KALLISTATIN IN HYPERTENSION

这个相互竞争的续订应用程序将继续探索卡利斯汀在高血压中的作用。Kalistatin是本实验室首次发现的组织激肽释放酶结合蛋白，是一种新的血浆丝氨酸蛋白酶抑制剂。在目前的资助期间，出现了许多重要的发现，支持卡利斯汀在调节血压和血管生物学方面发挥作用的假设。我们发现Kalistatin是一种有效的血管扩张剂，直接导致血压的一过性降低，离体主动脉环的血管松弛，以及灌流大鼠肾脏的血管扩张。过量表达kalistatin的转基因小鼠具有降压作用，并且kalistatin在自发性高血压大鼠体内的基因传递可显著且持久地降低血压。Kalistatin可调节血管细胞生长，其在球囊损伤大鼠动脉中的表达水平显著升高，外源性Klistatin可刺激原代培养的血管平滑肌细胞增殖。本研究的具体目的是：1)通过定点突变和结构域替换，分析Kalistatin在血管细胞增殖和血管松弛中的结构和功能关系；2)鉴定、鉴定和克隆血管中新的Klistatin结合蛋白；3)通过反义Klistatin基因转导和核酶抑制策略，分析Kallistatin在大鼠动脉球囊损伤模型血管细胞增殖和迁移中的作用；4)研究kallistatin基因在自发性高血压大鼠血压调节中的作用；5)分析kallistatin基因启动子区域及部分高血压人群、受累同胞和家系与高血压的遗传连锁关系。这项拟议的工作可以显著提高我们对kalistatin在血压调节和血管功能中的作用的理解，并可能为改进高血压和心血管疾病的检测和治疗提供新的工具和技术。

This competing renewal application will continue to explore the role of kallistatin in hypertension. Kallistatin was first discovered in our laboratory as tissue kallikrein-binding protein, a new plasma serine proteinase inhibitor. During the current funding period, many important findings have emerged in support of the hypothesis that kallistatin has a role in the regulation of blood pressure and vascular biology. We found that kallistatin is a potent vasodilator that directly causes a transient reduction of blood pressure, vasorelaxation in isolated aortic rings, and vasodilation of the renal vasculature in perfused rat kidney. Transgenic mice overexpressing kallistatin are hypotensive and somatic gene delivery of kallistatin caused a significant and prolonged reduction of blood pressure in spontaneously hypertensive rats. Kallistatin may regulate vascular cell growth, as its expression levels increase markedly in balloon-injured rat artery and exogenous kallistatin stimulates the proliferation of primary cultured vascular smooth muscle cells. The specific aims are: 1) to analyze structural and functional relationships of kallistatin on vascular cell proliferation and vasorelaxation by site-directed mutagenesis and domain substitutions; 2) To identify, characterize and clone new kallistatin-binding protein in blood vessels; 3) To analyze the role of kallistatin in vascular cell proliferation and migration with a balloon-injured rat artery model by antisense kallistatin gene delivery and by ribozyme inhibition strategy; 4) To study the role of kallistatin in blood pressure regulation by delivery of the kallistatin gene in spontaneously hypertensive rats, and 5) To analyze the promoter region of the kallistatin gene and genetic linkage and association between the human kallistatin gene and hypertension in selected hypertensive populations, affected siblings and family pedigrees. The proposed work could significantly advance our understanding of the role of kallistatin in blood pressure regulation and vascular function and may provide new tools and technologies for improved detection and treatment of hypertension and cardiovascular diseases.