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，并了解相关机制。MicroRNA是内源性的调节RNA，其主要通过结合靶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控因子，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在系统性高血压和高血压组织损伤的发展中的功能作用仍然未知。Dahl盐敏感（SS）大鼠是一种广泛使用的人类高血压和相关肾损伤的动物模型，特别是在非洲裔美国人中。consomic SS.13BN大鼠表现出显着减弱的高血压和肾损伤，并已被用作研究疾病的SS大鼠机制的对照。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-29 b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，miR-29 b在高血压肾损伤患者的肾脏中失调。然而，尚不清楚肾miR-29的不足是否有助于SS大鼠中高血压和肾损伤的发展，肾miR-29是否保护SS. 13 BN大鼠免于发展高血压，什么机制介导miR-29对高血压的任何作用，以及miR-29的表达如何在SS大鼠的肾脏中调节。我们推测，miR-29的不表达，特别是在肾脏中，有助于盐诱导的高血压和肾损伤的发展。在目的1中，我们将使用我们刚刚开发的组织特异性miR-29转基因大鼠和局部敲低miR-29来检查miR-29在SS大鼠中盐诱导的高血压和肾损伤的发展中的功能作用。在目标2中，我们将使用几种方法，包括我们刚刚开发的分子复合物拉出和深度测序方法，研究miR-29调控及其保护作用的机制。令人兴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.