miR-29 In Hypertension

描述（由申请人提供）：当前项目的目标是研究microRNA miR-29在高血压和肾损伤发展中的作用，并了解其机制。microrna是内源性的调节性rna，主要通过结合靶mrna的3'-非翻译区（UTR）来降低蛋白质表达。大量研究表明，microrna是基因表达的强大调节剂，在包括心血管和肾脏疾病在内的多种疾病过程中发挥着至关重要的作用。然而，大多数microrna在全身性高血压和高血压组织损伤发展中的功能作用尚不清楚。Dahl盐敏感（SS）大鼠是一种广泛应用于人类高血压及相关肾损伤的动物模型，尤其是非洲裔美国人。经济型SS. 13bn大鼠表现出明显减轻的高血压和肾损伤，并被用作研究SS大鼠疾病机制的对照。我们已经报道，与SS. 13bn大鼠相比，高盐饮食的SS大鼠肾脏中的microRNA miR-29b下调。miR-29直接抑制至少16个与细胞外基质（ECM）相关的基因，并有助于预防SS.13BN肾脏的间质纤维化。此外，我们在正在进行的人体研究中发现，高血压肾损伤患者的肾脏中miR-29b表达异常。然而，肾脏miR-29的不足是否参与了SS大鼠高血压和肾损伤的发生，肾脏miR-29是否保护SS. 13bn大鼠免于高血压的发生，miR-29对高血压的影响是通过何种机制介导的，以及miR-29在SS大鼠肾脏中的表达是如何被调节的，这些都尚不清楚。我们假设miR-29缺乏，特别是在肾脏中，有助于盐诱导的高血压和肾损伤的发展。在Aim 1中，我们将使用我们刚刚培育的组织特异性miR-29转基因大鼠和局部敲低miR-29来研究miR-29在SS大鼠盐性高血压和肾损伤发展中的功能作用。在Aim 2中，我们将使用几种方法研究miR-29调控及其保护作用的机制，包括我们刚刚开发的分子复合物提取和深度测序方法。令人振奋的初步数据支持拟议项目的可行性。

DESCRIPTION (provided by applicant): The goal of the current project is to investigate the role of microRNA miR-29 in the development of hypertension and renal injury and understand the mechanisms involved. MicroRNAs are endogenous, regulatory RNAs that primarily reduce protein expression by binding to the 3'-untranslated region (UTR) of target mRNAs. Numerous studies have demonstrated that microRNAs are powerful regulators of gene expression and play crucial roles in a wide range of disease processes including several cardiovascular and renal diseases. However, the functional role of most microRNAs in the development of systemic hypertension and hypertensive tissue injury remains unknown. The Dahl salt-sensitive (SS) rat is a widely used animal model of human hypertension and related renal injury especially in African Americans. The consomic SS.13BN rat exhibits significantly attenuated hypertension and renal injury and has been used as a control for studying disease mechanisms in the SS rat. We have reported that microRNA miR-29b is down-regulated in the kidneys of SS rats on a high-salt diet compared to SS.13BN rats. miR-29 directly suppresses at least 16 genes related to extracellular matrix (ECM) and helps to prevent interstitial fibrosis in SS.13BN kidneys. Moreover, we found in ongoing human studies that miR-29b was dysregulated in the kidneys of patients with hypertensive renal injury. However, it remains unknown whether the insufficiency of renal miR-29 contributes to the development of hypertension and renal injury in the SS rat, whether renal miR-29 protects SS.13BN rats from developing hypertension, what mechanisms mediate any effect of miR-29 on hypertension, and how the expression of miR-29 is regulated in the kidneys of SS rats. We hypothesize that miR-29 insufficiencies, specifically in the kidney, contribute to the development of salt-induced hypertension and renal injury. In Aim 1, we will examine the functional role of miR-29 in the development of salt-induced hypertension and renal injury in the SS rat using tissue-specific miR-29 transgenic rats that we just developed and local knockdown of miR-29. In Aim 2, we will examine mechanisms underlying the regulation of miR-29 and its protective effect using several approaches including a molecular complex pull-out and deep sequencing method that we just developed. Exciting preliminary data support the feasibility of the proposed project.