GENETICS OF VASOREGULATION AND CARDIOVASCULAR RESPONSES

血管调节和心血管反应的遗传学

• 批准号: 7673408
• 负责人: David Housman
• 金额: $ 76.58万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7673408
• 关键词: 2p24; 5q34; Affect; Aldosterone; American; Angiotensins; Animals; Antihypertensive Agents; Blood Pressure; Blood Vessels; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Case-Control Studies; Chronic; Class; Clinical; Common carotid artery; DNA; Data; ESR2 gene; End Point; Enrollment; Essential Hypertension; Estrogen Receptors; Family; Framingham Heart Study; Functional disorder; G-Protein-Coupled Receptors; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Heart; High Prevalence; Human; Hypertension; Hypertrophy; Inherited; Leucine Zippers; Link; Location; Maintenance; Measures; Medial; Mediating; Membrane Potentials; Molecular; Mus; Muscle Contraction; Mutation; Myosin ATPase; Myosin Light Chains; Nitric Oxide; Nitroglycerin; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Population; Potassium Channel; Prevalence; Protein Dephosphorylation; Protein Kinase; Proteins; Publishing; RGS2 gene; ROCK1 gene; Receptor Gene; Relaxation; Renin; Research Personnel; Score; Smooth Muscle Myocytes; System; Testing; Thick; Variant; Vascular Diseases; Vasodilation; Vasomotor; Work; animal data; base; blood pressure regulation; brachial artery; early onset; genetic variant; genome-wide linkage; human NOS2A protein; human RGS2 protein; inhibitor/antagonist; insight; intima media; member; myosin phosphatase; programs; research study; response; rho; vasoconstriction; vasomotion

Essential hypertension and vascular disease affects over 50 million Americans. Family-based studies show that hypertension can be inherited, however few causative genes have been identified. In search of causes of hypertension we have studied mechanisms regulating blood vessel contraction and relaxation, which contribute to blood pressure regulation. From this work two important mechanisms controlling vascular smooth muscle cell relaxation have been identified. First, protein kinases that increase and decrease myosin phosphatase activity causing cellular relaxation or contraction, respectively, have been found. Second, a potassium channel that regulates the resting potential of the smooth muscle cell, also regulates vasomotor tone and blood pressure. Experiments in whole animals and humans demonstrate clearly that these two fundamental systems regulating smooth muscle cell relaxation have a marked effect on chronic blood pressure control. New genomic data presented in this application and molecular, cellular and animal studies presented in Projects 2-4 show that abnormalities of either the myosin phosphatase or myosin light chain phosphorylation state or the BK(Ca) channel can cause vascular dysfunction and hypertension. We therefore hypothesize that genetic variations in the critical genes whose protein products regulate smooth muscle cell contraction and relaxation are associated with abnormal vasomotion, increased intima-media thickness and hypertension. To test this hypothesis we recently cross-referenced all loci implicated by published hypertension-associated genome-wide linkage studies with the location of genes that encode critical proteins in the final common pathway mediating vasorelaxation. We discovered that three of our candidate genes are located in regions associated with essential hypertension, providing a further strong impetus to the testing of our hypothesis. We now propose: 1) to identify human variants in genes important for vascular smooth muscle cell relaxation that are present in more than five percent of Americans, 2) determine if these genetic variants are associated with increased or reduced nitroglycerin-mediated blood vessel dilation or common carotid artery thickness, and 3) identify the association of these gene variants with blood pressure. We will test our hypotheses in three different groups representative of a cross-section of Americans. Considering the high prevalence of blood vessel disorders these studies may provide needed insight into the genetic causes of cardiovascular disease.

高血压和血管疾病影响着5000多万美国人。以家庭为基础的研究表明，高血压是可以遗传的，但几乎没有发现导致高血压的基因。为了寻找高血压的病因，我们研究了血管收缩和松弛的调节机制，这些机制有助于调节血压。从这项工作中，我们发现了两种控制血管平滑肌细胞松弛的重要机制。首先，已经发现了分别增加和降低肌球蛋白磷酸酶活性的蛋白激酶，导致细胞松弛或收缩。第二，一种钾通道，它调节平滑肌细胞的静息电位，也调节血管舒缩张力和血压。在整个动物和人类身上的实验清楚地证明了这两个 调节平滑肌细胞松弛的基本系统对慢性血压控制有显著效果。在本申请中提供的新的基因组数据以及在项目2-4中提供的分子、细胞和动物研究表明，肌球蛋白磷酸酶或肌球蛋白轻链磷酸化状态或BK(Ca)通道的异常可导致血管功能障碍和高血压。因此，我们假设，其蛋白产物调节平滑肌细胞收缩和松弛的关键基因的遗传变异与血管运动异常、内膜中层厚度增加和高血压有关。为了验证这一假设，我们最近交叉参考了已发表的高血压相关全基因组连锁研究涉及的所有基因座与编码基因的位置 调节血管松弛的最终共同途径中的关键蛋白质。我们发现，我们的三个候选基因位于与原发性高血压相关的区域，这为我们的假设检验提供了进一步的强大动力。我们现在建议：1)确定在超过5%的美国人中存在的对血管平滑肌细胞松弛重要的基因中的人类变异，2)确定这些基因变异是否与硝酸甘油介导的血管扩张或颈总动脉厚度增加或减少有关，以及3)确定这些基因变异与血压的关联。我们将在代表不同美国人的三个不同群体中测试我们的假设。考虑到血管疾病的高患病率，这些研究可能会提供必要的 洞察心血管疾病的遗传原因。