ADVANCING MENTORING AND RESEARCH IN MOUSE PATHOBIOLOGY

描述(申请人提供)：应聘者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使他能够对新的小鼠模型进行全面的生物医学评估，并构成了培训初级小鼠病理生物学专家的强大资格。该奖项将解放候选人50%的努力，从而使他能够：1)增加对初学者的指导；2)以最有效的方式进行正在进行的研究项目。候选人导师增加的直接受益者是该系的七名病理学住院医生，以及候选人实验室的三名博士后研究员、一名研究生和五名本科生。此外，PI将把他对初级调查人员的积极培训扩展到一些合作实验室。他将在加州大学兽医学院(CVM)建立转基因小鼠当代病理生物学培训计划，并积极参与国家培训论坛。在他的研究中，候选人将扩展他的早期假设，即RB的失活会导致小鼠优先形成具有神经内分泌分化的肿瘤。为此，提出了以下具体目标：1)验证选择性预防垂体和甲状腺肿瘤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)测试靶向纯合子缺失小鼠组织将优先导致具有神经内分泌分化的肿瘤的假设；以及3)评估作为靶细胞类型的作用的Rb失活可能对肿瘤的进展具有协同和拮抗作用的假设。这些研究将使我们更好地理解Rb特定细胞类型的作用机制，为开发与Rb缺乏相关的有效的小鼠神经内分泌肿瘤模型奠定坚实的基础，并为初学者提供大量的培训机会。综上所述，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.