pathogenesis preceding AAb appearance of the first islet autoantibody, and B) the period of seroconversion from single to multipe AAb+ or remaining single AAb+ and C) the period after multiple AAb appearance with a highly variable rate of progression to hyperglycemia. We have the expertise and technical ability to isolate cEVs from plasma, perform proteomic and RNAseq analysis on EVs, and perform immune and beta cell related functional assays. Our Research Plan is to generate cEVs from donors at different stages of T1D disease progression, to identify the uniquely packaged protein and RNA cargo from these cEVs, to evaluate the effects of the cEVs on immune cell functional phenotype and islet health and elucidate the functional relevance of the distinct molecular cargo targets. These studies will yield novel mechanistic insights into early disease pathogenesis and identify potential novel biomarkers for T1D initiation and progression.

NCI - National Cancer Institute

PROJECT SUMMARY/ABSTRACT In this grant cycle, Rutgers Cancer Institute had an unprecedented opportunity to expand clinical research to a significant number of additional hospitals of the RWJBarnabas Health (RWJBH) system. This unified and organized expansion was enabled by 1) Dr. Libutti’s roles as Cancer Center Director and Senior VP for Oncology Services of RWJBH; 2) Dr. Hochster’s roles as Rutgers Cancer Institute Associate Director for Clinical Research and Director of Oncology Research for RWJBH; and 3) development of a system-wide academic health system between Rutgers and RWJBH effective 01/01/2019 through a Master Affiliation Agreement. In this newly integrated and unified “one-site” model, Rutgers Cancer Institute has an unprecedented number of patients at its disposal for clinical research activities to impact the catchment areas' priorities and needs positively. The Office of Human Research Services (OHRS) serves as a centralized research administration, housing all administrative tasks at Rutgers Cancer Institute while providing oversight and direction for each clinical oncology research operation site throughout RWJBH. OHRS is responsible for working with Rutgers and system-wide clinical investigators to manage the business, clinical, and regulatory functions of all phases of pediatric and adult oncology cancer clinical trials throughout the health system. Our model is “one site with one CTMS, one IRB, and one EMR’, which is currently operational. The organizational structure, which reports to Drs. Libutti and Hochster is comprised of 158 FTEs with ten distinct offices divided and based on specialization within functional areas such as clinical operations, quality assurance, and regulatory affairs. In parallel with the growth of Rutgers Cancer Institute, screening, enrollment, and the number of available NCTN clinical trials increased significantly with the integration of RWJBH health system sites into OHRS. To date, the number of open trials has more than doubled (52 vs. 24 in 2019), and enrollments in NCTN clinical trials have increased by more than 500% (662 vs. 132). Minority enrollment has steadily increased from 29.9% in 2019 to 41.3% in 2024 over the grant period. During the current grant period, therapeutic trial accrual has risen by more than 400% (552 vs.132). In recent years, Rutgers investigators have held prominent roles within ECOG-ACRIN, NRG, and Alliance. Evidence of our success in scientific contributions is reflected in our investigators' significant leadership roles, memberships in key group studies, and authorship of numerous publications stemming from NCT trial participation. Moreover, Rutgers consistently mentors and engages young investigators in clinical trial research, as demonstrated by the recent appointment of two junior investigators who have assumed leadership roles in ECOG-ACRIN clinical trials.

National Institutes of Health

The National Institute of Allergy and Infectious Diseases (NIAID) seeks to advance its mission through the continued support of the Clinical Trials in Organ Transplantation in Children and Adults (CTOT-CA) program. The goal of the CTOT-CA is to improve the outcome of organ transplantation through clinical trials with mechanistic studies. The CTOT-CA will support multicenter clinical trials, with associated studies of immune mechanisms, in heart, lung, kidney, liver, and intestinal transplantation. The program will also support clinical trials of non-hematopoietic cellular transplantation as replacement therapies; vascularized composite tissue transplantation; and transplantation of bone marrow or mesenchymal stem cells, or of immunologically active cells, as adjuncts to organ transplantation. Grant authorities that allow NIAID to forecast this opportunity are as follows: Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 2 CFR Part 200.

National Institutes of Health

<p>The National Institute of Allergy and Infectious Diseases (NIAID) seeks to advance its mission through the&nbsp;continued&nbsp;support of the Clinical Trials in Organ Transplantation in Children and Adults (CTOT-CA) program.&nbsp;The goal of the CTOT-CA is to improve the outcome of organ transplantation through clinical trials with mechanistic studies. The CTOT-CA will support multicenter clinical trials, with associated studies of immune mechanisms, in heart, lung, kidney, liver, and intestinal transplantation. The program will also support clinical trials of non-hematopoietic cellular transplantation as replacement therapies; vascularized composite tissue transplantation; and transplantation of bone marrow or mesenchymal stem cells, or of immunologically active cells, as adjuncts to organ transplantation. Grant authorities that allow NIAID to forecast this opportunity are as follows: Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 2 CFR Part 200.&nbsp;&nbsp;</p>

