ADVANCING MENTORING AND RESEARCH IN MOUSE PATHOBIOLOGY

描述（由申请方提供）：候选人对转基因小鼠的病理生物学具有长期兴趣。 他在人类病理学方面的培训和在小鼠病理生物学方面的丰富经验允许对新型小鼠模型进行全面的生物医学评价，并构成了培训初级小鼠病理生物学家的强大资格。 该奖项将释放候选人的努力的50%，从而使他能够：1）增加他的指导开始调查;和2）进行正在进行的研究项目以最有效的方式。 在候选人的指导增加的直接受益者是七个病理学居民在部门，以及三个博士后研究员，一个研究生，和五个本科生在候选人的实验室。 此外，主要研究者将把他对初级研究者的积极培训扩展到一些合作实验室。 他将在科罗拉多大学兽医学院（CVM）建立一个转基因小鼠的当代病理生物学培训项目，并积极参加国家培训论坛。 在他的研究中，候选人将扩展测试他早期的假设，即Rb的失活导致小鼠优先形成具有神经内分泌分化的肿瘤。为此，提出了以下具体目的：1）检验选择性预防垂体和甲状腺肿瘤将导致优先形成具有神经内分泌分化的其他自发性肿瘤的假设; 2）检验小鼠组织中Rb的靶向纯合缺失将优先导致具有神经内分泌分化的肿瘤的假设;和3）评估Rb失活可能对肿瘤形成的进展具有协同和拮抗作用的假说，作为靶细胞类型的函数。 这些研究将使我们更好地了解Rb的细胞类型特异性作用的机制，为开发有效的Rb缺乏相关神经内分泌肿瘤小鼠模型奠定坚实的基础，并为培训初学者提供了许多机会。 总的来说，将候选人的时间从无关的职责中解放出来，将极大地促进他在转基因小鼠病理生物学方面的指导和富有成效的研究。

DESCRIPTION (provided by applicant): The Candidate has a long-term interest in the pathobiology of genetically modified mice. His training in human pathology and extensive experience in murine pathobiology permit for a comprehensive biomedical evaluation of novel mouse models, and constitute strong qualifications for the training of beginning mouse pathobiologists. The Award will free 50 percent of the Candidate's effort, thereby allowing him to: 1) increase his mentoring of beginning investigators; and 2) conduct ongoing research projects in the most effective manner. The immediate beneficiaries of this increase in the Candidate's mentoring are seven pathology residents at the department, as well as three postdoctoral fellows, one graduate, and five undergraduate students in the Candidate's laboratory. Additionally, the PI will extend his active training of beginning investigators to a number of collaborating laboratories. He will establish a training program in contemporary pathobiology of genetically modified mice at the College of Veterinary Medicine (CVM) at CU, and actively participate in national training forums. In his research, the Candidate will extend testing his earlier hypothesis that inactivation of the Rb results in preferential formation of neoplasms with neuroendocrine differentiation in mice. Towards this goal, the following Specific Aims are proposed: 1) to test the hypothesis that selective prevention of neoplasia in the pituitary and thyroid glands will result in preferential formation of other spontaneous tumors with neuroendocrine differentiation; 2) to test the hypothesis that targeted homozygous deletion of Rb in mouse tissues will preferentially result in neoplasia with neuroendocrine differentiation; and 3) to evaluate the hypothesis that Rb inactivation may have both synergistic and antagonistic effects on progression of neoplasia as a function of target cell type. These studies shall lead to our better understanding of mechanisms defining cell type-specific roles of Rb, lay a solid foundation for developing valid mouse models of neuroendocrine neoplasia associated with Rb deficiency, and provide numerous opportunities for training of beginning investigators. Taken together, freeing the Candidate's time from unrelated duties will greatly facilitate his efforts towards mentoring and productive research in the pathobiology of genetically modified mice.