Mechanisms regulating thymus growth and involution

描述（由申请人提供）：K 08奖的申请描述了一个多学科的5年培训计划，以促进我（菲利普加芬博士）作为一个独立的学术物理学家，科学家的职业发展。我最近完成了儿科血液学，肿瘤学和干细胞移植的奖学金，现在寻求扩大我的研究经验，以实现我的长期职业目标，成为一名独立的学术研究者，指导造血干细胞移植后胸腺功能和免疫重建的研究计划。我已经制定了这个长期目标，同时在调节胸腺生长和功能的机制方面取得了重大发现（最近发表- Garfin et. The Journal of Experimental Medicine，2013）。 基于我最近发现的调节胸腺大小和功能的RB-E2 F-FOXN 1模块，我假设肿瘤抑制途径调节胸腺生长和退化，这些途径抑制胸腺再生。为了验证这个假设，我提出了三个目标。 目的1：验证TEC中年龄依赖性细胞内机制确保胸腺退化并阻止胸腺生长和再生的假设。这一目标将使用RB家族蛋白的定时失活来鉴定促进和确保胸腺退化的机制。 目的2：验证Hippo/雅普通路调节胸腺大小和功能的假说。这一目标将测试第二个主要的生长控制途径在调节胸腺大小和功能中的作用。 目的3：验证脂肪细胞以RB依赖性方式促进胸腺退化的假设。这一目标将测试一种迄今尚未探索的细胞类型在胸腺退化中的作用。它还将测试RB家族在决定这些细胞命运中的作用。初步数据支持所有3个目标的可行性。 最终，对调节胸腺大小和退化的机制的更好理解将为旨在改善老年人和HSCT后的胸腺和免疫功能的治疗提供目标。 这个K 08奖将为我提供必要的支持和保护时间来完成以下培训目标：（1）成为胸腺和免疫生物学专家，（2）掌握基因表达，表观遗传学和免疫学的先进技术（3）继续发展规划和沟通科学探究的技能，以及（4）在第4年提交R 01申请。 为了实现这些目标，我组建了一个强大的指导团队，由遗传学、细胞生物学、胸腺、免疫学、表观遗传学和再生医学方面的专家组成，他们都成功地指导了年轻科学家。我的主要导师Julien Sage博士是RB生物学、再生医学、癌症生物学和复杂表型小鼠建模领域的领导者。他最近的三名博士后研究员完成了他们的培训，他们都领导着主要学术机构的独立实验室 （宾夕法尼亚儿童医院、弗吉尼亚大学和慕尼黑技术大学）。我的共同导师，肯尼思温伯格博士，是一位胸腺和免疫生物学专家，也是一位有成就的儿科干细胞移植医生。我的顾问委员会由大卫刘易斯博士（T细胞生物学专家）和托马斯兰多博士（表观遗传学、衰老和再生医学专家）组成。我的职业发展计划包括定期与辅导团队会面，教学，以及出席当地和国际会议并发表演讲。 此外，我将充分利用斯坦福大学丰富的知识环境和资源.斯坦福大学有一个庞大的，多产的，协作的教师队伍，在生物医学研究的许多领域的领导者丰富。有许多共享和核心设施，将使我能够完成我的研究，包括流式细胞术，基因组学和动物设施。斯坦福大学还提供各种各样的课程、研讨会和会议，使我能够扩展我的科学知识，并跟上生物医学研究的最新发展。 总之，本提案中提出的研究，培训计划和资源将支持我继续发展成为一名富有成效的独立调查员和医生科学家。

DESCRIPTION (provided by applicant): 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.