Investigation of Myc Oncoprotein in B lymphocyte Development and Transformation

Myc癌蛋白在B淋巴细胞发育和转化中的研究

基本信息

批准号：
8269009
负责人：
BRIAN M IRITANI
金额：
$ 11.53万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8269009
关键词：
Address Animals Award B-Cell Development B-Lymphocytes Binding Biochemical Biochemistry Biological Models Biology Biomedical Research Calcium Calcium Signaling Caring Cell Cycle Cell Proliferation Cell division Cells Clinical Cyclin D1 Data Development Elements Environment Family Family member Gene Targeting Generations Genes Genetic Genetic Transcription Genetically Engineered Mouse Growth Human Immunologic Techniques Investigation Knockout Mice Laboratory Animal Medicine Lead Learning Lymphocyte Lymphocyte Activation MYC gene Malignant Neoplasms Mammalian Cell Mentors Molecular Biology Molecular Immunology Mus N-myc Gene Oncogene Proteins Oncogenes Pathology Postdoctoral Fellow Principal Investigator Pump Reporter Research Research Personnel Research Training Resources Role Seminal Series Services Signal Pathway Tamoxifen Techniques Testing Time Training Transduction Gene Transgenic Mice Transgenic Organisms Veterinarians Work base c-myc Genes cancer type career chromatin immunoprecipitation design and construction experience investigator training lymphocyte proliferation mouse model overexpression pre-B cell receptor promoter research study retroviral transduction transcription factor undergraduate student

项目摘要

DESCRIPTION (provided by applicant): The extensive growth of transgenic and gene-targeted mouse models has resulted in an enormous need for mouse pathobiologists that combine strong research training with an extensive understanding of mouse biology and pathology. The Principal investigator's longterm career objectives are to: (1) make seminal contributions to our understanding of oncogene functions in the development and transformation of lymphocytes; (2) provide the highest quality environment and resources for training mouse pathobiologists; and (3) train veterinarians and investigators in the humane care and responsible use of animals in biomedical research. The principal investigator (P.I.) has extensive, high-quality research training in the generation and utilization of transgenic and knockout mice for research in Molecular Immunology and Cancer, as well as veterinary training and experience in laboratory animal medicine. However, the P.l.'s current clinical and administrative responsibilities severely limit the amount of time that the P.I. can be devote to mouse pathobiology research, and to act as a mentor for burgeoning mouse biologists. The purpose of this award application is to provide resources to help relieve the P.I. from administrative and clinical duties so that the P.I can focus on research and training in mouse pathobiology. The broad research objective of the investigative team is to understanding the roles, and mechanism of action, of the Myc oncogene family in the development and transformation of lymphocytes. Myc-family members (c-, N-, and Lmyc) normally function to control cell proliferation, and when deregulated, contribute to the genesis of many types of cancers. However, we still lack a clear understanding as to how Myc normally functions to stimulate cell division. The specific aims are: (1) To examine the hypothesis that Myc stimulates B lymphocyte development and expansion downstream of the pre-B cell receptor; (2) To examine the hypothesis that Myc stimulates B lymphocyte development and transformation in part by inducing the expression of cyclin D; (3) To examine the hypothesis that Myc amplifies calcium signaling which is important for Myc-induced proliferation and transformation. (4) To examine the hypothesis that Myc directly inhibits the expression of the calcium extrusion pump PMCA4. These Aims will address our overall hypothesis that Myc stimulates both proliferation and differentiation, in part by stimulating cyclin D expression, and amplifying calcium signaling pathways. Deregulated expression of the myc oncogene is profoundly involved in the genesis of up to 25 percent of a wide-spectrum of cancers in humans. Experiments described in this proposal will utilize transgenic and knockout mice to help elucidate the normal functions of Myc in lymphocyte development, and how deregulated Myc potently stimulates cells to divide in cancer.

描述（由申请人提供）：转基因和靶向基因的小鼠模型的广泛增长导致对小鼠病理生物学家的巨大需求，这些病理学家将强有力的研究培训与对小鼠生物学和病理学的广泛了解相结合。首席研究者的长期职业目标是：（1）为我们对淋巴细胞发展和转化中的癌基因功能做出开创性的贡献；（2）为培训鼠标病理学家提供最高质量的环境和资源；（3）培训兽医护理和负责使用动物在生物医学研究中的兽医和研究人员。首席研究员（P.I.）在转基因和基因敲除小鼠的分子免疫学和癌症研究以及实验室动物医学领域的兽医培训和经验方面，对转基因和基因敲除小鼠进行了广泛的高质量研究培训。但是，P.L.目前的临床和行政责任严重限制了P.I.可以专用于小鼠病理生物学研究，并充当迅速发展的小鼠生物学家的导师。本奖项申请的目的是提供资源以帮助减轻P.I.从行政和临床职责中，P.I可以专注于小鼠病理生物学的研究和培训。调查团队的广泛研究目标是了解MYC Oncogene家族在淋巴细胞发展和转化中的作用和作用机理。 MYC家庭成员（C-，N-和LMYC）通常在控制细胞增殖方面起作用，并且在放松管制时，会导致许多类型的癌症的起源。但是，我们仍然对MYC通常如何刺激细胞分裂的功能缺乏明确的了解。具体目的是：（1）检查MYC刺激前B细胞受体下游的B淋巴细胞发育和扩张的假设；（2）检查MyC刺激B淋巴细胞发育和转化的假设部分通过诱导细胞周期蛋白D的表达；（3）检查MYC放大钙信号传导的假设，这对于MYC诱导的增殖和转化很重要。（4）检查了MYC直接抑制钙挤出泵PMCA4的表达的假设。这些目的将解决我们的总体假设，即MYC刺激了增殖和分化，部分原因是刺激细胞周期蛋白D表达和扩增钙信号通路。 Myc致癌基因的表达表达与人类中多达25％的广谱癌症的起源深远有关。该提案中描述的实验将利用转基因和基因敲除小鼠来帮助阐明MYC在淋巴细胞发育中的正常功能，以及对MYC的失控如何有效刺激细胞在癌症中分裂。