Tyrosine Hydroxylase Sry and Hypertension

酪氨酸羟化酶与高血压

• 批准号: 7385950
• 负责人: DANIEL L ELY
• 金额: $ 34.85万
• 依托单位: UNIVERSITY OF AKRON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385950
• 关键词: Adrenal Glands; Affect; Animal Genetics; Animals; Australia; Backcrossings; Blood; Blood Flow Velocity; Blood Pressure; Cardiovascular system; Catecholamines; Chromosomes, Human, Y; Conscious; Consomic Strain; Data; Electroporation; Elevation; England; Enzymes; Excretory function; Fathers; Female; Gene Delivery; Gene Expression; Generations; Genes; Genetic Transcription; Genome; Human; Hypertension; In Vitro; Inbred SHR Rats; Inbred WKY Rats; Individual; Japan; Kidney; Laboratories; Measures; Modeling; Mothers; Mutation; Norepinephrine; Pathway interactions; Pattern; Phenotype; Physiological; Physiology; Population; Publishing; Rat Strains; Rate; Rattus; Renal Blood Flow; Renal function; Research; Research Personnel; Rest; Stroke; Sweden; Telemetry; Testing; Time; Tissues; Tyrosine 3-Monooxygenase; Y Chromosome; base; consomic; human study; interest; male; mutant; normotensive; programs; promoter; research study; response; sry Genes; urinary

DESCRIPTION (provided by applicant): Hypertension affects about 25% of individuals in Western are affected more than females in most mammalian populations. Human studies from England, Australia, Japan and Sweden have shown that blood pressure is higher in males with hypertensive fathers compared to those with hypertensive mothers. These findings support our hypothesis that a locus on the Y chromosome can cause blood pressure to increase in an animal genetic model of hypertension as found in humans. A consomic rat strain developed in our laboratory by backcrossing hypertensive SHR and normotensive WKY for over 19 generations has produced a strain that has a Y chromosome from a hypertensive father and the rest of the genome is derived from a normotensive WKY. This unique animal strain has an important locus on the Y chromosome that significantly increases blood pressure. We propose that this locus is the Sry gene and males have at least one mutation in the consomic strain. The main hypothesis of this proposal is that a mutant locus on the Y chromosome is the primary cause of the increased blood pressure through the mechanism of regulating tyrosine hydroxylase, the rate limiting enzyme in catecholamine synthesis. Experiments will be done that examine Sry expression patterns in kidney and adrenal gland before and during the time which blood pressure is increasing. Experiments will be performed to determine if Sry follows a similar expression pattern as seen with tyrosine hydroxylase. Finally, Sry gene delivery to kidney and adrenal gland will demonstrate that blood pressure follows the elevation of Sry and tyrosine hydroxylase. Kidney function will be assessed by renal blood flow and urinary excretion tests before and after Sry gene delivery. Blood pressure will be measured by telemetry and blood flow velocity by Doppler flow probe in conscious animals. The results of these animal studies should enhance our understanding of the mechanism of the Y chromosome effect upon blood pressure in humans.

描述（由申请人提供）：在西方，高血压对大约 25% 的个体的影响比大多数哺乳动物群体中的雌性更严重。英国、澳大利亚、日本和瑞典的人体研究表明，父亲患有高血压的男性血压高于母亲患有高血压的男性。这些发现支持了我们的假设，即在人类高血压的动物遗传模型中，Y 染色体上的一个基因座可导致血压升高。我们实验室通过将高血压 SHR 和正常血压 WKY 回交超过 19 代而开发出一种康体大鼠品系，该品系具有来自高血压父亲的 Y 染色体，而其余基因组则来自正常血压 WKY。这种独特的动物品系在 Y 染色体上有一个重要的位点，可以显着增加血压。我们推测这个位点是 Sry 基因，并且雄性在 consomic 品系中至少有一个突变。该提议的主要假设是，Y 染色体上的突变位点是通过调节酪氨酸羟化酶（儿茶酚胺合成中的限速酶）的机制导致血压升高的主要原因。将进行实验来检查血压升高之前和期间肾脏和肾上腺中的 Sry 表达模式。将进行实验以确定 Sry 是否遵循与酪氨酸羟化酶相似的表达模式。最后，将 Sry 基因递送至肾脏和肾上腺将证明血压随着 Sry 和酪氨酸羟化酶的升高而变化。在 Sry 基因递送之前和之后，将通过肾血流和尿液排泄测试来评估肾功能。将通过遥测技术测量血压，并通过多普勒血流探头测量有意识的动物的血流速度。这些动物研究的结果应该会增强我们对 Y 染色体对人类血压影响机制的理解。