The role of Galpha13 signaling in development and dissemination of lymphoma

 描述(由申请者提供)：本建议书描述了一项为期5年的培训计划，使申请者Jagan Muppidi博士能够增加他的科学知识，学习癌症生物学方面的新技能，并发展淋巴瘤生物学的独立研究计划。Muppidi博士的主要导师Jason Cyster博士是加州大学旧金山分校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。赛斯特博士是一位国际公认的免疫学家，长期以来一直对生发中心(GC)反应中涉及的组织线索感兴趣。穆皮迪博士的科学和事业发展将得到他的指导委员会成员的帮助。凯文·香农博士是加州大学旧金山分校儿科和分子肿瘤学系的教授，在指导内科科学家和开发新的血液系统恶性肿瘤小鼠模型方面有着良好的记录，是RAS信号方面的专家。加州大学旧金山分校医学系副教授伊曼纽尔·帕斯格博士是调节骨髓微环境中造血干细胞存活和功能的线索专家。GC B细胞样弥漫性大B细胞淋巴瘤(GCB-DLBCL)和Burkitt淋巴瘤(BL)是起源于GC B细胞的淋巴系统恶性肿瘤。虽然GC B细胞通常是非再循环的，并紧密地局限于GC壁龛，但GC来源的淋巴瘤是全身性疾病，即使在有限的疾病中，全身化疗也是主要的治疗方法。目前尚不清楚哪些因素对支持GC来源的恶性肿瘤进入循环是重要的，以及哪些微环境因素可以促进远处部位的疾病存活。基因GNA13(编码G蛋白Ga13)的频繁功能丧失突变在GCB-DLBCL和BL中已被描述。我们最近的工作表明，Ga13信号的中断可能有助于GC来源的恶性肿瘤的系统性传播。拟议研究的总体目标是了解GC生态位限制的丧失如何有助于生发中心(GC)B细胞来源的淋巴瘤的发展和/或扩散。这一目标将通过两个具体的目标来实现：1)表征由于Ga13突变而导致的GC限制的丧失是否对于促进淋巴瘤的发展和/或扩散是重要的；2)从功能上表征在GC衍生的淋巴瘤中发现的Ga13效应物ARHGEF1的表达变化，并确定该Ga13效应物的缺失是否足以驱动淋巴肿瘤的发生。这项拟议的研究可能会确定治疗靶点，可以用来为GC来源的淋巴瘤患者产生新的治疗策略。这项工作也可能有助于确定GC来源的淋巴瘤患者发展为播散性疾病的高风险，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.