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。 CVD风险增加与低水平的高密度脂蛋白有关 （HDL）。高密度脂蛋白缺乏是导致冠状动脉粥样硬化的重要原因之一 疾病，然而，最不了解的脂质紊乱。磷脂转移 蛋白（PLTP）是HDL代谢的重要调节剂，可能是一种 潜在的抗动脉粥样硬化因子。PLTP基因的突变， PLTP功能受损可能对发展 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， 主要研究者作为遗传学研究人员的知识和技能， 心血管疾病遗传学的新发现 疾病与拟议研究有关的具体目标包括：1） 通过筛查患有以下疾病的个体来确定HDL缺乏症的遗传原因： 由于PLTP基因的变异而改变HDL和/或PLTP水平， 梯度凝胶电泳2)使用“蛮力”测序来扫描 直接启动子区的PLTP基因在这些人中找到 改变PLTP功能的突变。3)基因多态性 通过突变检测方法，主要是通过开发 限制性片段长度多态性分析，以开发一种方法， 研究病例对照样本人群。4)为了发现潜在的种族 影响HDL代谢。5)为了表征遗传的生化效应， 目标1-3中确定的变体， 等位基因，以评估其功能意义，从而阐明 突变的作用机制。遗传学与临床 研究将提供教学基础。实验室培训 方法和分析，以及在UCSF脂质诊所将获得。 本研究的目的是提供重要的洞察PLTP的作用， HDL缺陷状态作为方法学的范例，可以应用于任何 基因位点来寻找心脏病的遗传原因。

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.