Role of B-cell oncogenes and microRNA-34 in B-lymphopoiesis and neoplasia

描述（由申请人提供）：本计划书概述了Dinesh S. Rao医学博士在血液病理学学术领域的五年职业发展计划。首席研究员（P.I.）在加州大学洛杉矶分校完成了病理学和血液病理学的结构化住院医师和奖学金培训。本文提出的结构化研究培训将在加州理工学院David Baltimore博士的实验室完成，作为加州大学洛杉矶分校-加州理工学院STAR计划的一部分。他是1975年诺贝尔生理学或医学奖的获得者，目前是Robert a . Millikan生物学教授和名誉主席，是一位杰出的生物学家，拥有丰富的经验，指导许多内科科学家进入学术职位。P.l。加州理工学院的基础科学环境和加州大学洛杉矶分校的医疗资源的协同作用将使他的职业发展受益。私家侦探还将从加州大学洛杉矶分校的一个科学家和医生委员会以及加州理工学院的一个论文委员会那里获得职业和科学建议。本提案的总体目标是研究microRNA-34 （miR-34）和b细胞癌基因在正常和肿瘤b细胞分化中的作用。正在测试的具体假设是：(i)人类淋巴瘤的发生是由于b细胞癌基因c-MYC、BCL2和BCL6的异常不受限制的表达；（ii） miR-34通过转录后限制癌基因表达，在末端b细胞分化中发挥作用；（iii） miR-34失调介导的癌基因表达下调在b细胞肿瘤的发生中起作用。拟进行的实验将需要慢病毒将c-MYC、BCL2和BCL6转导到人CD34+细胞中，引入小鼠，并使用各种分子、细胞生物学、生化、组织学等技术对小鼠进行表型分析。通过骨髓移植实验，我们将研究microRNA-34在b细胞发育中的作用。最后，我们将研究miR-34是否减轻上述人源化淋巴瘤模型中b细胞瘤的发展。这些研究有望揭示影响b细胞发育的新机制，并可能在淋巴瘤的诊断和治疗方面取得重要进展。

DESCRIPTION (provided by applicant): This proposal outlines a 5-year career development plan for Dinesh S. Rao, M.D. in anticipation of a career in academic hematopathology. The principal investigator (P.I.) has completed a structured residency and fellowship training in pathology and hematopathology at UCLA. The structured research training proposed herein will be completed in the laboratory of David Baltimore, Ph.D., at the California Institute of Technology, as part of the UCLA-Caltech STAR program. Dr. Baltimore, the recipient of the Nobel Prize in Physiology or Medicine in 1975, and currently the Robert A. Millikan Professor of Biology and President Emeritus, is a pre-eminent biologist with extensive experience mentoring numerous physician-scientists into academic positions. The P.l.'s career development will benefit from the synergy of the basic scientific environment at Caltech and the medical resources at UCLA. The P.I. will also receive career and scientific advice from a committee of scientists and physicians at UCLA, as well as a thesis committee at Caltech. The overall goal of this proposal is to study the roles of microRNA-34 (miR-34) and B-cell oncogenes in normal and neoplastic B-cell differentiation. The specific hypotheses being tested are: (i) Human lymphomagenesis results from aberrant unrestricted expression of the B-cell oncogenes, c-MYC, BCL2 and BCL6; (ii) miR-34 plays a role in terminal B-cell differentiation by restricting oncogene expression post-transcriptionally; and (iii) Dysregulation of miR-34 mediated downregulation of oncogene expression plays a role in the genesis of B-cell neoplasia. The proposed experiments will entail lentiviral transduction of c-MYC, BCL2 and BCL6 into human CD34+ cells, introduction into mice, and phenotypic analysis of the mice using various molecular, cell biological, biochemical, histologic and other techniques. Using bone marrow transfer experiments, we will examine the role of microRNA-34 in B-cell development. Lastly we will examine if miR-34 mitigates development of B-cell neoplasia in the humanized lymphoma model described above. These studies promise to highlight new mechanisms that effect B-cell development and may lead to important advances in the diagnosis and treatment of lymphoma. RELEVANCE: Lymphomas and leukemias, which are both cancers of white blood cells, are a major cause of suffering and death in numerous Americans each year. By concentrating on the study of human lymphoma, this study attempts to discover new insights into the biological processes that promote their development. Hence, these studies have a direct relevance to public health and most importantly, to patients living with these diseases.