Development of GDNF Receptor Conditional Knockout Mice

GDNF受体条件性敲除小鼠的研制

• 批准号: 7420970
• 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/7420970
• 关键词: Acute; Address; Adult; Age; Aging; Anatomy; Animals; Binding; Biological Models; Birth; Cells; Cessation of life; Clinical; Collaborations; Corpus striatum structure; Coupled; Data; Dependence; Development; Developmental Biology; Developmental Process; Disease; Disruption; Dopaminergic Cell; Drug Formulations; Ensure; Environment; Family; GDNF gene; GDNF receptors; Generations; Genes; Genetic Techniques; Germ Lines; Goals; Growth Factor; Human; Interruption; Kidney; Knock-in Mouse; Knock-out; Knockout Mice; Laboratories; Lead; Learning; Life; Ligands; Light; Maintenance; Maryland; Methods; Modeling; Mus; Mutant Strains Mice; Mutation; National Institute of Mental Health; Neonatal; Neonatal Mortality; Neurodegenerative Disorders; Neurology; Neurons; Numbers; Parkinson Disease; Pathologic; Pathology; Perinatal; Phenotype; Phosphotransferases; Play; Point Mutation; Protein Kinase; Protein Tyrosine Kinase; Proteins; Quality of life; Receptor Inhibition; Research; Research Personnel; Role; Signal Transduction; Specificity; Substantia nigra structure; Symptoms; System; Thinking; Time; Toxin; Training; Universities; Week; Work; cell type; chemical genetics; day; disability; dopaminergic neuron; gastrointestinal; genetic manipulation; glial cell-line derived neurotrophic factor; inhibitor/antagonist; interest; malformation; mature animal; model development; mouse model; nervous system disorder; neurturin; nigrostriatal system; novel; persephin; postnatal; preference; programs; receptor; recombinase; success; theories

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。胶质细胞源性神经营养因子（GDNF）是一种有前途的潜在治疗方法。GDNF是一种天然存在的生长因子，已在多种模型系统中显示其支持在PD中丢失的那些多巴胺能细胞的存活。试图通过产生缺乏这种因子或其受体的小鼠来更多地了解GDNF的功能，但由于伴随的肾脏和胃肠道异常导致出生后早期死亡而受到阻碍。通过使用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，并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GDNF信号传导的细胞类型特异性和时间特异性中断的存活小鼠。这些小鼠将被用作模型系统，以检查内源性GDNF在人PD中丢失的那些细胞的出生后发育和维持中的作用。申请人在约翰霍普金斯的Ted Dawson博士的实验室中所做的初步工作已经产生了实现该目标的初步数据。他对发育生物学和神经退行性疾病的兴趣导致了该项目的制定，并来自NIMH，马里兰州大学和约翰霍普金斯大学的先前研究以及神经病学的临床培训。Dawson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）和特异性激酶抑制（Shokat博士）领域的领导者建立的合作，使该项目的成功潜力很高。这与申办者实验室和约翰霍普金斯神经科的丰富环境相结合，总体上预示着申请人将实现成为独立研究临床医生的最终目标。