Development of GDNF Receptor Conditional Knockout Mice

描述(申请人提供)：帕金森病(PD)是一种常见的神经系统疾病，其症状会无情地发展为严重残疾和生活质量下降。一种有希望的潜在治疗方法是胶质细胞系衍生神经营养因子(GDNF)。GDNF是一种自然产生的生长因子，已在各种模型系统中被证明支持帕金森病中丢失的多巴胺能细胞的生存。试图通过缺乏该因子或其受体的小鼠来了解更多关于GDNF功能的努力，但由于伴随着导致出生后早期死亡的肾脏和胃肠道异常而受挫。通过使用申请者最近开发的在多巴胺能神经元中表达Cre重组酶的小鼠，并通过使用强大的新的化学/遗传技术来产生受体抑制，申请者的总目标是培育出具有细胞类型特异性和时间特异性的GDNF信号中断的存活小鼠。这样的小鼠将被用作一个模型系统，以检验内源性GDNF在人类帕金森病失去的细胞的出生后发育和维持中的作用。申请者在约翰·霍普金斯大学泰德·道森博士的实验室里所做的初步工作已经产生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导致了这一项目的制定，并源于NIMH、马里兰大学和约翰霍普金斯大学之前的研究以及神经学的临床培训。道森实验室(赞助商)在帕金森氏病模型方面的专业知识，以及与生长因子(金蒂博士)和特定激酶抑制(肖卡特博士)领域的领导者建立的合作，使该项目获得成功的可能性很大。这一点，再加上赞助商实验室和约翰霍普金斯大学神经病学系的丰富环境，对于实现申请者成为一名独立研究临床医生的最终目标来说是个好兆头。

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.