NCI - National Cancer Institute

Project Summary Allogeneic stem cell transplantation (allo-SCT) is the only potentially curative therapy for AML. However, relapse of AML post-transplant remains the major cause of failure and continues to be a significant challenge. Understanding the mechanism behind post-transplant relapse is crucial for developing effective prevention and treatment strategies. Studies suggest that relapse after allo-SCT is multifactorial, involving the expansion of residual leukemia, potentially with new driver mutations. Immune escape mechanisms enable leukemic cells to evade the graft-versus-leukemia effect, in addition to T cell exhaustion and dysregulation. One strategy to prevent relapse is maintenance or pre-emptive therapy with anti-leukemic agents, with a low risk of graft failure and good tolerability after allo-SCT. To address this, we have conducted multiple clinical trials and are currently running a phase II trial evaluating venetoclax (Ven) with azacitidine (AZA) posttransplant, (NCT04128501). In this trial, patients receive this combination either for maintenance or to eradicate minimal residual disease (MRD) after transplant. Additionally, we are collecting longitudinal blood and bone marrow samples from participating patients as part of this study. In this proposed study, our aims are as follows: 1) To characterize the mutational landscape at diagnosis, post-transplant, and at relapse in AML patients receiving venetoclax and azacitidine after allogeneic SCT, utilizing single cell DNA sequencing to explore relapse mechanisms 2) To define T cell evolution in AML patients receiving venetoclax and azacitidine post- transplant, and the immune mechanisms that eradicate MRD with this combination. We have unique advantages in this research. Current data on post-transplant genetics mainly derive from next generation sequencing, whole exome sequencing, or flow cytometry, all with limitations. High throughput single-cell genomic analysis enables the detection of mutation cooccurrences within individual cells and determination of the order in which mutations appear. Post-transplant milieu cannot be analyzed solely by disease-specific genetic alterations but also immune-related changes. Given the association of T cell clonal emergence and immunotherapy response, we will also analyze T cell receptor repertoires and immune profiles post-transplant. This will help determine whether a specific subgroup benefit from Ven and AZA, particularly for patients with impending relapse, such as those with MRD detection. As a summary, in this exploratory grant, we will focus on mutational landscape and T-cell clonality to assess responders to Ven and AZA in the post-transplant setting. If successful, our project will provide critical information to identify which patients are more likely to benefit from Ven and AZA for disease prevention and guide tailored post-relapse treatments based on individual disease and immune-related findings.

NCI - National Cancer Institute

PROJECT SUMMARY Anaplastic thyroid cancer (ATC) primarily affects elderly individuals and has a dismal prognosis compared to other thyroid cancer subtypes. One of the hallmarks of ATCs is their admixture with myeloid cells, primarily macrophages. The recent development of combinatorial treatment with BRAF and MEK inhibitors led to improved outcomes in Class 1 BRAF-mutant ATC patients. Although their initial response to MAPK inhibition is substantive, responses are not durable, leading to a median overall survival (OS) of ~15 months7. With aging, somatic mutations in hematopoietic stem and progenitor cells (HSPCs) promote clonal expansion over non- mutant HSPCs. When this is present in the absence of malignant transformation it is termed clonal hematopoiesis (CH). CH mutations arise most frequently in epigenetic modifier genes, such as DNMT3A and TET2. CH is associated with an increased risk of atherosclerotic cardiovascular disease and other diseases associated with aging. We showed in a pan-cancer analysis that CH, in particular CH with putative driver mutations (CH-PD), is associated with adverse outcomes in solid tumor patients, including those with ATC. The specific interactions between CH leukocytes and tumor cells in the TME and their impact on therapeutic response remain uncharted. We find that TET2-mutant CH is enriched in the TME of patients with ATC and other solid tumors. We developed syngeneic immunocompetent mouse models of concurrent Tet2-mutant CH and orthotopically implanted BrafV600E-driven ATC to explore the mechanisms involved. Using single cell-CITE-RNASeq we found that Tet2- mutant macrophages selectively infiltrate mouse BrafV600E-mutant ATC and cause resistance to BRAF-MEK inhibition through overexpression of Tgfβ-family ligands. Importantly, inhibition of the effects of Tgfβ at three distinct nodes restores sensitivity to MAPK pathway inhibition, opening a path for synergistic strategies to improve outcomes of patients with ATCs and concurrent CH. The mechanisms by which Tgfβ activation render ATCs insensitive to MAPK inhibition remain to be defined. We will investigate whether macrophage Tgfβ ligand overproduction induces resistance to MAPK inhibitors through cancer cell autonomous mechanisms and/or by its immune suppressive effects and use genetic approaches to nominate the key Tgfβ ligands responsible for treatment resistance. The mechanisms delineating how DNMT3A CH leads to worse outcomes in solid cancers in general, and ATC in particular, have eluded explanation. We will determine whether Dnmt3a-CH affects ATC biology and response to therapy in mice and test the hypothesis that this is driven by the infiltrating mutant myeloid population. Finally, we found that CH-PD is associated with worse OS in patients with ATC, but the effect of individual CH genes has not been established. We will determine whether specific CH genotypes impact OS in ATC and if this manifests at low CH variant allelic fractions (VAF) using a high sensitivity assay. We will also investigate whether advanced thyroid cancers of any type with a high tumor-to-blood CH VAFratio (i.e. CH mutant cell enrichment in the tumor as compared to blood) have worse clinical outcomes.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY/ ABSTRACT Coagulopathy manifesting as disseminated intravascular coagulation (DIC) with associated bleeding and venous thromboembolism (VTE) is a common complication in patients with acute myeloid leukemia (AML), occurring in 10-20% patients at diagnosis and within the first 30 days of treatment. With improvements in supportive care, the overall survival of AML patients has improved, but early mortality from DIC remains a major challenge. While DIC is extensively studied in acute promyelocytic leukemia (APL), which is a small and distinct subgroup of AML, mechanisms of DIC and subsequent bleeding and VTE risk are not clearly understood in non-APL AML (referred to as AML from here on). Majority of the studies examining DIC in AML have focused on the tissue factor pathway and there is limited understanding of the role of endothelial dysfunction and the contact pathway of coagulation in coagulopathy of AML. Examining novel biomarkers in these pathways may explain the mechanisms of bleeding, and high VTE risk due to central venous catheters in AML patients. Clonal hematopoiesis (CH) refers to the acquisition of somatic mutations in driver genes in the hematopoietic stem cells that lead to increased risk of leukemia, cardiovascular disease including venous thromboembolism (VTE) and hemorrhagic stroke in the general population. A select group of mutations known as “adverse risk clonal mutations” (ACMs) in TP53, ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2 genes are associated with poor prognosis in AML. DIC is often observed in patients with high-risk AML, which is characterized by high white count, lactate dehydrogenase and blast%; these features are also seen in individuals who harbor FLT3-ITD mutation and other ACMs. The overall objectives of this proposal are to harness the resources from the University of Alabama at Birmingham (UAB) AML cohort (PI: Dr. Gangaraju) of 761 patients that have next generation sequencing data for clonal mutations to: (1) Examine the association between ACMs and DIC at AML diagnosis, and between ACMs and 30-day bleeding and VTE risk, and (2) Identify novel biomarkers of endothelial dysfunction and contact pathway of coagulation associated with ACMs at AML diagnosis and with 30-day bleeding and VTE risk in AML. This cohort has rich phenotypic data on demographics, comorbidities, labs at AML diagnosis and validated outcomes of interest including bleeding and VTE. A sub- group of patients provided plasma samples for biomarker studies, and the study team has expertise in measurement of the biomarkers proposed in this application. Investigating the mechanistic pathways of DIC, VTE and bleeding risk in AML aligns with NHLBI’s mission to understand the mechanisms of these complications in cancer. This will be the first step towards achieving my long-term goal of identifying AML patients at increased risk of bleeding and VTE, and examining strategies to provide safer and efficacious anticoagulation in these complex patients.

