Boston Children'S Hospital

NIH Research Projects · FY 2025 · 1992-07

This training grant in developmental endocrinology and metabolism at Boston Children's Hospital (BCH) intends to provide funding for 4 postdoctoral fellows per year to engage in research training leading to independent careers in academic pediatric endocrinology. The program is designed to address the shortage in academic pediatric subspecialists, including pediatric endocrinologists, and train future physician-sicentist leaders who will use research to address pressing problems such as obesity and diabetes. The trainees (4 slots per year) are largely selected from a pool of 6 to 9 highly qualified pediatric endocrinology postdoctoral fellows who are in the BCH Division of Endocrinology Fellowship Program or less than one year after completion of the program. The intended average duration of training is two years. Trainees enter the program with either the MD (or equivalent), MD/PhD or occasionally the PhD degree. The 32 trainers include 13 clinically active pediatric endocrine physician-scientists, 10 physician-scientists of other disciplines, 11 MD/PhDs, and 6 PhD scientists. BCH is the major training site, but fellows also train at Massachusetts General Hospital, Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, Joslin Diabetes Center, and the Whitehead Institute. The major areas of research emphasis in this training grant include clinical, translational and basic laboratory research in diabetes mellitus and its complications, obesity and its complications, diet/metabolism and health, neuroendocrinology, skeletal health and biology, intestinal biology and developmental endocrinology, sex differences and endocrine disease, and endocrine cancers. Training consists of didactic courses, including in quantitative methods, ethical conduct of research, and reproducibility/rigor, and an intensive period of individually mentored research. Of the 34 trainees during the past 15 years who have completed training on this T32 grant, 30 are faculty in academic pediatric or research institutions, two are in industry, and one is at the FDA. Of these 30, there are 13 Assistant Professors, 5 Associate Professors, 1 Professor, 2 Division Chiefs, and 10 Program Directors. Their record of publication is strong, as is their record of grant funding: 12 have had independent NIH K awards, 4 have had R03 or R21 awards, and 5 have one or more R01s. This program takes advantage of the breadth of scientific expertise of the training faculty within the Division of Endocrinology, as well as in the larger BCH community and surrounding Harvard environment. We provide trainees with a rigorous and stimulating training environment, with many excellent courses, cutting-edge seminars, and outstanding mentors who deploy the latest research methods. With highly qualified trainees and a track record of past success, we hope to continue to train a next generation of diverse academic pediatric endocrinologists and physician-scientist leaders.

NIH Research Projects · FY 2025 · 1986-08

The prevalence of pediatric allergic, immunological and rheumatologic disorders has been steadily increasing with more than 15% of children now affected. However, the number of physicians trained to treat children with these conditions as well as to investigate the genetics, pathogenesis and innovative approaches to therapy of these disorders remains disproportionately small. In addition, the role of the immune response in modulating the clinical course of infectious disease is coming into sharp focus with the COVID-19 pandemic. There is a great need both to advance understanding of the basic immunobiology underlying these conditions and to generate a highly qualified workforce of investigators who will do this work. Recent advances in understanding of the immune system, along with the emergence of powerful yet complex research technologies in molecular biology, transcriptomics, metabolomics, human genetics, epigenetics, structural biology, cell biology and immunology have not only created fertile ground for advancement of understanding of immunological mechanisms but have made it essential for trainees to develop understanding of and experience in these approaches. Such training will prepare MD and PhD scientists to advance our knowledge through basic research, clinical investigation and the implementation of novel therapeutic strategies. Equally important, it will generate a cadre of physician scientists ready to train the next generation of investigators. The proposed training program will recruit a diverse group of the most talented and committed young pediatric physician scientists as well as PhD’s (all postdoctoral) committed to clinically relevant immunology research and will provide them with an intensive training experience in research in an unparalleled environment. In the year prior to enrollment in the program, physicians will receive one year of clinical training (not funded by this grant). All training will be within the general discipline of Immunology, with a broad representation of immunological disorders (including asthma, food allergy, atopic dermatitis, primary immune deficiency syndromes, systemic lupus erythematosus, Kawasaki disease) and basic immunological mechanisms (such as tolerance, immunogenomics, epigenetics, innate immunity, cellular immunology and immune responses to SARS-CoV-2) covered by an internationally recognized faculty in the Harvard Medical School community. A three-year training experience is proposed for 9 trainees per year, each with MD, MD-PhD or PhD credentials.

