PULMONARY HYPRTENSION--MECHANISMS AND FAMILY REGISTRY

肺动脉高压——机制和家族登记

• 批准号: 2224215
• 负责人: JAMES E LOYD
• 金额: $ 22.62万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-04-01 至 1999-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2224215
• 关键词: DNA; cardiovascular disorder epidemiology; cell line; chromosome deletion; chromosome inversion; chromosome translocation; disease /disorder proneness /risk; family genetics; genetic disorder; genetic markers; genetic registry /resource /referral center; histocompatibility antigens; histocompatibility typing; human genetic material tag; human subject; karyotype; linkage mapping; molecular pathology; nucleic acid repetitive sequence; patient /disease registry; pulmonary hypertension; statistics /biometry; tissue resource /registry

This project will investigate basic mechanisms of Primary Pulmonary Hypertension (PPH), a lethal disease which causes progressive obstruction of small pulmonary arteries. The first component of this study is to establish a natiOnal registry of familial PPH (FPPH). The primary goal of the family registry is to establish and expand the database of FPPH pedigrees to definitively establish the mode of inheritance of FPPH, which our initial segregation analysis suggests is autosomal dominant. The FPPH family registry will provide the framework for the linkage analysis of the molecular search for basic mechanisms of PPH. We will develop a tissue bank for specimens (DNA & transformed lymphocytes) from families and patients with pulmonary hypertension, both for our investigations locally and to be a national resource for other interested investigators. Our search will use three different approaches to investigate for a FPPH gene locus. First, we will perform karyotyping and high resolution chromosome studies to search for a chromosomal translocation, interstitial deletion, or inversion, the finding of which would implicate a specific gene locus. Second, we will pursue the proposed association of human leukocyte antigen (HLA) tissue type with familial PPH in a parallel attempt to identify a related locus about which to perform an intensified molecular search, using regional mapping studies of closely linked markers. Finally, we will perform linkage analysis in selected PPH families which have the most informative inheritance patterns, using PCR based microsatellite markers for selected candidate genes, including those for transforming growth factor beta, endothelin, beta globin, and HLA. An additional promising approach will include a search for linkage of FPPH to genes with GC-rich trinucleotide repeats, as has recently been successful for other diseases with genetic anticipation, including Fragile X syndrome, myotonic dystrophy, and Huntington's disease. This is a vitally important proposal, we know of no other projects designed to search for the basic molecular mechanism of Primary Pulmonary Hypertension, a critically important disease.

该项目将研究原发性肺疾病的基本机制 高血压（PPH），一种导致进行性梗阻的致命疾病 肺小动脉。这项研究的第一个组成部分是 建立国家家族性 PPH 登记处 (FPPH)。主要目标是 户籍处将建立和扩大FPPH数据库 家谱最终建立了 FPPH 的遗传模式， 我们最初的分离分析表明是常染色体显性遗传。 FPPH 家庭登记处将为家庭关系的关联分析提供框架 PPH 基本机制的分子研究。我们将开发一种组织 来自家庭和的样本库（DNA 和转化淋巴细胞） 肺动脉高压患者，均用于我们当地的调查 并成为其他感兴趣的研究人员的国家资源。我们的 搜索将使用三种不同的方法来调查 FPPH 基因 轨迹。首先，我们将进行核型分析和高分辨率染色体 寻找染色体易位、间质缺失的研究， 或倒位，其发现将暗示特定的基因位点。 其次，我们将追求人类白细胞抗原的拟议关联 (HLA) 组织类型与家族性 PPH 并行尝试识别 进行强化分子搜索的相关位点， 使用紧密相连的标记的区域绘图研究。最后，我们将 在选定的具有最多 PPH 家族中进行连锁分析 信息丰富的遗传模式，使用基于 PCR 的微卫星标记 对于选定的候选基因，包括那些用于转化生长的基因 β因子、内皮素、β珠蛋白和 HLA。另一个有希望的 该方法将包括寻找 FPPH 与富含 GC 的基因的联系 三核苷酸重复，最近在其他疾病中取得了成功 具有遗传预期，包括脆性 X 综合征、肌强直 营养不良和亨廷顿病。这是一个非常重要的提议 据我们所知，没有其他项目旨在寻找基本分子 原发性肺动脉高压的发病机制极为重要 疾病。