Neuropathology of a Mouse Model for Phenylketonuria

苯丙酮尿症小鼠模型的神经病理学

• 批准号: 7073455
• 负责人: JENNIFER E EMBURY
• 金额: $ 10.68万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-16 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7073455
• 关键词: adeno associated virus group; behavior test; developmental neurobiology; disease /disorder model; gene therapy; genetically modified animals; hypothalamus; laboratory mouse; magnetic resonance imaging; mesencephalon; neuropathology; neuroregulation; nonhuman therapy evaluation; phenylketonurias; recombinant virus; tissue /cell culture; transfection /expression vector

DESCRIPTION (provided by applicant): Dr. Embury, a veterinarian, has recently completed residency training in Anatomic Pathology. The objective of her training was to gain expertise in characterizing genetically-engineered animals, with a goal of an academic position in basic research involving laboratory animals. Dr. Embury initially participated (1998-1999) in the construction and molecular characterization of AAV- based gene therapy vectors for the treatment of Phenylketonuria (PKU) in the Pahenu2 mouse model. This metabolic disorder is one of the most common human birth defects and results in severe CNS disturbances. After completing her residency, she returned on a full-time basis and is currently engaged in the pathological evaluation of Pahenu2 mice. She will continue this investigation, as well as increase her knowledge of neuropathology, in line with her career goals of a faculty position involved in the characterization of genetically engineered animal models. The immediate objectives of this proposal are to examine the neuropathogenesis of PKU in the Pahenu2 mouse model, both validating the results of gene therapy and providing preclinical data. The three Specific Aims are: 1) Characterize histopathologic lesions within the posterior periventricular hypothalamic nuclei and the mesencephalon in Pahenu2 mice; 2) Establish a time course of neuropathologic development in Pahenu2 neonatal mice; and 3) Evaluate the efficacy of gene therapy treatment on neurological deficits in Pahenu2 mice. This work will be conducted in the Department of Biochemistry and Molecular Biology and the McKnight Brain Institute, University of Florida College of Medicine. Dr. Laipis, the primary mentor, has phenotypically corrected PKU in the Pahenu2 mouse with AAV-based vectors, and will provide the host laboratory and necessary support for the research program. Additional faculty, experienced in neuropathology, neurodevelopment and rodent behavior have agreed to participate in Dr. Embury's training and experiments. We believe that the experimental plan presented in this proposal, combined with selected courses in neuroscience and research methods as well as continued participation in clinical case presentations in neuropathology can provide the specialized training needed for her development. In addition, she will have continued exposure to and participation in the molecular biological methods of biomedical research through her involvement in the Laipis laboratory.

描述（由申请人提供）： Embury 博士是一名兽医，最近完成了解剖病理学住院医师培训。她接受培训的目的是获得基因工程动物特征方面的专业知识，目标是在涉及实验动物的基础研究中获得学术地位。 Embury 博士最初（1998-1999 年）参与了基于 AAV 的基因治疗载体的构建和分子表征，用于治疗 Pahenu2 小鼠模型中的苯丙酮尿​​症 (PKU)。这种代谢紊乱是最常见的人类出生缺陷之一，会导致严重的中枢神经系统紊乱。完成住院医师实习后，她全职回国，目前从事Pahenu2小鼠的病理评估工作。她将继续这项研究，并增加她对神经病理学的了解，这符合她参与基因工程动物模型表征的教员职位的职业目标。该提案的直接目标是在 Pahenu2 小鼠模型中检查 PKU 的神经发病机制，既验证基因治疗的结果，又提供临床前数据。三个具体目标是： 1) 表征 Pahenu2 小鼠脑室周围下丘脑核和中脑内的组织病理学病变； 2) 建立Pahenu2新生小鼠神经病理学发育的时间进程； 3) 评估基因疗法对 Pahenu2 小鼠神经功能缺损的疗效。这项工作将在佛罗里达大学医学院生物化学与分子生物学系和麦克奈特脑研究所进行。主要导师Laipis博士使用基于AAV的载体对Pahenu2小鼠的PKU进行了表型纠正，并将为该研究项目提供宿主实验室和必要的支持。在神经病理学、神经发育和啮齿动物行为方面经验丰富的其他教师已同意参加 Embury 博士的培训和实验。我们相信，本提案中提出的实验计划，结合神经科学和研究方法的选定课程以及继续参与神经病理学的临床病例演示，可以为她的发展提供所需的专门培训。此外，她将通过参与莱皮斯实验室，继续接触和参与生物医学研究的分子生物学方法。