U.S. National Science Foundation

The Cognitive Neuroscience (CogNeuro) program seeks to fund proposals that can advance our understanding of the neural mechanisms underlying human cognition and behavior. Funded proposals typically relate precise and rich quantifications of physiological responses and behavior in ways that advance theory (Intellectual Merit). Funded proposal also typically strengthen the field through, for example, outreach, mentoring the next generation of diverse cognitive neuroscientists, and/or increasing awareness and utilization of the research the field produces (Broader Impacts). <span style="text-decoration: underline;">Intellectual Merit</span> In general, successful proposals provide a theoretical motivation and consist of a series of experiments/analyses that test the differential predictions of that theory; they go beyond quantifying physiology during certain tasks and behaviors. Research topics considered for funding include but are not limited to: perception, recognition, categorization, implicit and explicit memory, working memory, attention, language, decision-making, and social reasoning. Commensurate with the inherently multidisciplinary nature of the field and the limitations of any single technique, a wide variety of physiological methods are considered, including but not limited to: neuroimaging (e.g., fMRI, EEG, MEG), non-invasive stimulation (e.g. TMS, tDCS), lesion analysis, intracranial recording, optogenetics, genetics, optical imaging, computational modeling, and pharmacological interventions in both human and non-human primates and other animal models. The program is particularly interested in proposals that achieve or enable convergence across multiple techniques. Critically, proposals will be returned without review if they are focused on: 1) either behavior or physiology and lack a specific link between them, 2) understanding clinical populations, 3) non-human animals without a clear benefit to our understanding of humans. <span style="text-decoration: underline;"></span> <span style="text-decoration: underline;">Broader Impacts</span> In general, successful proposals make impacts beyond traditional academic routes, such as publishing research or teaching undergraduate courses. Strong broader impacts can be quite varied but will typically involve specific efforts strengthening the field and/or increasing its visibility that leverage the characteristics of the institution, department, and/or researcher. Consider the following non-exhaustive examples: 1) STEM education and outreach, particularly in underserved communities, 2) directly involving undergraduates and high-school students in research, 3) making tools and applications for the general public, 4) science journalism or advocacy. These efforts can, but need not, directly relate to the proposed research. It is also encouraged to include budget for these efforts if warranted. <span style="text-decoration: underline;">Mentoring Plans</span> Strong mentoring plans generally go beyond inclusion in standard lab activities and incorporate specific ideas for forwarding the careers of young scientists and trainees that leverage the setting and content of the proposed research. <span style="text-decoration: underline;"></span> <span style="text-decoration: underline;">General Directions</span> Prior to the development of a full proposal, investigators are strongly encouraged to submit a one-page summary of the proposed research to a program director to evaluate its appropriateness for the CogNeuro program. Please contact the director early enough to allow for revisions and incorporation what may be extensive feedback. The summary should include an overview of your research and statements of intellectual merit and broader impacts, the two NSF review criteria. See the Merit Review Fact Sheet for more important facts about the NSF merit review process. Please read the NSF Proposal &amp; Award Policies &amp; Procedures Guide (PAPPG) carefully, as it will be strictly adhered to even if other directives or communications appear to contradict it. Currently, the average standard/CAREER award size is $175,000-$225,000 per year for 3-5 years. Awards in excess of $1.0 million are exceptionally rare and almost always multidisciplinary. Please be judicious in your requests, understanding the realities of the limited funding available for all proposals. See the Listing of Active Cognitive Neuroscience Awards for additional award information. Declined proposals are ineligible for resubmission until a minimum of one year has passed since the due date of their initial submission, unless specifically allowed by the PO in the feedback received during the decline process. This moratorium allows investigators the time required to digest the results of the merit review and revise their proposal accordingly. A proposal that has not been substantially revised will be returned without review as per the PAPPG. PIs are strongly encouraged to submit the Single Copy Document titled &ldquo;List of Suggested Reviewers&rdquo; with their full proposal. Sharing of data and other materials is an expectation for funded research. Please consult the NSF Dear Colleague Letter: Effective Practices for Data for more details. Interested in talking with a program director? Send a one-page description of the proposed research to sbe-cogneuro@nsf.gov.

