GENETIC HETEROGENEITY IN ENDOTHELIAL GENE EXPRESSION

内皮基因表达的遗传异质性

• 批准号: 6946584
• 负责人: ROBERT P HEBBEL
• 金额: $ 53.85万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6946584
• 关键词: adolescence (12-20); bioinformatics; capillary bed; clinical research; gene expression; genetic transcription; genotype; human subject; microarray technology; oligonucleotides; patient oriented research; sickle cell anemia; single nucleotide polymorphism; stroke; vascular endothelium

This project addresses genetic heterogeneity in endothelial gene expression. Our overarching hypothesis is that the clinical phenotype of human vascular diseases will be influenced significantly by inherited differences in gene expression by endothelial cells. The unique combination of two relatively new technologies allows us to actually test this concept, directly and in humans: reporter endothelial cells can be obtained from peripheral blood sampling in the form of blood outgrowth endothelial cells (BOEC), and endothelial gene expression can be monitored by microarray profiling. This initial test of the hypothesis will focus on sickle anemia, a "single gene" disorder in which two very distinct clinical phenotypes can be reliably identified: at-risk for stroke versus not-at-risk for stroke; the at risk-group will be subdivided into those with versus those without moya moya. W e hypothesize that adolescents with HbSS who are at-risk for stroke (n=25) will exhibit different endothelial polymorphisms than the sickle subjects who are not-at-risk for stroke (n=25 each); we also hypothesize that at-risk subjects with moya moya (n=25) will exhibit different polymorphisms from those without moya moya (n=25). 25 non-sickle race and age matched adolescents will serve as controls. In Aim #1, microarray profiling of BOEC gene expression will be used to identify constitutive endothelial gene expression. In Aim #2, we will in parallel perform cell biologic experiments to examine for exaggerated endothelial responsiveness of several types felt to be high-probability for involvement in the stroke phenotype. In Aim #3 we will verify significance of candidate gene or response pathways implicated in Aims #1 and #2. In Aim #4, we will use data from a separate ongoing SNP study that looks for SNP associations with sickle stroke, to inform microarray analysis and thereby combine power of the two approaches.

该项目解决内皮基因表达的遗传异质性。我们的总体假设是，人类血管疾病的临床表型将受到内皮细胞基因表达遗传差异的显着影响。两种相对较新的技术的独特组合使我们能够直接在人体中实际测试这个概念：报告内皮细胞可以以血液生长内皮细胞（BOEC）的形式从外周血采样中获得，并且可以通过微阵列分析来监测内皮基因表达。该假设的初步检验将集中于镰状贫血，这是一种“单基因”疾病，其中两种截然不同的临床表型可以可靠地被诊断出来。 确定：有中风风险与无中风风险；高危人群将被分为有烟雾病的人群和没有烟雾病的人群。 我们假设有中风风险的 HbSS 青少年 (n=25) 将表现出与没有中风风险的镰刀型受试者 (n=25) 不同的内皮多态性；我们还假设患有烟雾病的高危受试者（n = 25）将表现出与没有烟雾病的受试者（n = 25）不同的多态性。 25 名非镰刀种族和年龄匹配的青少年将作为对照。在目标#1中，BOEC基因表达的微阵列分析将用于鉴定组成型内皮基因表达。在目标#2中，我们将同时进行细胞生物学实验，以检查几种被认为很可能发生的夸大内皮反应性。 参与卒中表型。在目标#3 中，我们将验证目标#1 和#2 中涉及的候选基因或反应途径的重要性。在目标 4 中，我们将使用来自一项正在进行的单独 SNP 研究的数据，该研究寻找 SNP 与镰状中风的关联，为微阵列分析提供信息，从而结合两种方法的力量。