Tyrosine Hydroxylase Sry and Hypertension

描述（由申请人提供）：在大多数哺乳动物种群中，西方约有25%的个体受高血压影响，其影响程度高于女性。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，即在人类高血压动物遗传模型中，Y染色体上的一个位点可以导致血压升高。我们实验室通过将高血压SHR和正常WKY回交19代，培育出一株经济大鼠，其Y染色体来自高血压父亲，其余基因组来自正常WKY。这种独特的动物品种在Y染色体上有一个重要的位点，可以显著增加血压。我们认为这个位点是Sry基因，雄性在经济菌株中至少有一个突变。该建议的主要假设是，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。在血压升高之前和期间，将进行实验来检查肾和肾上腺中Sry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相似的表达模式。最后，Sry基因传递到肾脏和肾上腺将证明血压随Sry和酪氨酸羟化酶的升高而升高。在Sry基因传递前后，通过肾血流量和尿排泄测试来评估肾功能。在有意识的动物身上，用遥测法测量血压，用多普勒血流探头测量血流速度。这些动物研究的结果应该加强我们对Y染色体影响人类血压的机制的理解。

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.