U.S. National Science Foundation

The Collaboratory to Advance Mathematics Education and Learning (CAMEL) for K-12 initiative aims to advance mathematics learning and education through purposeful collaboration that draws on the interdisciplinary Science of Learning (including neuroscience; cognitive, developmental, and social sciences; computer science; machine learning; engineering; and education research), deep experiences in education practice and teaching, and innovations in the use of data science, AI and technology. Through an agreement with philanthropic partners, including the Walton Family Foundation (WFF), CAMEL consists of two phases. Phase I invites proposals for the creation of new research networks to support the generation of high value datasets that aim to advance math learning and education. These research networks must include researchers who study the basic science of learning, education practitioners, and data scientists. The high value dataset may come from either generating a new dataset or by increasing the value of an existing dataset. Phase II, open only to awardees of Phase I, establishes a collaboratory, which is a socio-technological platform that prioritizes community-building and capacity-building to sustain collaborative efforts to advance math learning and education in K-12. Expanding Participation in STEM, NSF Priorities and Gold Standard Science: NSF prioritizes cutting-edge discovery science and engineering research, advancing technology and innovation, and creating opportunities for all Americans. NSF has established priorities set forth by Congress, the administration and the NSF director to promoteNSF's mission. Proposers should review the list ofNSF prioritiesand are encouraged to align their proposals with them, where appropriate. NSF also expects the highest standards of scientific rigor, integrity and adherence to appropriate tenets ofGold Standard Sciencein proposals, as appropriate for the field of science and research modality.

Rockwell Collins Foundation

Funds STEM education, community development, and workforce readiness in aerospace industry communities.

NIGMS - National Institute of General Medical Sciences

Summary Leukocyte motility is critical for immunology, inflammation, and hemostasis. Immune cells exchange molecular information by direct contact, enabled by motility within secondary lymphoid organs. In inflammation, neutrophils crawl into sites of infection after adhering to blood vessel walls. Hematopoietic stem and progenitor cells (HSPCs) migrate into to bone marrow after adhesion to the blood vessel wall under flow. In work largely funded by NIGMS, the Hammer laboratory has worked to understand the chemo- mechanics of leukocyte migration for over two decades. We have used traction force microscopy (TFM), in which we measure the forces exerted by cells during motility by monitoring the defection of fiduciary beads embedded within an elastic polyacrylamide gel. We have used this method to measure the traction forces of neutrophils and macrophages, as well as many other cell types. With the technique of TFM in hand, we are now positioned for significant breakthrough in our molecular understanding of traction stresses during leukocyte motility, owing to the development of methods to delete or alter intracellular components within a cell. Of specific interest is the fascinating phenomenon of upstream migration, in which leukocytes migrate against the direction of flow on surfaces presenting intercellular adhesion molecule-1 (ICAM-1). Using CRISPR-Cas9, we now are able do a directed screen of molecules that have been implicated in cell migration, and specifically, upstream migration, to understand precisely how these molecules contribute to the generation of traction forces in leukocytes. We will use two cultured cells lines – KG1a cells (a model HSPCs) and HL-60 cells (a model neutrophil) – that allow us to compare the role of different intracellular effector molecules in cell motility to establish universal mechanisms. We will conduct a directed screen of a limited but important set of effector molecules which have been implicated in upstream migration and leukocyte motility, such as cytoskeletal regulators and Rho-GTPases. Our elucidation of traction stresses will be complemented by immuno-fluorescent staining of the spatial distribution of adhesion receptors and actin cytoskeleton to provide information about cell organization. This MIRA is organized in three projects. In Project 1, we will perform traction mapping of KG1a cells during upstream migration. We will then screen candidate controllers of upstream migration using CRISPR-Cas9 and then measure how deletion affects both directional motility and traction stresses. In Project 2, we will use CRSIPR-Cas9 to screen a family of motility modulators and study their effect on HL-60 cell chemokinesis and chemotaxis. In Project 3, we will use TFM to measure the traction stresses of HL-60 cells during upstream migration and when upstream migration is reversed through CRISPR-Cas9 deletion. Then, we will measure the correlation between upstream migration of HL-60 cells and trans-endothelial migration on HUVEC monolayers.

