Mechanisms regulating thymus growth and involution

胸腺生长和退化的调节机制

• 批准号: 8765570
• 负责人: PHILLIP M GARFIN
• 金额: $ 16.06万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2014-09-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8765570
• 关键词: Adipocytes; Advisory Committees; Affect; Age; Aging; Animals; Autoimmunity; Award; Biology; Biomedical Research; Cancer Biology; Cell Differentiation process; Cell Maturation; Cell physiology; Cells; Cellular Immunity; Cellular biology; Childhood; Coculture Techniques; Complex; Core Facility; Data; Development; Development Plans; Elderly; Environment; Epigenetic Process; Faculty; Family; Fatty acid glycerol esters; Fellowship; Flow Cytometry; Foundations; Gene Deletion; Gene Expression; Genetic; Genetically Engineered Mouse; Genomics; Goals; Growth; Health Benefit; Hematopoietic Stem Cell Transplantation; High Dose Chemotherapy; Homologous Gene; Immune; Immune system; Immunology; Individual; Infection; Institution; International; Journals; Knowledge; Laboratories; Lead; Life; Malignant Neoplasms; Mature T-Lymphocyte; Medicine; Mentors; Molecular; Mus; Natural regeneration; Organ Size; Output; Pathway interactions; Patients; Pediatric Hematology/Oncology; Pediatric Hospitals; Pennsylvania; Phenotype; Phosphotransferases; Physicians; Play; Postdoctoral Fellow; Production; Protein Family; Publishing; Radiation therapy; Recovery; Regenerative Medicine; Regulation; Research; Research Personnel; Research Training; Resources; Risk; Role; Scientist; Secure; Site; Stem cell transplant; T-Lymphocyte; Techniques; Testing; Thymic epithelial cell; Thymus Gland; Time; Training; Training Programs; Transplantation; Tumor Suppressor Proteins; Universities; Virginia; Work; age related; aged; animal facility; base; career; career development; cell type; experience; fly; immune function; improved; meetings; mouse model; multidisciplinary; mutant; novel; novel therapeutics; prevent; programs; public health relevance; reconstitution; regenerative; research study; skills; symposium; therapeutic target; time use; tumor

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.

描述（由申请人提供）：本申请申请K08奖描述了一项多学科的5年培训计划，以促进我（Phillip Garfin博士）作为独立的学术医师科学家的职业发展。我最近完成了一项小儿血液学，肿瘤学和干细胞移植的研究金，现在试图扩大我的研究经验，以实现我成为独立学术研究者的长期职业目标，指导了胸腺功能研究和免疫重建研究计划，并在血管植物干细胞移植后进行了免疫结构。我已经制定了这一长期目标，同时对调节胸腺生长和功能的机制进行了重大发现（最近出版-Garfin等人，《实验医学杂志》，2013年）。 在我最近发现的调节胸腺大小和功能的RB-E2F-FOXN1模块的基础上，我假设肿瘤抑制途径调节了胸腺的生长和相关性，并且这些途径抑制了胸腺的再生。为了检验这一总体假设，我提出了三个目标。 目的1：检验以下假设：TEC中的年龄依赖性细胞内机制可确保胸腺侵入并防止胸腺生长和再生。该目标将使用RB蛋白质家族的定时失活，以确定促进和确保胸腺相关性的机制。 目标2：测试河马/YAP途径调节胸腺大小和功能的假设。该目标将测试第二个主要生长控制途径在调节胸腺大小和功能中的作用。 目标3：检验以下假设，即脂肪细胞以RB依赖性方式促进胸腺差异。该目标将测试迄今未探索的细胞类型在胸腺反应中的作用。它还将测试RB家族在确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，对调节胸腺大小和相关机制的机制有了改进的理解，将为旨在改善老年人和HSCT的胸腺和免疫功能的疗法提供靶标。 该K08奖将为我提供实现以下培训目标所需的支持和受保护的时间：（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和免疫学和免疫学和免疫学（3）的高级技术的高级技术，以继续开发计划和沟通科学询问的技能，并在一年中提交一年的训练，并（4）在Insperific of Scient和（4）提交R01 r01 i i。遗传学，细胞生物学，胸腺，免疫学，表观遗传学和再生医学专家 - 他们都成功地指导了年轻的科学家。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的小鼠建模领域的领导者。他的三个最重要的博士后研究员完成了他们在主要学术机构的所有领导独立实验室的培训 （宾夕法尼亚州儿童医院，弗吉尼亚大学和慕尼黑技术大学）。我的同事肯尼斯·温伯格（Kenneth Weinberg）博士是胸腺和免疫生物学的专家，也是一位出色的小儿干细胞移植医师。我的咨询委员会由David Lewis博士（T细胞生物学专家）和Thomas Rando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与指导团队的定期会议，教学事务，以及在当地和国际会议上的出席和演讲。 此外，我将利用富裕的智力环境在斯坦福大学提供的资源。斯坦福大学拥有大型，富有成效的合作教师，在许多生物医学研究领域的领导者都有丰富的领导者。有许多共享和核心设施可以使我能够完成研究，包括流程仪，基因组学和动物设施。斯坦福大学还提供各种课程，研讨会和会议，这将使我能够扩大自己的科学知识，并与生物医学研究的最新发展保持一致。 该提案中提出的研究，培训计划和资源一起将支持我持续发展成为一位富有成效的独立研究者和医师科学家。