This application for a K08 award describes a multidisciplinary 5-year training program to facilitate my (Dr. Phillip Garfin) career development as an independent academic physician-scientist. I recently completed a fellowship in Pediatric Hematology, Oncology, and Stem Cell Transplantation and now seek to expand my research experience to attain my long-term career goal of becoming an independent academic investigator, directing a research program in thymus function and immune reconstitution following hematopoietic stem cell transplantation. I have developed this long-term goal while making significant discoveries into the mechanisms that regulate thymus growth and function (recently published - Garfin et. al. The Journal of Experimental Medicine, 2013). Building on my recent discovery of an RB-E2F-FOXN1 module that regulates thymus size and function I hypothesize that tumor suppressive pathways regulate thymus growth and involution and that these pathways inhibit thymic regeneration. To test this overall hypothesis, I propose three aims.
Aim 1 : To test the hypothesis that age-dependent intracellular mechanisms in TECs secure thymic involution and prevent thymic growth and regeneration.
This aim will use timed inactivation of the RB family of proteins to identify the mechanisms that promote and secure thymic involution.
Aim 2 : To test the hypothesis that the Hippo/YAP pathway regulates thymic size and function.
This aim will test the role of a second major growth-controlling pathway in the regulation of thymus size and function.
Aim 3 : To test the hypothesis that adipocytes promote thymic involution in an RB-dependent manner.
This aim will test the role of a heretofore unexplored cell type in thymic involution. It will also test the role of the RB family in determinig the fate of these cells. Preliminary data support the feasibility of all 3 aims. Ultimately, an improved understanding of the mechanisms that regulate thymus size and involution will provide targets for therapies aimed at improving thymus and immune function in the elderly and following HSCT. This K08 award will provide me with the support and protected time necessary to accomplish the following training objectives: (1) to become an expert in thymus and immune biology, (2) to master advanced techniques of gene-expression, epigenetics, and immunology (3) to continue to develop skills for planning and communicating scientific inquiry, and (4) to submit an R01 application during year 4. To achieve these goals, I have assembled a strong mentoring team of experts in genetics, cell-biology, thymus, immunology, epigenetics, and regenerative medicine - all of whom have successfully mentored young scientists. My primary mentor, Dr. Julien Sage, is a leader in the field of RB biology, regenerative medicine, cancer biology, and mouse modeling of complex phenotypes. His three most-recent post-doctoral fellows to complete their training all lead independent laboratories at major academic institutions (Children's Hospital of Pennsylvania, the University of Virginia, and Technical University Munich). My co-mentor, Dr. Kenneth Weinberg, is an expert in thymus and immune biology as well as an accomplished Pediatric Stem Cell Transplant physician. My advisory committee consists of Dr. David Lewis (an expert in T cell biology) and Dr. Thomas Rando (an expert in epigenetics, aging, and regenerative medicine). My career development plan includes regular meetings with the mentoring team, didactics, and attendance and presentation at local and international meetings. In addition, I will take advantage of the rich intellectual environment an resources available at Stanford University. Stanford has a large, productive, collaborative faculty, rich with leaders in many fields of biomedical research. There are many shared and core facilities that will enable me to complete my studies, including flow-cytometry, genomics, and animal facilities. Stanford also offers wide variety of courses, seminars, and conferences that will enable me to expand my scientific knowledge and to keep abreast of the most recent developments in biomedical research. Together, the research, training plan, and resources presented in this proposal will support my continued development into a productive independent investigator and physician scientist.
Age, high-dose chemotherapy, and radiation therapy cause the thymus to involute (shrink), reducing T cells production, weakening the immune system, and resulting in increased risk of infection, cancer, and autoimmunity. Relatively little is known abou the mechanisms in the thymus that regulate thymic involution. The research proposed here studies the mechanisms that regulate thymus growth, size, involution, and function with the eventual goal of identifying therapeutic targets that can be used to restore thymus function after involution.
