Animal Models for Studying the Genetics of Hypertension

描述(由申请人提供)：我们的长期目标是揭开高血压的遗传学。下一笔拨款的重点是研究遗传因素如何影响高血压的后果，重点是揭示影响血管和肾脏问题严重程度的因素，这些问题发生在先兆子痫妇女和患有微血管病变(MA)的接受抗血管生成治疗的癌症患者中。子痫前期(PE)是妊娠高血压和蛋白尿的一种常见形式。它约占孕产妇死亡的15%，并极大地增加了未来患心血管疾病的风险。循环中抗血管生成因子sFlt1(血管内皮生长因子受体的可溶性形式)和Seng(组织生长因子β受体的可溶性形式)的异常升高与PE有关。PE和MA的许多病理后果可以通过表达sFlt1和/或Seng的重组腺病毒(RAdv)在啮齿动物身上复制，我们假设遗传因素影响后果的严重性，它们在其他形式的高血压中也是重要的。利用新型转基因小鼠，其中循环sFlt1或Seng水平可以通过喂养无毒膳食补充剂吲哚-3-甲醇(I3C)而可逆地增加，特定的目的(I)将检验这一假设，即可溶性因素主要通过增加全身血管阻力来影响血压(BP)。在新的小鼠中，sFlt1下游的内皮素1(ET1)和/或转化生长因子1的表达可以全局或组织地从野生型水平的10%到300%变化，特定目的(Ii)将测试这一假设，即Edn1(编码ET1)和/或Tgfb1(编码转化生长因子1)的表达轻微变化会影响基础BP。特殊目的(III)将检验这样一种假设，即暴露于高sFlt1和Seng的后果会因先前存在的遗传因素而加剧或改善。将检测Edn1、Tgfb1和Ace基因表达水平变化的影响。这些实验有望阐明sFlt1和Seng诱导的高血压和蛋白尿的生理、病理和遗传相互作用。他们有可能提出新的干预措施，既可以推迟或避免对患有严重先兆子痫的妇女进行早产诱导，也可以避免对患有微血管病变的癌症患者停止使用血管内皮生长因子抑制剂。

DESCRIPTION (provided by applicant): Our long-term objective is to unravel the genetics of hypertension. The coming grant is focused on learning how genetic factors influence the consequences of hypertension, with emphasis on uncovering factors affecting the severity of the vascular and renal problems which develop in pre-eclamptic women and in cancer patients under anti-angiogenic therapy who develop microangiopathy (MA). Pre-eclampsia (PE) is a common form of pregnancy-associated hypertension and proteinuria. It accounts for ~15% of maternal deaths, and carries with it a greatly increased risk for future cardiovascular disease. Abnormal increases in the circulating anti-angiogenic factors sFlt1 (a soluble form of the receptor for vascular endothelial growth factor, VEGF) and sEng (a soluble form of co-receptor for tissue growth factor beta, TGF-beta) are associated with PE. Many of the pathological consequences of PE and of MA can be replicated in rodents with recombinant adenoviruses (rAdVs) expressing sFlt1 and/or sEng, and we hypothesize that genetic factors affect the severity of the consequences, and that they are also important in other forms of hypertension. Using novel transgenic mice in which circulating sFlt1 or sEng levels can be increased reversibly by feeding indole-3-carbinol (i3c), a non-toxic dietary supplement, specific aim (i) wil test the hypothesis that the soluble factors affect blood pressure (BP) primarily by increasing systemic vascular resistance. Using novel mice in which endothelin1, (ET1), a factor downstream of sFlt1, and/or TGF¿1 expression can be varied globally or tissue-specifically from 10% to 300% of wild type levels, specific aim (ii) will test the hypothesis that modest variations in expression of Edn1 (coding for ET1) and/or Tgfb1 (coding for TGF¿1), affect basal BP. Specific aim (iii) will test the hypothesis that the consequences of exposure to high sFlt1 and sEng are exacerbated or ameliorated by pre-existing genetic factors. The effects of altered expression levels in Edn1, Tgfb1 and Ace will be examined. These experiments are expected to elucidate physiological, pathological and genetic interactions mediating the hypertension and proteinuria induced by sFlt1 and sEng. They have the potential of suggesting new interventions which may be able to postpone or avoid both the need for inducing early parturition in women with severe pre-eclampsia, and the need to discontinue the use of VEGF inhibitors in cancer patients who develop microangiopathy.