The role of Galpha13 signaling in development and dissemination of lymphoma

 描述（由申请人提供）：本提案描述了一个为期5年的培训计划，以使申请人Jagan Muppidi博士能够增加其科学知识，学习癌症生物学的新技能，并在淋巴瘤生物学方面制定独立的研究计划。Muppidi博士的主要导师Jason Cyster博士是UCSF微生物学和免疫学系的教授，也是霍华德休斯医学研究所的研究员。Cyster博士是一位国际公认的免疫学家，长期以来一直对参与生发中心（GC）反应的组织线索感兴趣。Muppidi博士的科学和职业发展将得到他的导师委员会成员的帮助。Kevin Shannon博士是UCSF儿科和分子肿瘤学系的教授，在指导医生科学家和开发新型造血系统恶性肿瘤小鼠模型方面有着良好的记录，并且是Ras信号传导方面的专家。Emmanuelle Passegue博士是UCSF医学系的副教授，是调节骨髓微环境中造血干细胞存活和功能的线索的专家。GC B细胞样弥漫性大B细胞淋巴瘤（GCB-DLBCL）和伯基特淋巴瘤（BL）是源自GC B细胞的淋巴恶性肿瘤。虽然GC B细胞通常是非再循环的，并严格限制在GC龛，GC衍生的淋巴瘤是全身性疾病，全身化疗是治疗的主要手段，即使在有限的阶段疾病。目前还不知道什么因素是重要的支持GC衍生的恶性肿瘤传播到循环和微环境因素可以促进疾病的生存在遥远的网站。在GCB-DLBCL和BL中已经描述了基因GNA 13（编码G蛋白Ga 13）中的频繁功能缺失突变。我们最近的工作表明，Ga 13信号的破坏可能有助于GC衍生的恶性肿瘤的全身传播。拟议研究的总体目标是了解GC生态位限制的丧失如何促进生殖中心（GC）B细胞源性淋巴瘤的发展和/或传播。这一目标将在两个具体目标中实现：1）表征由于Ga 13突变导致的GC限制的丧失对于促进淋巴瘤发展和/或传播是否重要; 2）在功能上表征在GC衍生的淋巴瘤中发现的Ga 13效应物ARHGEF 1表达的改变，并确定该Ga 13效应物的丧失是否足以驱动淋巴瘤发生。拟议的研究可能会确定治疗目标，可用于为GC衍生淋巴瘤患者产生新的治疗策略。这项工作也可能是有用的，在确定患者与GC衍生淋巴瘤的高风险发展为播散性疾病，因此需要更积极的一线治疗。

 DESCRIPTION (provided by applicant): This proposal describes a 5-year training program to enable the applicant, Dr. Jagan Muppidi, to increase his scientific knowledge, learn new skills in cancer biology and develop an independent research program in lymphoma biology. Dr. Muppidi's primary mentor, Dr. Jason Cyster, is a Professor in the Department of Microbiology and Immunology at UCSF and an Investigator of the Howard Hughes Medical Institute. Dr. Cyster is an internationally recognized immunologist with a long-standing interest in organizational cues involved in the germinal center (GC) reaction. Dr. Muppidi's scientific and career development will be aided by the members of his mentorship committee. Dr. Kevin Shannon, a Professor in the Department of Pediatrics and Molecular Oncology at UCSF, has a strong track record of mentoring physician-scientists and developing novel mouse models of hematopoietic malignancy and is an expert in Ras signaling. Dr. Emmanuelle Passegue, an Associate Professor in the Department of Medicine at UCSF, is an expert in the cues regulating survival and function of hematopoietic stem cells in the bone marrow microenvironment. GC B cell-like diffuse large B cell lymphoma (GCB-DLBCL) and Burkitt Lymphoma (BL) are lymphoid malignancies that are derived from GC B cells. Although GC B cells are normally non-recirculatory and tightly confined to the GC niche, GC-derived lymphomas are systemic diseases and systemic chemotherapy is a mainstay of treatment even in limited stage disease. Little is currently known about what factors are important for supporting dissemination of GC-derived malignancies into circulation and what microenvironmental factors can promote the survival of disease at distant sites. Frequent loss of function mutations in the gene GNA13 (encoding the G-protein Ga13) have been described in GCB-DLBCL and BL. Our recent work has suggested that that disruption of Ga13 signaling may contribute to systemic dissemination of GC-derived malignancy. The overall goal of the proposed research is to understand how loss of GC niche confinement contributes to the development and/or dissemination of germinal center (GC) B cell-derived lymphomas. This goal will be accomplished in two specific aims: 1) Characterize whether loss of GC confinement due to mutation of Ga13 is important for promoting lymphoma development and/or dissemination; 2) Functionally characterize alterations in expression of the Ga13 effector, ARHGEF1 found in GC-derived lymphomas and determine whether loss of this Ga13-effector is sufficient to drive lymphomagenesis. The proposed research may identify therapeutic targets that could be used to generate novel treatment strategies for patients with GC-derived lymphomas. This work may also be useful in identifying patients with GC-derived lymphoma at high risk for developing disseminated disease and therefore require more aggressive front line therapy.