NIH

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neuromuscular disease that places extreme financial, physical, and emotional burdens on affected Veterans and their caregivers. Currently, ALS remains without a cure and is commonly diagnosed at advanced disease stages when treatments are ineffective. Though the loss of motor neurons is a disease hallmark, it is now clear that various tissues and cells play a role in the pathogenesis and progression of ALS. As such, multi-factorial therapeutic targeting is an increasingly necessary approach for developing and testing ALS treatments. This therapeutic gap represents an unmet need in ALS. My CDA-2 funding has supported pre-clinical animal studies to assess and optimize the therapeutic potential of the secretome, or conditioned culture medium, from adipose-derived stem cells (ASCs). We and others have determined that systemic mesenchymal stem cell (MSC) secretome therapy, including ASC secretome, imparts neurologic, survival, and other benefits in the mSOD1G93A mouse model of ALS. Preliminary studies have also revealed a significant ASC-CM-mediated reduction in key serum inflammatory biomarkers, which hints at a possible mechanism of its action. However, when given before, through and into late stages of disease, the benefits facilitated by this secretome therapy eventually declines. As such, a clinically relevant adjunctive treatment could enhance the therapeutic benefits of ASC secretome therapy. Trans-spinal direct current stimulation (tsDCS) represents an approach to potentially improve the efficacy of ASC secretome long-term. For the proposed study, we will treat mSOD1G93A ALS mice with ASC secretome derived from ASCs grown using our patented optimized culture approach for neurological disease treatment and test whether regular tsDCS extends the therapeutic benefits in ALS. Our hypothesis is that combining daily systemic ASC secretome therapy and weekly tsDCS beginning at symptom onset will synergistically slow disease progression and extend the therapeutic benefits of ASC secretome. Our long-term goal is to not only extend life, but also improve quality of life for ALS-afflicted Veterans and their families. SPECIFIC AIM 1. Demonstrate whether regular trans-spinal lumbar electrical stimulation supplemented with systemic ASC secretome therapy improves functional and survival outcomes in mSOD1G93A mice. The goal of this Aim is to determine whether weekly tsDCS combined with systemic ASC secretome or control medium therapy ameliorates motor dysfunction and prolongs lifespan in mSOD1G93A mice. As part of a modified Neuroscore we will assess limb extension, grip strength, and locomotor function to assess the onset and progression of symptoms. Overall survival and lifespan from symptom onset will also be analyzed. SPECIFIC AIM 2. Evaluate whether combined tsDCS and ASC serum therapy impart histological motor neuron survival and neuromuscular junction (NMJ) innervation benefits. To test the hypothesis that our proposed therapy could impact the underlying neurodegenerative characteristics differentially from outward behavioral and functional measures such as neurological function, quality of life, and survival, we will perform histologic analysis of lumbar spinal cord and hindlimb muscle to assess MN survival and NMJ innervation. As MN and NMJ are typically fully degenerated at humane end-stage (the endpoint in Aim 1), we will treat a separate cohort of mice with ASC secretome, control medium, and weekly tsDCS between 70-90 days of age, a period we have documented secretome effects on moderate stages of neuromuscular degeneration therapy. Following sacrifice at 90 days, lumbar spinal cord and gastrocnemius muscle will be sectioned and immunolabeled for MN quantification and NMJ innervation, respectively.

Comcast NBCUniversal Foundation

Supports digital equity, STEM education, and community development programs in communities served by Comcast nationwide.

NHLBI - National Heart Lung and Blood Institute

Project Summary Hematopoietic stem cells (HSCs) sustain blood production throughout an organism’s lifetime. They are clinically significant as the key therapeutic component of bone marrow transplants for treating a multitude of hematological and non-hematological disorders. However, HSC transplantation is limited by scarcity of compatible donors. Despite significant efforts, generating large numbers of bona fide HSCs in vitro from induced pluripotent stem cells (iPSCs) remains a major challenge. This inability likely stems from an incomplete understanding of the developmental cues necessary for HSC specification. In vertebrate embryos, HSCs are specified from hemogenic endothelium lining the ventral wall of the dorsal aorta (DA) and require signals from the surrounding microenvironment. Previous work in our laboratory demonstrated that neural crest cells (NCC) migrate to the DA and direct HSCs specification in zebrafish via locally secreted or displayed signals. NCCs of the trunk differentiate into sympathetic neurons, which secrete catecholamines. In mice, catecholamines are required for HSC maturation. However, inhibition of catecholamine production in zebrafish did not affect HSC specification, pointing to the idea that an earlier phase of HSC specification directed by NCCs is independent of catecholamines. Although HSC programming is highly conserved across vertebrates, the requirement for NCCs in specifying HSCs has not yet been examined in mouse, and the cues provided by NCCs for HSC specification remain elusive. My preliminary data in mouse reveal that NCCs migrate into proximity of the DA during the HSC specification window and are found closely associated with nascent HSCs locating them at the right time and place to provide inductive signals for HSC specification. Interestingly, preliminary data in mouse and zebrafish show that NCCs do not contact the DA directly, except via filopodial extensions. To determine whether NCCs mediate HSC specification in mouse, I will map the association of migrating NCCs to the DA and emerging NCCs by lineage tracing and specifically ablate NCCs before they reach the DA with an inducible diphtheria toxin receptor mouse model. Finally, I will determine if NCCs mediate HSC specification through filopodial communication with the DA by generating a novel optogenetic zebrafish line permitting tissue specific knock out of Myosin X, required for filopodia formation and maintenance, in living animals and visualize any loss of HSCs using advanced live imaging technology.

