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，大约25%的人受高血压影响，在大多数哺乳动物种群中，高血压比女性受影响更严重。来自英国、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比母亲患有高血压的男性血压更高。这些发现支持了我们的假设，即Y染色体上的一个基因座可以导致人类高血压动物遗传模型中的血压升高。我们实验室通过19代回交高血压SHR和正常血压WKY培育的共生体大鼠产生了一种Y染色体来自高血压父亲的菌株，其余基因组来自正常血压WKY。这种独特的动物品系在Y染色体上有一个重要的基因座，可以显著提高血压。我们推测该基因座是Sry基因，并且男性在共体型菌株中至少有一个突变。这一设想的主要假设是，Y染色体上的一个突变基因是通过调节儿茶酚胺合成中的限速酶酪氨酸羟化酶的机制而导致血压升高的。实验将在血压升高之前和期间检测Sry在肾脏和肾上腺的表达模式。将进行实验以确定Sry是否遵循与酪氨酸羟化酶类似的表达模式。最后，将Sry基因转移到肾脏和肾上腺将证明血压随Sry和酪氨酸羟基酶的升高而升高。肾功能将通过肾血流和尿液排泄测试在Sry基因传递前后进行评估。清醒动物的血压将通过遥测测量，血流速度将通过多普勒探头测量。这些动物研究的结果应该会加强我们对Y染色体对人类血压影响的机制的理解。