Hypertensive kidney disease: Novel pathogenic and therapeutic pathway

描述(由申请人提供)：CHGA(嗜铬粒蛋白A)途径的紊乱与高血压肾病有关，高血压肾病是一种主要在非裔美国人中发现的破坏性疾病。在对非裔美国人CHGA基因的研究中，我们发现了一条新的、顺序的事件途径的证据，在该途径中，mRNA 3‘-UTR3’-UTRC+87T(Rs7610)破坏了一个小的/非编码的RNA识别基序(microRNA hsa-miR-107)，改变了CHGA mRNA的翻译，最终导致儿茶酚胺释放抑制肽(儿茶酚胺释放抑制肽)的形成减少，与高血压ESRD相关。最近，我们已经能够稳定合成的儿茶素抗降解，使用逆转录(R-I)肽仿制策略。策略在这项提案中，我们将探索这一连续途径中的两个点-CHGA 3‘-UTR多态和儿茶素多肽-试图开发最终可能在新的治疗方法中出现的药理探针。我们已经为每个目标制定了令人信服的初步数据(原则证明)。这些目的引出了可检验的假说，这些假说可以通过概述的实验来证实或反驳。目的-1：CHGA mRNA3‘-UTRmicroRNA基序。我们将表征人类3‘-UTRCHGA多态性C+87T(Rs7610)以及它是如何破坏Micro-RNA(hsa-miR-107)识别的。我们预计，这一步骤将阐明儿茶素形成下降的触发因素，并建议进行合理的干预。目的-2：CHGA片段儿茶素多肽的仿制。我们将表征该级联的一个积极(或“拯救”)特征的稳定合成变体：CHGA肽儿茶素，包括其最近合成的稳定的逆转录(R-I)模拟物。在这里，我们预期实现更高的活跃性、稳定性和行动持续时间。意义这两个目的出现在为NIDDK的重要疾病状态开发的新的致病途径中。因此，我们预计，我们的研究应该为目前难以解决的健康差距提供新的治疗方法。因此，该提案提供了一个机会来确定致病途径的遗传基础、其机制后果及其在一种重要人类疾病发展风险中的作用。

DESCRIPTION (provided by applicant): Derangements in the CHGA (chromogranin A) pathway are associated with hypertensive renal disease, a devastating illness found principally in African Americans. During studies of the CHGA gene in African Americans, we have developed evidence for a novel, sequential pathway of events whereby common genetic variation in the 3'-UTR of the mRNA sets off a pathogenic cascade: CHGA 3'-UTR C+87T (rs7610) disrupts a small/non-coding RNA recognition motif (micro-RNA hsa-miR-107), to alter CHGA mRNA translation, eventuating in a decrease in formation of the catestatin (catecholamine release inhibitory) peptide, in association with hypertensive ESRD. Recently we have been able to stabilize synthetic catestatin against degradation, using a Retro-Inverso (R-I) peptidomimetic strategy. Strategy in this proposal, we will explore two points in this sequential pathway - the CHGA 3'-UTR polymorphism and the catestatin peptide - in an attempt to develop pharmacological probes that could eventuate in novel therapeutic approaches. We have already developed compelling preliminary data (proof of principle) for each Aim. The aims give rise to testable hypotheses that can be confirmed or refuted by the experiments outlined. Aim-1: CHGA mRNA 3'-UTR micro-RNA motif. We will characterize the human 3'-UTR CHGA polymorphism C+87T (rs7610) and how it disrupts micro-RNA (hsa-miR-107) recognition. We anticipate that this step will elucidate the trigger for decline in catestatin formation, and sugget logical interventions. Aim-2: CHGA fragment catestatin peptidomimetics. We will characterize stable synthetic variants of a positive (or "rescue") feature of the cascade: the CHGA peptide catestatin, including its recently synthesized, stable Retro-Inverso (R-I) mimetic. Here we anticipate achieving enhanced activity, stability, and duration of action. Significance these two Aims emerge from a novel pathogenic pathway developed for a disease state of importance to NIDDK. We therefore anticipate that our studies should provide new inroads into therapeutic approaches for a currently intractable health disparity. The proposal thus represents an opportunity to define the genetic basis of a pathogenic pathway, its mechanistic consequences, and its role in risk for development of an important human disease.