Phospholipid Transfer Protein Mutations In Dyslipidemias

描述：(申请人提供) 心血管疾病(CVD)是西方世界的主要死亡原因。 心血管疾病风险增加与低水平高密度脂蛋白有关 (高密度脂蛋白)。高密度脂蛋白缺乏是导致冠状动脉病变的重要原因之一 疾病，然而，对血脂紊乱的了解最少。磷脂转移 蛋白质(PLTP)是高密度脂蛋白代谢的重要调节因子，可能是一种 血浆中潜在的抗动脉粥样硬化因子。PLTP基因的突变 PLTP功能受损可能会对发展产生重大影响 动脉粥样硬化性血管疾病。临床遗传学的具体目标 培训内容包括：1.获得遗传学方面的临床和研究培训 心血管疾病的基础。2.进行研究，以推动 首席研究员作为遗传学研究人员和 心血管遗传学原创性发现的延续 疾病。与拟议研究相关的具体目标包括：1) 通过筛查具有以下特征的个体来确定高密度脂蛋白缺乏的遗传原因 通过变性改变高密度脂蛋白和/或PLTP水平以使PLTP基因发生变异 梯度凝胶电泳法。2)使用“强力”测序来扫描 在这些个体中发现PLTP基因的直接启动子区域 改变PLTP功能的突变。3)基因多态 通过突变检测方法揭示的，主要是通过开发 限制性内切酶片段长度多态性分析 研究病例对照样本总体。4)发现潜在的种族 对高密度脂蛋白代谢的影响。5)确定遗传基因的生化效应 通过进行变异体的表达研究在AIMS 1-3中识别变异体 等位基因来评估它们的功能意义，从而阐明 突变的作用机制。遗传学与临床课程设计 研究将提供教学基础。实验室培训 方法和分析，以及在加州大学旧金山分校的脂肪诊所将获得。 研究的目标是提供对PLTP在 高密度脂蛋白缺陷状态作为一种方法论范例，可应用于任何 在寻找心脏病的遗传原因中的基因位点。

DESCRIPTION: (provided by the applicant) Cardiovascular disease(CVD) is the leading cause of death in the western world. Increased CVD risk is associated with low levels of high-density lipoprotein (HDL). HDL deficiency is one of the most important causes of coronary artery disease and yet, the least understood of lipid disorders. Phospholipid transfer protein (PLTP) is an important regulator of HDL metabolism and may be a potential antiatherogenic factor in plasma. Mutations in the PLTP gene that compromise PLTP function may have significant implications for development of atherosclerotic vascular disease. The specific aims of the clinical genetics training include: 1. To acquire clinical and research training in the genetic basis of cardiovascular disease. 2. To conduct research which will advance the principal investigator's knowledge and skills as a genetics researcher and for continued generation of original discovery in the genetics of cardiovascular disease. Specific aims related to the proposed research include: 1) To determine the genetic cause of HDL deficiency by screening individuals with altered HDL and/or PLTP levels for variations in the PLTP gene by denaturing gradient gel electrophoresis. 2) To employ 'brute force' sequencing to scan the immediate promoter region of the PLTP gene in these individuals to find mutations that alter the function of PLTP. 3) To genotype polymorphisms revealed by mutation detection methodologies, primarily by development of restriction fragment length polymorphism assays so as to develop a means of studying case-control sample populations. 4) To discover potential ethnic influences on HDL metabolism. 5) To characterize biochemical effects of genetic variants identified in aims 1-3 by conducting expression studies of variant alleles to assess their functional significance, thus, elucidating the mechanisms by which the mutations act. Coursework in Genetics and Clinical Research will provide the didactic foundation. Training in laboratory methodology and analysis as well as in the UCSF Lipid Clinic will be obtained. The research objectives are to provide vitalinsight into the role of PLTP in HDL deficient states as a paradigm for methodology that can be applied to any gene locus in the search for genetic causes of heart disease.