Investigation of Myc Oncoprotein in B lymphocyte Development and Transformation

描述（由申请人提供）：转基因和基因靶向小鼠模型的广泛发展导致了对小鼠病理生物学家的巨大需求，他们需要将强大的研究训练与对小鼠生物学和病理学的广泛理解结合起来。首席研究员的长期职业目标是：(1)对我们对淋巴细胞发育和转化中的癌基因功能的理解做出开创性的贡献；(2)为培养小鼠病理生物学家提供最优质的环境和资源；(3)培训兽医和调查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。首席研究员（P.I.）在分子免疫学和癌症研究的转基因和基因敲除小鼠的产生和利用方面受过广泛、高质量的研究培训，并在实验动物医学方面受过兽医培训和经验。然而，p.l.。目前的临床和行政职责严重限制了私家侦探用于小鼠病理生物学研究的时间，以及作为新兴小鼠生物学家的导师的时间。本奖项申请的目的是提供资源，帮助私家侦探减轻行政和临床职责，使私家侦探可以专注于小鼠病理生物学的研究和培训。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）通常起着控制细胞增殖的作用，当失调时，会导致许多类型癌症的发生。然而，对于Myc在正常情况下如何刺激细胞分裂，我们仍然缺乏清晰的认识。具体目的是：(1)验证Myc刺激B细胞前受体下游的B淋巴细胞发育和扩增的假设；(2)验证Myc通过诱导细胞周期蛋白D的表达部分刺激B淋巴细胞发育和转化的假设；(3)验证Myc放大钙信号的假说，钙信号在Myc诱导的增殖和转化中起重要作用。(4)验证Myc直接抑制钙挤出泵PMCA4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癌基因的不受管制表达与人类多达25%的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Myc不受调节如何有效地刺激癌细胞分裂。

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.