ADVANCING MENTORING AND RESEARCH IN MOUSE PATHOBIOLOGY

描述（由申请人提供）：候选人对转基因小鼠的病理生物学有长期的兴趣。他在人类病理学方面的训练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估，并为培养初级小鼠病理生物学家提供了强有力的资格。该奖项将免除候选人50%的努力，从而使他能够：1)增加对初级调查人员的指导；2)以最有效的方式进行正在进行的研究项目。候选人指导人数增加的直接受益者是该系的7名病理学住院医师，以及候选人实验室的3名博士后、1名研究生和5名本科生。此外，PI将把他对初级研究人员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）建立转基因小鼠当代病理生物学培训计划，并积极参加国家培训论坛。在他的研究中，候选人将扩展他早期的假设，即Rb的失活导致小鼠神经内分泌分化肿瘤的优先形成。为此，我们提出以下具体目的：1)验证选择性预防垂体、甲状腺肿瘤形成将导致其他具有神经内分泌分化的自发性肿瘤优先形成的假设；2)验证小鼠组织中Rb的靶向纯合缺失会优先导致具有神经内分泌分化的肿瘤发生的假设；3)评估Rb失活可能对肿瘤进展具有协同和拮抗作用的假设，作为靶细胞类型的功能。这些研究将使我们更好地理解Rb的细胞类型特异性作用机制，为建立有效的Rb缺乏相关的小鼠神经内分泌肿瘤模型奠定坚实的基础，并为初学研究者的培训提供大量机会。综上所述，将候选人的时间从不相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.