GENETICS OF CEREBROVASCULAR DISEASE

脑血管疾病的遗传学

• 批准号: 2234942
• 负责人: KLAUS LINDPAINTNER
• 金额: $ 16.09万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2234942
• 关键词: alleles; animal breeding; familial hypertension; gene dosage; gene expression; genetic mapping; genetic markers; genetic polymorphism; genetic strain; genotype; linkage mapping; nucleic acid sequence; pathologic process; phenotype; point mutation; polymerase chain reaction; radionuclides; spontaneous hypertensive rat; stroke

The long term objectives of the proposed research are athe identification of disease-causing genes an the characterization of their pathogenetic mechanism in hypertensive cerebrovascular disease. Hypertensive cerebrovascular disease is a major cause of stroke, and the third leading cause of death and disability in our society. While elevated blood pressure is an important risk factor, there is increasing evidence that other, blood pressure-independent, genetic factors play an significant role int he pathogenesis of cerebrovascular disease. Epidemiologic data suggest that the disease is inherited as a polygenic, quantitative trait, similar to primary hypertension. The complexity of polygenic diseases in man, accentuated by their heterogeneous and multifactorial nature, discourages attempts aimed at identifying disease-related genes or loci in humans. Alternatively, inbred animal strains showing the trait of interest as a genetically determine phenotype, represent a useful approximation, the study of which may reveal information that subsequently can be applied to human disease. We propose, therefore, to use the stroke-prone, spontaneously hypertensive rat (SHRSP), an experimental animal that is genetically predisposed to develop hypertensive cerebrovascular disease in a manner closely resembling human pathology, as a model that allows studies in which some of the confounding factors invariably present in humans can be avoided. Following the paradigm of cosegregation analysis for the dissection of disease-relevant genetic loci, we will establish an F2 intercross cohort by breeding the SHRSP with the spontaneously hypertensive rat (SHR), another hypertensive animal strain that, however, does not develop stroke. This strategy removes blood pressure, an important confounding variable, from the analysis, and provides a hybrid population in which the tendency towards stroke shows variation according tot he relative dosage of stroke-relevant genes that a given individual has received as a result of free segregation of alleles, while blood pressure, in contrast, shows minimal variation, as we have shown in preliminary studies. This algorithm provides a powerful approach to search for pathogenetically important genes, and also, in contrast to comparative studies, the only one that establishes causality between gene and phenotype. The proposed studies will pursue the following specific aims; (i) Preliminary studies demonstrate the SHRSP, but not SHR, when fed a specific diet (elements of which have also been shown in epidemiologic studies to increase the risk for stroke in man, show a high, early incidence of stroke, yet blood pressures are identical to SHR. An F2 hybrid cohort prepared by crossbreeding the two strains will be phenotypically characterized with regard to stroke, using latency until stroke as the major discriminating phenotype parameter. (ii) In addition to a moderate number of genetic markers already identified as polymorphic among SHR and SHRSP, a broader mapping panel will be generated using several complimentary approaches, including the development of new microsatellites, point mutation polymorphisms, and RAPD typing. In addition, polymorphic markers for a limited number of candidate genes will be developed. (iii) DNA prepared from the SHRSP/ SHR cross will be genotyped using the panel of polymorphic markers prepared and linkage analysis performed. (iv) If linkage to a marker is established, a variety of molecular and classical genetic approaches will be entertained, including the development of new, more densely spaced markers in the region of interest (e.g. by chromosome jumping) and the breeding of congenic lines.

拟议研究的长期目标是确定 致病基因及其致病特征 高血压脑血管病的发病机制。 高血压 脑血管疾病是中风的主要原因，位居第三位 我们社会的死亡和残疾原因。 血液升高的同时 压力是一个重要的风险因素，越来越多的证据表明 其他与血压无关的遗传因素也起着重要作用 脑血管疾病的发病机制。 流行病学数据表明 该疾病是作为多基因、数量性状遗传的，类似于 至原发性高血压。 人类多基因疾病的复杂性， 由于其异质性和多因素性质，阻碍了 旨在识别人类疾病相关基因或基因座的尝试。 或者，近交动物品系显示出感兴趣的性状 基因决定表型，代表一个有用的近似值， 其研究可能会揭示随后可应用于的信息 人类疾病。 因此，我们建议使用易中风、 自发性高血压大鼠（SHRSP），一种实验动物 高血压脑血管病的遗传倾向 一种与人类病理学非常相似的方式，作为允许研究的模型 其中人类中总是存在的一些混杂因素可以 应避免。 遵循共分离分析范式 解剖疾病相关的遗传位点，我们将建立一个F2 通过将 SHRSP 与自发性高血压进行杂交队列 大鼠（SHR），另一种高血压动物品系，然而，它不 发展中风。 这种策略可以消除血压，这是一个重要的 混杂变量，来自分析，并提供混合群体 其中中风的趋势显示出根据他的变化 特定个体所具有的中风相关基因的相对剂量 由于等位基因的自由分离而获得，而血压， 相反，显示出最小的变化，正如我们在初步中所示 研究。 该算法提供了一种强大的搜索方法 具有重要的致病基因，并且与比较基因相比 唯一一项确定基因与基因之间存在因果关系的研究 表型。 拟议的研究将追求以下具体目标； (i) 初步研究表明，当喂食 特定的饮食（其中的要素也已在流行病学中得到证实） 增加男性中风风险的研究表明，早期中风风险较高 中风的发生率，但血压与 SHR 相同。 F2 通过杂交这两种菌株制备的杂交群体将 中风的表型特征，使用潜伏期直到 中风作为主要的区分表型参数。 (二) 此外 已鉴定为多态性的中等数量的遗传标记 在 SHR 和 SHRSP 之间，将使用以下方式生成更广泛的绘图面板 几种互补的方法，包括开发新的 微卫星、点突变多态性和 RAPD 分型。 在 此外，有限数量的候选基因的多态性标记将 得到开发。 (iii) 从 SHRSP/SHR 杂交制备的 DNA 将被 使用准备好的多态性标记组和连锁进行基因分型 进行分析。 (iv) 如果建立了与标记的连锁，则品种 分子和经典遗传学方法将受到欢迎， 包括在该地区开发新的、间隔更密集的标记 感兴趣的（例如通过染色体跳跃）和同类繁殖 线。