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

描述（由申请人提供）：摘要本提案的主要目的是发展候选人在骨髓移植后免疫病理学实验室研究方面的学术生涯。在两年半的时间里，该候选人获得了哈佛大学癌症中心Paul Calebrisi K12 Grant （Bruce Chabner博士，PI）的资助，在达纳-法伯癌症研究所Jerome Ritz博士的实验室担任博士后。这位候选人现在提出了北卡罗来纳大学教堂山分校（UNC）的指导计划，她于2009年6月1日开始担任该大学的终身教职。北卡罗来纳大学K08指导计划将由Albert Baldwin博士领导，他将作为候选人的主要导师。鲍德温博士是NFkB信号的领先专家，在成功指导年轻研究人员方面有着长期的记录。他为候选人制定了一个全面的指导计划，主要侧重于发展她在TNF家族成员受体信号方面的知识和实验专业知识。候选人的共同导师将是serdy博士，他是Lineberger癌症中心的医学、微生物学和免疫学教授，也是免疫学部门的共同负责人。serdy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nih资助的实验室研究，专注于趋化因子受体和免疫调节细胞在GVHD中的作用。由候选人的主要合作者之一Thomas Shea博士开发的综合临床数据库，结合UNC的IRB组织采购协议，将使Sarantopoulos博士能够收集和表征接受同种异体造血干细胞移植（HSCT）的患者的样本。此外，丹娜-法伯癌症中心的Jerome Ritz博士、杜克大学的Nelson Chao博士和Fred Hutchinson癌症中心的Stephanie Lee博士将合作为候选人提供新鲜和冷冻保存的HSCT患者样本。最后，Sarantopoulos博士召集了一个当地的北卡罗来纳大学专家科学咨询委员会，该委员会由北卡罗来纳大学微生物与免疫学系的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之前所学到的知识与TNF家族成员受体信号的详细、具体的学徒培训结合起来。研究将集中在异体造血干细胞移植（HSCT）治疗癌症患者后发生的重要免疫病理研究。本研究项目的长期目标是了解B细胞活化因子TNF家族（BAFF）及其相关信号通路的作用。所提出的实验将允许未来开发针对慢性GVHD的新型靶向治疗药物，并提高癌症患者的总体生存率。北卡罗来纳大学和莱恩伯格综合癌症中心提供的指导、教学和研究计划以及学术和研究基础设施将确保候选人成功过渡到美国国立卫生研究院资助的独立研究者。

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. PUBLIC HEALTH RELEVANCE: NARRATIVE Allogeneic hematopoietic cell transplantation (HCST) is the only known curative option for many of the approximately 40 per 100,000 Americans afflicted with life-threatening blood-borne cancers. After HCST, chronic graft versus host disease (cGVHD) develops in 30-70% of patients carrying an impact on survival that has not improved significantly over the last 30 years. The current research will advance knowledge about immunopathologic mechanisms in human cGVHD. Our findings have implications for treatment of neoplastic, autoimmune and infectious diseases.