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

描述(由申请人提供)：这份建议书概述了Dinesh S.Rao医学博士的5年职业发展计划，以期在学术血液病理学方面取得成功。首席调查员(P.I.)在加州大学洛杉矶分校完成了病理学和血液病理学方面的有组织的住院医师和研究员培训。作为加州大学洛杉矶分校-加州理工学院STAR计划的一部分，这里提议的结构化研究培训将在加州理工学院大卫·巴尔的摩博士的实验室完成。巴尔的摩博士是1975年诺贝尔生理学或医学奖的获得者，现任罗伯特·A·米利根生物学教授和荣誉退休总统，他是一位杰出的生物学家，拥有指导众多内科科学家进入学术职位的丰富经验。S的职业发展将得益于加州理工大学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。私家侦探还将接受加州大学洛杉矶分校的科学家和医生委员会以及加州理工学院的论文委员会提供的职业和科学建议。这项建议的总体目标是研究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)人类淋巴癌的发生是由于B细胞癌基因c-myc、bcl2和bcl6的异常不受限制的表达；(Ii)miR-34通过在转录后限制癌基因的表达而在B细胞的终末分化中发挥作用；以及(Iii)miR-34调控异常的癌基因表达下调在B细胞肿瘤的发生中发挥了作用。拟议的实验将包括将c-myc、bcl2和bcl6慢病毒转导入人CD34+细胞，导入小鼠，并使用各种分子、细胞生物学、生化、组织学和其他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，我们将检查miR-34是否减轻了上述人源化淋巴瘤模型中B细胞肿瘤的发展。这些研究有望突出影响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。 相关性：淋巴瘤和白血病都是白血球癌症，每年都是导致无数美国人痛苦和死亡的主要原因。通过集中研究人类淋巴瘤，这项研究试图发现促进其发展的生物过程的新见解。因此，这些研究与公众健康直接相关，最重要的是，与患有这些疾病的患者有直接关系。

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.