NIH

Significance to VA: Defects of the craniomaxillofacial (CMF) skeleton are among the top reasons for Veterans seeking reconstructive surgery. CMF defects commonly occur in Veterans due to active combat as well as civilian life for etiologies spanning trauma, stroke, cancer, and cerebral aneurysms. Among CMF defects, the most devastating is the skull defect due to the necessity of an intact skull for cerebral protection, normal neurologic functioning, as well as psychological well-being and vocational opportunities, particularly when the defects are large and visible. The current clinically available materials for cranial defect reconstruction are limited by donor site morbidity for autologous bone and complications and cost for alloplastic materials, thereby providing an opportunity to develop strategies targeting skull regeneration. Innovation and Impact: This project introduces a novel anisotropic composite material consisting of nanoparticulate mineralized collagen glycosaminoglycan (MC-GAG) and a phosphate-eluting hydrogel (aMCGPh) to enhance osteogenesis and skull regeneration. This approach builds on extensive prior data on the base material MC-GAG combined with the observation that augmenting phosphate ion delivery in a temporospatially controlled manner can improve osteoprogenitor differentiation via the sodium phosphate cotransporters PiT-1 and PiT-2. The innovative materials-only strategy eliminates the need for growth factors or preloaded progenitor cells, offering a safe, cost-effective, and scalable option for cranial defect repair. Successful outcomes would provide Veterans with an off-the-shelf regenerative solution available at point-of- care in the operating room. Specific Aims 1. To evaluate the in vitro effects of aMCGPh on osteogenic differentiation of primary human mesenchymal stem cells (hMSCs). Objective: Characterize the contributions of phosphate dosage, diffusion, and mechanical properties of the respective hydrogels on the two aMCGPh variants on osteogenic gene expression and cell-mediated mineralization compared to MC-GAG. 2. To assess the in vivo safety and efficacy of aMCGPh in a rabbit calvarial defect model. Objective: Evaluate in vivo bone healing, biomechanics, inflammation, vascularization, and local and systemic safety of aMCGPh variants for calvarial regeneration. Methodology: Aim 1 will evaluate two dosages of aMCGPh with two different distances for phosphate diffusion, the necessity of PiT-1 and PiT-2 using knockdown studies, and the importance of mechanical properties of the hydrogel component to assess the impact of the phosphate-eluting hydrogel depot on hMSC osteogenic differentiation measured using gene expression, protein expression, and matrix mineralization studies. Aim 2 will assess efficacy of aMCGPh on in vivo rabbit cranial defect healing using radiographic, biomechanical, histologic studies as well as determine safety using bloodwork and distant tissue necropsy. In vivo comparison groups will include: unreconstructed defects, autologous bone-reconstructed defects, MC- GAG-reconstructed defects, and two dosages of aMCGPh-reconstructed defects. Path to Translation/Implementation: Our proposed studies are unified in the goal of delivering a useful, regenerative material for a common surgical problem in Veterans. Our preliminary work has outlined a promising composite material for skull defects, aMCGPh, for which we have already obtained a provisional patent (VA Invention ID 2023-139; Provisional Patent No. 63/503,824). This project will generate preclinical safety and performance data in preparation for an Investigational Device Exemption application to the FDA.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY/ABSTRACT The goal of this project is to develop tools to determine the mechanisms by which single amino acid variants affect myosin structure and function at multiple scales. Major challenges have been that: 1) a limited number of human β-myosin structures; 2) the computational expense (CPU time) to simulate the dynamics of such a large protein, and 3) difficulty in obtaining tissue from patients with disease causing variants. To overcome these challenges, we developed new structure-based, dynamics models of the chemo-mechanical cycle of β-myosin. These models are generated from new human crystal and cryo-EM structures, augmented by known structures available from bovine muscle. Our Molecular and Brownian Dynamics models contain F-actin structure to study how its interactions with β-myosin affects signaling between the nucleotide binding pocket, the actin-myosin interface, converter domain and other regions of myosin. These simulations are augmented by our novel inter- protein pathway analysis based on graph theory. We will use stochastic-kinetic models of sarcomeres to simulate contraction and relaxation with variable amounts of myosin variants. We will use gene edited human inducible pluripotent stem cells (hiPSCs) to validate our results. Our culture conditions result in myofibrils expressing predominantly β-myosin and demonstrate kinetics of adult myofibrils. We will purify myosin from these hiPSC- CMs for biochemical kinetic measures of the chemo-mechanical cycle. Each of these mechanical states results from structural changes in myosin and its association with actin. Additional studies will be performed at the level of myofibrils to study how mutations affect contractile function. We will also use single molecule, super-resolution to study high resolution structural changes in thick filaments from hiPSC-CMs, and Molecular Dynamics models of the Interacting Heads Motif structure of myosin on the thick filament backbone. This platform will be used to predict the effect of a selected group of variants of uncertain significance (VUSs).

