BAFF Pathology: Novel Therapeutic Targets in Chronic Graft versus Host Disease

描述(由申请者提供)：本建议的主要目的是发展候选人在骨髓移植后发展的免疫病理学实验室研究的学术生涯。在两年半的时间里，候选人一直由哈佛癌症中心的Paul Calebrisi K12 Grant(Bruce Chabner博士，Pi)资助，在Dana-Farber癌症研究所的Jerome Ritz博士的实验室担任博士后。这位候选人现在在北卡罗来纳大学教堂山分校提出了一项导师计划，她于2009年6月1日开始在那里担任终身教职。北卡罗来纳大学K08导师计划将由阿尔伯特·鲍德温博士领导，他将担任候选人的主要导师。鲍德温博士是NFkB信号方面的顶尖专家，在成功指导年轻研究人员方面有着长期的记录。他已经为候选人制定了一个全面的指导计划，主要专注于发展她在肿瘤坏死因子家族成员受体信号方面的知识和实验专长。候选人的共同导师将是瑟罗迪博士，他是医学、微生物学和免疫学的特聘教授，也是莱恩伯格癌症中心免疫学部门的联合负责人。Serody博士被公认为移植物抗宿主病(GVHD)领域的领导者，他领导了几项由NIH资助的实验室研究，重点是趋化因子受体和免疫调节细胞在GVHD中的作用。候选人的主要合作者之一Thomas Shea博士与北卡罗来纳大学的IRB组织采购协议一起开发的全面临床数据库将使Sarantopoulos博士能够收集和鉴定接受异基因造血干细胞移植(HSCT)患者的样本。此外，达纳-法伯癌症中心的杰罗姆·里茨博士、杜克大学的Nelson Chao博士和弗雷德·哈钦森癌症中心的Stephanie Lee博士将合作，向候选人提供新鲜的和冷冻保存的HSCT患者样本。最后，Sarantopoulos博士组建了一个北卡罗来纳大学当地的专家科学咨询委员会，该委员会由北卡罗来纳大学微生物学和免疫学系的Stephen Clarke博士和Barbara Vilen博士组成，他们都是B细胞病理生物学方面的专家。她的导师和专家咨询委员会将使候选人能够将她以前所学到的和所取得的成就与在肿瘤坏死因子家族成员受体信号方面的详细、具体的学徒培训结合起来。研究将集中在癌症患者接受异基因造血干细胞移植(HSCT)治疗后发生的重大免疫病理研究。本研究的长期目标是了解肿瘤坏死因子家族的B细胞激活因子(BAFF)及其相关信号通路的作用。拟议的实验将允许未来开发新的靶向治疗慢性移植物抗宿主病的药物，并提高癌症患者的总体存活率。指导、教学和研究提案以及北卡罗来纳大学和莱恩伯格综合癌症中心提供的学术和研究基础设施将确保候选人成功过渡到NIH资助的独立研究人员。

DESCRIPTION (provided by applicant): ABSTRACT The major objective of this proposal is the development of the candidate's academic career in laboratory research of immune pathology that develops after bone marrow transplantation. For 2.5 years, the candidate was funded by a Paul Calebrisi K12 Grant (Dr. Bruce Chabner, PI) at the Harvard Cancer Center as a post- doctoral in Dr. Jerome Ritz' laboratory at Dana-Farber Cancer Institute. The candidate now proposes a mentorship plan at the University of North Carolina (UNC), Chapel Hill where she began a tenure-track faculty position on June 1st, 2009. The UNC K08 mentorship program will be headed by Albert Baldwin, Ph.D., who will serve as the candidate's primary mentor. Dr. Baldwin is a leading expert in NFkB signaling with a long track record of successfully mentoring young investigators. He has developed a comprehensive mentorship plan for the candidate primarily focused on developing her knowledge and experimental expertise in TNF family member receptor signaling. The candidate's co-mentor will be Dr. Serody who is an endowed Professor of Medicine, Microbiology and Immunology and co-leader of the Immunology Section in the Lineberger Cancer Center. Dr. Serody is recognized as a leader in the field of Graft versus Host Disease (GVHD) having led several NIH-funded laboratory studies focused on the role of chemokine receptors and immune regulatory cells in GVHD. A comprehensive clinical data base developed by one of the candidate's key collaborators, Dr. Thomas Shea, in conjunction with an IRB tissue procurement protocol at UNC will allow Dr. Sarantopoulos to collect and characterize samples from patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT). In addition, Dr. Jerome Ritz from Dana-Farber Cancer Center, Dr. Nelson Chao from Duke University and Dr. Stephanie Lee from Fred Hutchinson Cancer Center will collaborate and supply the candidate with fresh and cryopreserved HSCT patient samples. Finally, Dr. Sarantopoulos has assembled a local UNC expert scientific advisory committee comprised of Dr. Stephen Clarke and Dr. Barbara Vilen in the, Department Microbiology & Immunology at UNC, both experts in B cell pathobiology. Her mentors and expert advisory committee will enable the candidate to combine what she has previously learned and accomplished with detailed, specific apprenticeship training in TNF family member receptor signaling. Research will focus on studies of significant immune pathology that develops in patients after treatment for cancer with allogeneic hematopoietic stem cell transplantation (HSCT). The long-term goal of this research project is to understand the role of B cell Activating Factor of the TNF family (BAFF) and its associated signaling pathways. The proposed experiments will allow for future development of novel targeted therapeutic agents for chronic GVHD and improved overall survival of cancer patients. The mentorship, didactics, and research proposal along with the academic and research infrastructure provided by UNC and the Lineberger Comprehensive Cancer Center will ensure the candidate's successful transition to an NIH-funded independent investigator.