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

• 批准号: 7664581
• 负责人: BRIAN M IRITANI
• 金额: $ 11.02万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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/7664581
• 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; Students; 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

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）：转基因和基因靶向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，这些小鼠病理生物学家将联合收割机强大的研究培训与对小鼠生物学和病理学的广泛理解相结合。首席研究员的长期职业目标是：（1）为我们了解淋巴细胞发育和转化中的癌基因功能做出开创性贡献;（2）为培训小鼠病理生物学家提供最优质的环境和资源;（3）培训兽医和研究人员在生物医学研究中对动物进行人道关怀和负责任的使用。主要研究者（P.I.）在分子免疫学和癌症研究中，在转基因和基因敲除小鼠的产生和利用方面具有广泛的高质量研究培训，以及在实验室动物医学方面的兽医培训和经验。然而，P.L.目前的临床和行政职责严重限制了P.I.可以致力于小鼠病理生物学研究，并作为新兴小鼠生物学家的导师。此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，使私人侦探可以专注于研究和培训小鼠病理生物学。研究小组的广泛研究目标是了解Myc癌基因家族在淋巴细胞发育和转化中的作用和作用机制。Myc家族成员（c-，N-和Lmyc）通常起控制细胞增殖的作用，当失调时，有助于许多类型癌症的发生。然而，我们仍然缺乏对Myc如何正常发挥作用以刺激细胞分裂的清晰理解。具体目标是：（1）检验Myc刺激前B细胞受体下游的B淋巴细胞发育和扩增的假设;（2）检验Myc刺激B淋巴细胞发育和转化的假设部分地通过诱导细胞周期蛋白D的表达;（3）检验Myc放大钙信号传导的假设，钙信号传导对于Myc诱导的增殖和转化是重要的。(4)为了检验Myc直接抑制钙挤压泵PMCA 4表达的假设。这些目标将解决我们的总体假设，即Myc刺激增殖和分化，部分通过刺激细胞周期蛋白D的表达，并放大钙信号通路。myc癌基因表达失调与高达25%的人类广谱癌症的发生密切相关。本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，以及解除调节的Myc如何有效地刺激细胞在癌症中分裂。