Consolidated Edison Foundation

Supports clean energy education, STEM programs, and environmental sustainability in the greater New York City area.

NCATS - National Center for Advancing Translational Sciences

Project Summary INTS12 is a chromatin interacting subunit of the mammalian Integrator complex that binds to accessible chromatin and controls various aspects of transcription such as elongation and termination. INTS12 interacts with negative elongation factors as well as RNA Polymerase II and regulates its pausing and release into productive elongation. Studies on INTS12 biology in various mammalian systems such as hematopoietic tissues is lacking despite ample evidence of its presence and likely contributions to hematopoietic development and disease. For instance, INTS12 is highly expressed in early stage erythroid progenitor cells during ex vivo erythroid differentiation of human CD34+ hematopoietic stem cells, and it is significantly reduced in the rare hemolytic anemia Congenital Dyserythropoietic Anemia Type IV (CDA IV; CDAN4), which affects young children and renders them transfusion dependent. This proposal will address our core hypothesis that INTS12 function is important for transcription regulation during normal human red cell development and reduced INTS12 levels in CDA IV red cells contributes to ineffective erythropoiesis due to disrupted RNA Polymerase II elongation control. To achieve this, a newly established erythroid progenitor cell line called BEL-A that can be expanded indefinitely, and differentiated to mature erythroid cells will be used. Aim1 will focus on INTS12 chromatin binding in normal wild type (WT) and CDA IV mutant BEL-A cells, and this will be correlated with existing unpublished chromatin accessibility and transcription factor binding data from erythroid stage-matched WT and CDA IV BEL-A cells. Further, the effect of depleting or overexpressing INTS12 on red cell development in WT and CDA IV will also be characterized. In Aim2, we will explore INTS12 functions in transcription by assessing the impact of INTS12 perturbations such as depletion and overexpression on nascent gene expression and RNA Polymerase II occupancy. These data will be correlated with INTS12 occupancy determined from Aim1, and any alterations in nascent transcription leading to changes in RNA Pol II pausing and elongation due to perturbed INTS12 levels will suggest that INTS12 contributes to altered transcription regulation in CDA IV. Transcription elongation by RNA Polymerase II is highly regulated and involves many transcription co- factors and epigenetic mechanisms, some of which are chemotherapy targets for certain hematological malignancies. Further, INTS12 interacts with chromatin using a conserved PHD domain that is being investigated as a potential chemotherapy target using derivatives of a class of compounds known as Amiodarones. The knowledge harnessed from this proposal will thus enable future investigations into INTS12 and Integrator complex biology in erythropoiesis, as well as translational studies on the potential for INTS12 as a therapeutic target in CDA IV patients.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY Hematopoietic stem cells (HSCs) reside in specialized microenvironments in the bone marrow (BM) that comprise multiple cellular constituents, including nerves, with vital regulatory functions. Our previous studies established that the nociceptive nervous system is an essential BM niche component controlling HSC mobilization from the bone marrow into the peripheral blood. Our new preliminary resutls reveal that aging is associated with a progressive loss of nociceptive innvervation in the bone marrow, and that supplementaiton of nociceptive nerve-derived CGRP attenuates the expansion and BM HSCs in aged mice, restores their engraftment ability, and reverses the myeloid-biased differentiation. Based on these findings, we hypothesize that nociceptive nerve-derived CGRP is a critical rejuvenating signal for aged HSCs, and that targeted chemogenetic activation of BM nociceptive neurons using DREADDs can be harnessed to reverse HSC aging in vivo. In the Specific Aim 1, we will determine whether CGRP administration reverses bona fide aging hallmarks and identify the downstream molecular programs that mediate this rejuvenation. In Specific Aim 2, we will investigate whether local activation of BM nociceptive neurons using DREADDs rejuvaentes old HSC in vivo. Together, these proposed studies will shed light into the critical functions of an under-appreciated component of the HSC niche and uncover novel therapeutic strategies for age-associated hematopoietic diseases.

