Investigation of Myc Oncoprotein in B lymphocyte Development and Transformation

描述(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，他们将强大的研究培训与对小鼠生物学和病理学的广泛理解结合在一起。首席研究员的长期职业目标是：(1)为我们理解癌基因在淋巴细胞发育和转化中的功能做出开创性的贡献；(2)为培训小鼠病理生物学家提供最高质量的环境和资源；以及(3)在生物医学研究中培训兽医和研究人员对动物的人文关怀和负责任的使用。首席调查员(P.I.)在产生和利用转基因和基因敲除小鼠用于分子免疫学和癌症研究方面拥有广泛、高质量的研究培训，以及兽医培训和实验动物医学经验。然而，P.L.S目前的临床和行政职责严重限制了P.I.可以用于小鼠病理生物学研究的时间，并限制了P.I.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，帮助P.I.从行政和临床职责中解脱出来，以便P.I.可以专注于老鼠病理生物学的研究和培训。研究小组的主要研究目标是了解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，当解除调控时，会导致许多类型癌症的发生。然而，对于Myc如何正常发挥刺激细胞分裂的作用，我们仍然缺乏明确的了解。其具体目的是：(1)检验Myc刺激前B细胞受体下游B淋巴细胞发育和扩张的假说；(2)检验Myc部分通过诱导细胞周期蛋白D的表达来刺激B淋巴细胞发育和转化的假说；(3)检验Myc放大钙信号对Myc诱导的增殖和转化至关重要的假说。(4)验证Myc直接抑制钙挤压泵PMCA4表达的假说。这些目标将解决我们的总体假设，即Myc刺激增殖和分化，部分是通过刺激细胞周期蛋白D的表达，并放大钙信号通路。Myc癌基因表达的失控与高达25%的人类广泛癌症的发生密切相关。这项建议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，以及解除调控的Myc如何有效地刺激癌症中的细胞分裂。

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.