The role of Galpha13 signaling in development and dissemination of lymphoma

Galpha13信号在淋巴瘤发生和传播中的作用

• 批准号: 8947837
• 负责人: Jagan Muppidi
• 金额: $ 17.55万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8947837
• 关键词: ARHGEF1 gene; Abdomen; Address; Animals; Appearance; B-Lymphocytes; Biological Markers; Biology; Blood; Blood Circulation; Bone Marrow; Burkitt Lymphoma; Cancer Biology; Cell Line; Cell Survival; Cells; Collaborations; Coupled; Cues; Data; Development; Disease; Disease Progression; Distant; Frequencies; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genes; Goals; Growth; Guanine Nucleotide Exchange Factors; Guanine Nucleotides; Health; Hematopoietic Neoplasms; Hematopoietic stem cells; Heterogeneity; Immunologist; Immunology; In Vitro; Institutes; Knowledge; Learning; Length; Limited Stage; Lymph; Lymphatic; Lymphoma; Lymphomagenesis; Malignant - descriptor; Malignant Neoplasms; Malignant lymphoid neoplasm; Medical; Medicine; Mentors; Mentorship; Microbiology; Monomeric GTP-Binding Proteins; Mus; Mutation; Neck; Pathway interactions; Patients; Physicians; Proteins; RNA Splicing; Reaction; Receptor Signaling; Regulation; Research; Research Personnel; Role; Sampling; Scientist; Signal Transduction; Site; Sphingosine-1-Phosphate Receptor; Structure of germinal center of lymph node; Systemic disease; Tertiary Protein Structure; Training Programs; Tumor Cell Line; Tumor Suppressor Proteins; Variant; Work; aged; career development; cell motility; chemotherapy; exome sequencing; high risk; in vivo; interest; large cell Diffuse non-Hodgkin' s lymphoma; loss of function mutation; lymph nodes; member; molecular oncology; mouse model; novel; pediatric department; professor; programs; rho; skills; therapeutic target; tool; training project; treatment strategy

 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.

 描述（由申请人提供）：该提案描述了一个为期 5 年的培训计划，旨在使申请人 Jagan Muppidi 博士能够增加其科学知识，学习癌症生物学的新技能，并开发淋巴瘤生物学的独立研究计划。 Muppidi 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。Cyster 博士是一位国际公认的免疫学家，拥有悠久的历史。 Muppidi 博士对参与生发中心 (GC) 反应的组织线索的兴趣将得到他的指导委员会成员 Kevin Shannon 博士（加州大学旧金山分校儿科和分子肿瘤学系教授）的帮助。 Emmanuelle Passegue 博士在指导医师科学家和开发造血系统恶性肿瘤的新型小鼠模型方面拥有丰富的经验，是 Ras 信号传导方面的专家，也是该系的副教授。 UCSF 医学博士是调节骨髓微环境中造血干细胞存活和功能的专家 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) 是淋巴恶性肿瘤。虽然 GC B 细胞通常是非再循环的并且严格局限于 GC 生态位，但 GC 衍生淋巴瘤是全​​身性疾病，全身化疗是主要治疗方法。即使在有限期疾病中，目前对于哪些因素对于支持 GC 衍生的恶性肿瘤传播到循环系统中起重要作用以及哪些微环境因素可以促进远处部位疾病的存活仍知之甚少。 G 蛋白 Ga13）已在 GCB-DLBCL 和 BL 中得到描述，表明 Ga13 信号传导可能有助于破坏 GC 衍生的恶性肿瘤的系统性传播。拟议研究的目的是了解 GC 生态位限制的丧失如何促进生发中心 (GC) B 细胞衍生淋巴瘤的发展和/或传播。该目标将通过两个具体目标来实现：1) 表征 GC 是否丧失。 Ga13 突变引起的限制对于促进淋巴瘤的发展和/或传播很重要；2) Ga13 效应子、GC 衍生淋巴瘤中发现的 ARHGEF1 表达的功能性改变确定这种 Ga13 效应子的缺失是否足以驱动淋巴瘤发生。这项研究可能会确定可用于为 GC 衍生淋巴瘤患者制定新治疗策略的治疗靶点。衍生性淋巴瘤具有发生播散性疾病的高风险，因此需要更积极的一线治疗。