NCI - National Cancer Institute

PROJECT SUMMARY In cancer and chronic infection, T cells develop into a dysfunctional state called exhaustion because of persistent antigen stimulation. Exhausted T cells upregulate immune checkpoints, display dysregulated metabolism, and progressively lose effector function and the ability to persist and develop immune memory. T cell exhaustion hinders the clearance of pathogens and malignant cells by the immune system and limits the effectiveness of immunotherapies such as chimeric antigen receptor (CAR) T cell therapy. Therefore, understanding how T cells adapt to chronic antigen receptor signaling is critical for developing more effective immunotherapies. A stem-like CD8 T cell subset has been identified in chronic infections and cancers. Stem-like CD8 T cells mediate long-term immunity by self-renewal and replenishing other CD8 T cell subsets. Stem-like properties in T cells are essential for the efficacy of immunotherapies. We have identified key transcription factors that regulate the differentiation of stem-like CD8 T cells. However, the molecular program underlying the adaptation of stem-like CD8 T cells to chronic antigen receptor signaling is incompletely understood. Our recent findings show that the redox sensing KEAP1-NRF2 pathway is critical for the differentiation of stem-like CD8 T cells and adaptation of CD8 T cells to chronic antigen receptor signaling. In the proposed study, we will determine how the KEAP1-NRF2 pathway regulates the adaptation of CD8 T cells to persistent antigen receptor signaling through preventing TCR hyperactivation and promoting metabolic fitness. Our study will shed important new light on the development of more potent and efficacious immunotherapies for cancers and chronic infections. Furthermore, KEAP1 and NRF2 have been extensively investigated as potential drug targets for chronic diseases. Therefore, our findings hold significant promises for informing interventions that aim at modulating this pathway.

NASA Johnson Space Center

The National Aeronautics and Space Administration (NASA) Headquarters Office of Education, in cooperation with the NASA Johnson Space Center and other NASA Centers, is releasing a Cooperative Agreement Notice (CAN) for NASA Internships. On or about January 16, 2013, this CAN will be available electronically through the NASA Solicitation and Proposal Integrated Review and Evaluation System (NSPIRES) at http://nspires.nasaprs.com/ and then clicking the link through the menu listings "Solicitations" to "Open Solicitations." Institutions eligible to respond to this CAN are limited to higher education institutions, nonprogit organizations, and consortia or groups of organizations and institutions serving higher education students, whose mission includes capturing student interest and/or improving student performance in science, technology, engineering, mathematics (STEM) or related fields. The estimated annual value of the award is $3,000,000 to $10,000,000 per year, for a period of performance not to exceed 5 years. It is anticipated that this award will be an indefinite quantity and cost reimbursement cooperative agreement. The recipient of this single award will support sub-agreements at 10 NASA centers delineated by unique cooperative agreement numbers assigned by the NASA Shared Services Center. All centers will follow the same guidelines. The breakdown by center is necessary to ensure costs are tracked correctly. This will allow each NASA facility to easily transfer funding from any technical or administrative organization for support of NASA Internships. The single entity recipient of this award will be responsible for identifying and submitting costs and drawdowns per each center's cooperative agreement number. Due to the variability of this funding model, the successful proposer must have an accounting system considered adequate for tracking and reporting costs applicable to the agreement from multiple funding sources. (See Table 2, Section II for a list of current NASA intern ship locations.) NASA is looking for a flexible and scalable partner who can be innovative and impactful while delivering, sustainable, demonstrable and measureable results. A Notice of Intent (NOI) is requested to assist NASA in assessing the possible response to this CAN; and to determine the number of subject matter experts required for the Proposal Review Panel. NOIs should be submitted by the proposer to NSPIRES by midnight (11:59 p.m.) Eastern Time, February 13, 2013. Instructions for submitting the NOI and the proposal in NSPIRES are found under Section III of this announcement (Proposal and Submission Information). Interested proposers must register with NSPIRES before it can be accessed for use. In order to avoid any conflict of interest in assigning reviewers to proposals, please include a list of participating/partnering institutions in your NOI. All proposals in response to this CAN must be submitted electronically via the NASA Solicitation and Proposal Integrated Review and Evaluation System (NSPIRES) (http://nspires.nasaprs.com ) or Grants.gov. Electronic proposals must be submitted in their entirety by 11:59:59 PM Eastern Time on the proposal due date of March 13, 2013. Respondents without access to the Web or who experience difficulty using the NSPIRES proposal site (http://nspires.nasaprs.com ) may contact the Help Desk at nspires?help@nasaprs.com or call 202-479-9376. This solicitation leading to the award of a Cooperative Agreement is issued pursuant to title 14 CFR Part 1260 for educational and nonprofit institutions and 14 CFR part 1274 for commercial organizations. Notwithstanding the posting of this opportunity at FedBizOpps.gov, Grants.gov, or at both sites, NASA reserves the right to determine the appropriate award instrument for each proposal selected pursuant to this announcement. The points of contact for technical and programmatic questions regarding this CAN are: Technical Officers: Ms. Carolyn Knowles Office of Education NASA Headquarters 300 E Street, SW Washington, DC 20546 Carolyn.knowles-1@nasa.gov Mr. Robert Musgrove Office of Education Johnson Space Center 2101 NASA Parkway Houston, TX 77058 robert.p.musgrove@nasa.gov NASA Internship Solicitation Support: Tamra Ross NASA Research &amp; Education Support 2345 Crystal Drive - Suite 500 Arlington, VA 22202 tkross@nasaprs.com 202-479-9030, Ext. 213 202-479-0511 (fax) Questions regarding this announcement must be presented in writing to Tamra Ross at tkross@nasaprs.com within 30 calendar days of the release date in order that responses may be obtained and disseminated within 5 business days. Oral questions will not be answered due to the possibility of misunderstanding or misinterpretation. Questions and responses will be posted on the NSPIRES website at http://nspires.nasaprs.com .