DBH as a Modifying Gene in Neurodegenerative Diseases

简介（由申请人提供）：申请人Cyrus Zabetian博士在耶鲁大学/ VACHS做了三年的博士后。明年他将加入华盛顿大学神经学系，在那里他未来的导师，dr。托马斯·伯德和杰拉德·谢伦伯格，在神经遗传学方面建立了一个极好的研究项目。他的培训将包括参加实验室会议、研讨会、结构化课程和年度科学会议。他将成为临床和分子神经遗传学、儿茶酚胺生物化学和生物统计学领域丰富的研究人员合作网络的一部分。Zabetian博士的长期计划是在五年内成为一名独立的实验室调查员，并继续积极参与患者护理和神经病学服务的住院医师培训。

DESCRIPTION (provided by applicant): The applicant, Dr. Cyrus Zabetian, has spent the past three years as a postdoctoral fellow at Yale University/ VACHS. He will join the neurology faculty at the University of Washington next year where his future mentors, Drs. Thomas Bird and Gerard Schellenberg, have established a superb research program in neurogenetics. His training will include participation in laboratory meetings, seminars, structured courses, and annual scientific meetings. He will become part of a rich collaborative network of researchers with expertise in clinical and molecular neurogenetics, catecholamine biochemistry, and biostatistics. Dr. Zabetian's long-term plans are to become established as an independent laboratory investigator within five years, and remain actively involved in patient care and resident training on the neurology service. In neurodegenerative disease research, identifying genetic mechanisms underlying compensatory changes in surviving neurons promises to lead to improved strategies of diagnosis and treatment. The project proposed in this application seeks to determine if a newly discovered promoter polymorphism (C-1021T) influences regulation of the DBH gene with potential clinical consequences in Parkinson's disease (PD), and is divided into three parts. The goal of part I is to evaluate whether homozygosity for the T allele of C-1021 T, which is associated with low levels of plasma DBH enzyme, is predictive of an earlier onset and more severe symptoms of sympathetic failure in patients with PD. A group of forty subjects homozygous for either the C or T allele will be selected from a population of 400 clinic patients with PD and assessed longitudinally using indices of sympathetic function. Part II seeks to determine whether C-1021T strongly associates with DBH expression in noradrenergic tissues. Levels of DBH protein and mRNA will be compared in postmortem human adrenal medulla specimens, homozygous for either the C or T allele, using western blots and quantitative real time RT-PCR, respectively. Part III will assess whether C-1021T is directly functional. If preliminary results are favorable, two transgenic mouse lines homozygous for either the T or C allele will be created in which the proximal 2 kb of the endogenous mouse DBH promoter is replaced by homologous human sequence. Comparing plasma and tissue levels of DBH protein and catecholamines in the two lines will detect the effect of each allele on DBH expression.