Development of GDNF Receptor Conditional Knockout Mice

GDNF受体条件性敲除小鼠的研制

• 批准号: 7113793
• 负责人: JOSEPH Mark SAVITT
• 金额: $ 17.61万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7113793
• 关键词: gene targeting; genetically modified animals; laboratory mouse; neurotrophic factors; technology /technique development

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a common neurologic disorder whose symptoms progress relentlessly toward severe disability and loss of quality of life. One promising potential therapy is glial cell line-derived neurotrophic factor (GDNF). GDNF is a naturally occurring growth factor that has been shown in a variety of model systems to support the survival of those dopaminergic cells that are lost in PD. Attempts to learn more about the functions of GDNF through the generation of mice lacking this factor or its receptors have been thwarted by accompanying renal and gastrointestinal abnormalities leading to early postnatal death. Through the use mice recently developed by the applicant that express Cre recombinase in dopaminergic neurons and by using powerful new chemical/genetic techniques to generate receptor inhibition, the applicant's overall goal is to generate viable mice that have cell-type specific and temporally-specific interruption of GDNF signaling. Such mice will be used as a model system to examine the role of endogenous GDNF in the postnatal development and maintenance of those cells lost in Human PD. Initial work done by the applicant in the laboratory of Dr. Ted Dawson at Johns Hopkins has generated preliminary data toward accomplishing this goal. His interest in developmental biology and neurodegenerative disease led to the formulation of this project and is derived from previous research at the NIMH, University of Maryland and Johns Hopkins University and from clinical training in neurology. The expertise in models of Parkinson's disease found in the Dawson laboratory (Sponsor) and collaborations set up with leaders in the field of growth factors (Dr. Ginty) and specific kinase inhibition (Dr. Shokat) make the potential for success in this project high. This coupled with the rich environment present in the sponsor's laboratory and in the Johns Hopkins Neurology Department in general bode well for accomplishing the applicant's ultimate goal of becoming an independent research clinician.

描述（由申请人提供）：帕金森病（PD）是一种常见的神经系统疾病，其症状不断发展为严重残疾和生活质量下降。一种有前途的潜在疗法是神经胶质细胞源性神经营养因子（GDNF）。 GDNF 是一种天然存在的生长因子，已在多种模型系统中显示可支持 PD 中丢失的多巴胺能细胞的存活。通过培育缺乏该因子或其受体的小鼠来更多地了解 GDNF 的功能的尝试因伴随的肾脏和胃肠道异常导致出生后早期死亡而受阻。通过申请人最近开发的在多巴胺能神经元中表达Cre重组酶的小鼠，以及通过使用强大的新化学/遗传技术来产生受体抑制，申请人的总体目标是产生具有细胞类型特异性和时间特异性的GDNF信号传导中断的存活小鼠。这些小鼠将被用作模型系统，以检查内源性 GDNF 在出生后发育和维持人类 PD 中丢失的细胞中的作用。申请人在约翰·霍普金斯大学 Ted Dawson 博士实验室所做的初步工作已经生成了实现这一目标的初步数据。他对发育生物学和神经退行性疾病的兴趣促成了该项目的制定，该项目源自 NIMH、马里兰大学和约翰·霍普金斯大学之前的研究以及神经病学的临床培训。道森实验室（赞助商）在帕金森病模型方面的专业知识以及与生长因子（Ginty 博士）和特定激酶抑制（Shokat 博士）领域的领导者建立的合作使得该项目成功的可能性很高。这与申办者实验室和约翰·霍普金斯大学神经病学部的丰富环境相结合，对于实现申请人成为一名独立研究临床医生的最终目标来说是个好兆头。