NIH Research Projects · FY 2025 · 1983-12

PROJECT SUMMARY: The overarching goal of our Training Program is to prepare MD, MD/PhD pediatricians, and PhD scientists for careers in independent research on topics relevant to digestive diseases in infancy, childhood, and adult life. The rationale for our program is founded upon the idea that meaningful and strong intellectual, mentoring, and financial support for newly emerging scientists will enable the recruitment of talented young people to our field and foster early success in their long-term career development as effective independent investigators pursuing meaningful science relevant to health and disease of the alimentary tract. We offer training in 4 broad areas relevant to our field of gastroenterology: 1) Epithelial Cell and Molecular Biology - including Stem Cell/Developmental Biology and Enteric Neurobiology; 2) Innate and Adaptive Mucosal Immunology; 3) Microbial Pathogenesis, Gut Microbiome, and effects on Metabolism; and 4) Clinical Research. The training program provides an in-depth comprehensive and strongly mentored scientific experience for each trainee in a research group at the forefront of its field. Eight postdoctoral positions are requested. 35 NIH-funded highly accomplished core research faculty support this effort, providing great depth and diversity of scientific training and over $52 million in combined current research support. Opportunities for cross-fertilization among faculty members and their trainees are abundant. The Program Director is Dr. Scott B. Snapper MD PhD, Egan Family Professor of Pediatrics, Harvard Medical School, and a widely respected investigator and mentor. Program steering committee includes Drs. Wayne Lencer MD, Meena Rao MD PhD, Jon Kagan PhD and Rachel Rosen MD MPH. An External Advisory Board provides oversight to the program. Scholarship Oversight Committees (SOCs) are assembled for each trainee to provide oversight (and further mentoring) in personal scientific and career development. Didactic course work is encouraged for both basic and clinical research training and supplemented with relevant seminars and journal clubs, a course in the responsible conduct of research, and an annual research retreat. For clinical research trainees, the program supports matriculation through a Master’s Degree in Medical Science or Public Heath (MMSc or MPH) from Harvard Medical School or Harvard School of Public Health. Since 1997, 72 (70%) of our past 103 Trainees remain in academics, 20 (19%) in industry, 4 (4%) in government (NIH/FDA), and only 7 (7%) are in clinical practice or have left academics. 18% of our past Trainees have achieved independent NIH research awards (RO1 or equivalent), 32% have achieved NIH K-series awards, and 57% have achieved other NIH (e.g., F32), Foundation, or other (institutional) Career Development Awards. Our T32 training program continues to have a broad-based effort to recruit URM trainees and faculty. Importantly, our program has populated the faculty of academic institutions across the nation and internationally.

NIH Research Projects · FY 2025 · 1983-04

7. Project Summary/Abstract. During the past funding period, we discovered that the cohesin-mediated loop extrusion process involved in genome-wide modulation of chromosome architecture plays fundamental roles in V(D)J recombination and the generation of antibody diversity. In developing progenitor B cells, we found that cohesin-mediated loop extrusion linearly presents Ig heavy chain locus (Igh) VH, D, and JH gene segments to the RAG endonuclease for V(D)J recombination. Our preliminary data indicate that long-range V(D)J recombination in the Igk light chain locus may occur, at least in part, by a mechanistically distinct process from that of Igh. We propose 2 specific aims to elucidate the potentially differential mechanisms of Igh versus Igk long-range V(D)J recombination. A major hypothesis guiding Aim 1 and Aim2 studies is that Igh achieves long range V(D)J recombination via linear RAG chromatin scanning that leads to predominantly deletional recombination events. A major hypothesis to be tested for Aim 2 is that Igk is structurally-optimized to employ a related loop extrusion-based mechanism that accommodates both robust deletional and inverted Vk-to- Jk joining. These hypotheses are supported by a wealth of published and preliminary data derived in large part from powerful new technologies that we developed during the current funding period. In particular we developed LAM-HTGTS-V(D)J-Seq to assay V(D)J recombination with unprecedented sensitivity and LAM-3C- HTGTS to map sequence interactions across chromatin domains at far higher resolution than prior assays. We further developed G1-arrested, RAG inducible v-Abl transformed pro-B cell cell ("v-Abl cell") approaches to test roles specific cis elements or trans-acting factors in long-range RAG chromatin-scanning through introduced Igh or Igk locus modifications and/or targeted protein depletion. Aims 1 and 2 experiments together will compare and contrast, in depth, the long-range mechanisms used by Igh and Igk to incorporate Vs into the V(D)J recombination reaction. While most initial Aim 1 and 2 studies will employ v-Abl cells; all key results will be confirmed/extended by studies of normal progenitor and precursor B cell populations These studies may reveal new paradigms for understanding V(D)J recombination in vivo and illuminate the range of mechanisms employed for long-range V(D)J recombination in antigen receptor loci. Addressing Aim 1 and 2 goals should greatly impact the immunology field by providing major new insights into fundamental mechanisms that establish highly diverse primary antibody repertoires. The studies proposed in Aim 1 and 2 will also further elucidate how impediments in the scanning path focus cryptic RSS targets within impeded areas of chromatin for incorporation into the RAG complex and subsequent rearrangement. Thus, these studies should provide critical information for understanding how RAG targets cryptic RSSs in other genes and promotes common translocations or interstitial deletions frequently found in B and T lymphocyte cancers of developing lymphocytes in humans.

