Animal Models for Studying the Genetics of Hypertension

描述（由申请人提供）：我们的长期目标是解开高血压的遗传学。即将到来的资助重点是了解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（MA）的抗血管生成治疗的癌症患者中。先兆子痫（PE）是妊娠相关高血压和蛋白尿的常见形式。它占孕产妇死亡的15%，并大大增加了未来心血管疾病的风险。循环抗血管生成因子sFlt 1（血管内皮生长因子VEGF受体的可溶形式）和sEng（组织生长因子β TGF-β辅助受体的可溶形式）的异常增加与PE相关。PE和MA的许多病理后果可以在啮齿动物中用表达sFlt 1和/或sEng的重组腺病毒（rAdVs）复制，我们假设遗传因素影响后果的严重程度，并且它们在其他形式的高血压中也很重要。使用新型转基因小鼠，其中循环sFlt 1或sEng水平可以通过喂食吲哚-3-甲醇（i3 c）（一种无毒膳食补充剂）可逆地增加，具体目的（i）将检验可溶性因子主要通过增加全身血管阻力影响血压（BP）的假设。使用新的小鼠，其中内皮素1（ET 1）（sFlt 1的下游因子）和/或TGF β 1表达可以在野生型水平的10%至300%之间整体地或组织特异性地变化，具体目标（ii）将测试Edn 1（编码ET 1）和/或Tgfb 1（编码TGF β 1）表达的适度变化影响基础BP的假设。具体目标（iii）将检验暴露于高sFlt 1和sEng的后果会因预先存在的遗传因素而加剧或改善的假设。将检查Edn 1、Tgfb 1和Ace表达水平改变的影响。这些实验有望阐明sFlt 1和sEng介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，这些干预措施可能能够推迟或避免重度先兆子痫妇女诱导早期分娩的需要，以及在发生微血管病的癌症患者中停止使用VEGF抑制剂的需要。

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.