Tyrosine Hydroxylase Sry and Hypertension

酪氨酸羟化酶与高血压

• 批准号: 6918324
• 负责人: DANIEL L ELY
• 金额: $ 35.67万
• 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/6918324
• 关键词: adrenal glands; blood pressure; electroporation; enzyme induction /repression; gene expression; gene mutation; genetic susceptibility; hypertension; kidney function; laboratory rat; male; norepinephrine; sex linked trait; spontaneous hypertensive rat; telemetry; tyrosine 3 monooxygenase; ultrasound blood flow measurement

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）：在大多数哺乳动物人群中，高血压影响西方人的25％的人受到女性的影响更多。来自英格兰，澳大利亚，日本和瑞典的人类研究表明，与高血压母亲相比，高血压父亲的男性血压更高。这些发现支持我们的假设，即Y染色体上的基因座会导致血压在人类中发现的高血压动物遗传模型中增加。在我们的实验室中，通过反跨高血压SHR和正常的WKY在我们的实验室中产生的综合大鼠菌株产生了一种菌株，该菌株具有来自高血压父亲的y染色体，其余基因组源自正常的WKY。这种独特的动物菌株在Y染色体上具有重要的基因座，可显着增加血压。我们建议该基因座是Sry基因，而男性在综合菌株中至少具有一个突变。该提议的主要假设是，Y染色体上的突变基因座是通过调节酪氨酸羟化酶的机制升高血压的主要原因，该机制是Catecholamine合成中的速率限制酶。将进行实验，以检查血压在增加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，SRY基因递送至肾脏和肾上腺将证明血压遵循SRY和酪氨酸羟化酶的升高。肾功能将通过肾脏血流和SRY基因递送前后的肾脏排泄测试进行评估。有意识的动物中，多普勒流量探针将通过遥测和血流速度来测量血压。这些动物研究的结果应增强我们对Y染色体对人体血压作用的机制的理解。