NIH Research Projects · FY 2025 · 1983-01

ABSTRACT The goal of the Research Training Program in Pediatric Cardiovascular Disease is to attract and train highly qualified MD, MD-PhD, and PhD scientists dedicated to advancing the understanding, diagnosis, treatment, and prevention of pediatric and congenital heart disease. The program is based in the Department of Cardiology at Boston Children’s Hospital (BCH), a leading national and international center for pediatric cardiology and treatment of congenital heart disease. The 34 Faculty Mentors in this T32 include outstanding and highly collaborative scientists - drawn from BCH, Harvard Medical School (HMS) and its affiliated hospitals, and MIT - with expertise in basic, translational, and clinical research relevant to pediatric cardiovascular disease. Together, they hold $34.9M in total support for the current year. Of those supported in the past 15 years, 91% remain active in research, 76% continue in academia, and 18% are from under- represented groups. A Research Training Executive Committee (RTEC), comprising the Program Directors and four current mentors, will oversee the progress of fellow training, career development, and mentoring, approve new mentors, and ensure that existing mentors meet the metrics of the training program. We are requesting 8 trainee positions, on average supporting the training of 4 with MD or MD-PhD degrees and 4 with PhD degrees each year. Entry into the T32 training program is highly competitive – from our highly talented candidate pool, ~7% are selected for T32 support. We will expose trainees to the clinical, translational, or basic research techniques that represent the current state of the art. A Core Curriculum will include training in biostatistics, Work-in-Progress meetings, a cardiovascular seminar series, a hands-on didactic series in cardiac anatomy, and career development seminars. Trainees will also participate in an annual retreat and regular meetings attended by T32 trainees and mentors. Through these interchanges, clinically-oriented trainees will gain understanding of fundamental cardiovascular biology, and basic science trainees will gain understanding of important clinical problems. The program allows trainees to further tailor their training to specific research interests by taking advantage of the stellar opportunities for formal coursework and the myriad of scientific seminars and lectures at BCH, HMS, the Harvard School of Public Health, and MIT. We also teach trainees the importance of teamwork, the clear communication of research findings, responsible conduct of human and laboratory research, and mentoring skills. Milestones and metrics for trainee progress and the training program itself are outlined and will be overseen by the RTEC. Considerable institutional support includes supplementation of trainee stipends and travel funds, and support for the EAC and program activities. Excellent training in rigorous experimental bench research and in translational and clinical investigation within an interactive and vibrant program will prepare graduates to become leaders in pediatric cardiology and cardiovascular research.

NIH Research Projects · FY 2025 · 1975-07

The T32 Pathophysiology of Human Blood Cells, now in its 42nd year of funding, is seeking renewal to continue a long-standing focus on training physician-scientists in pediatric Hematology/Oncology. The object of the training program is to provide robust, PhD-post-doctoral level research experiences and scholarly research training in Hematology/Oncology, so as to render trainees success at transition to independent careers making substantive contributions to biomedical research, both basic and translational. The program has continued the long-standing overall philosophy that training of physician-scientists requires an extended protected mentorship runway. The training program continues to grow in this last cycle with addition of multiple new faculty and focus on enhancing our pipeline of trainees. In addition to maintaining the program’s strengths in hematopoietic stem cell biology, hematopoiesis, neutrophil biology/innate immunity, red cell biology/hemoglobin expression and an overall emphasis in translational research, we have expanded our efforts in areas of gene therapy and stem cell transplant. In addition, programs are in place to target undergraduate science classes and MD/PhD students at Harvard Medical School/MIT to enhance the future pipeline of trainees coming to this T32. The 60+ mentoring faculty on this training grant include outstanding scientists many with exemplary publication and training records. In spite of pressures on the NIH budget, research funds to the Division currently total $85.8 M in direct costs per year including 104 NIH grants. The training faculty is highly collaborative, and Boston Children’s Hospital, Dana-Farber Cancer Institute, the Whitehead, Broad and Koch Institutes at MIT, Harvard, and the Harvard Catalyst (CTSA) academic environments provide stellar opportunities for formal coursework and a myriad of scientific seminars and lectures. Of those applying for positions to this program in the current 5-year cycle, 9% were accepted. There are formal processes in place for regular trainee and faculty feedback. Success of trainees as judged by success in obtaining NIH training grants and independent faculty positions is outstanding and nearly 100% of entering fellows remain in Hematology/ Oncology in scientific careers. Indeed, graduates of this training program continue to fill important leadership roles in the field with significant numbers serving in academic or pharmaceutical/ biotech leadership positions. This success continues in the latest funded cycle. As a more proximate measure of success of our training and mentorship and as stated in the narrative section, under the guidance of Dr. R Orkin, in the past ~15 years, 44 K08 applications were submitted by our trainees. Of those with definitive funding decisions 87% were funded and 6 (1 Ao and 5 A1) await word of funding. Success rates for other career awards are as follows: K01s (12/17, 71% funded), K07s (2/2; 100%), K23s (1/4, 25% funded), K99s (17/25; 68% funded). Here we request renewal with funding for 11 training slots.