Hypertensive kidney disease: Novel pathogenic and therapeutic pathway

描述（由申请人提供）：CHGA（嗜铬粒蛋白A）通路紊乱与高血压肾病有关，这是一种主要发生在非裔美国人身上的毁灭性疾病。在对非裔美国人CHGA基因的研究中，我们发现了一种新的、连续的事件途径的证据，即mRNA的3'-UTR的常见遗传变异引发了一个致病级联：CHGA 3'-UTR C+87T （rs7610）破坏一个小/非编码RNA识别基序（微RNA hsa-miR-107），改变CHGA mRNA的翻译，最终导致与高血压ESRD相关的catestatin（儿茶酚胺释放抑制）肽的形成减少。最近，我们已经能够稳定合成的抗降解catestatin，使用逆转录- inverso （R-I）拟态肽策略。在本提案中，我们将探索这一顺序途径中的两点- CHGA 3'- utr多态性和catestatin肽-试图开发可能最终产生新的治疗方法的药理学探针。我们已经为每个目标开发了令人信服的初步数据（原理证明）。这些目标产生了可检验的假设，这些假设可以通过概述的实验来证实或驳斥。Aim-1: CHGA mRNA 3'-UTR微rna基序。我们将描述人类3'-UTR CHGA多态性C+87T （rs7610）及其如何破坏微rna （hsa-miR-107）识别。我们预计这一步将阐明睾丸素形成下降的触发因素，并提出合理的干预措施。目的-2:CHGA片段catestatin肽仿物。我们将描述级联阳性（或“拯救”）特征的稳定合成变体：CHGA肽catestatin，包括其最近合成的稳定的retrov - inverso （R-I）模拟物。在这里，我们期望实现增强的活动性，稳定性和持续时间的行动。这两个目标来自于一种新的致病途径，这种途径是为NIDDK重要的疾病状态而开发的。因此，我们预计我们的研究应该为目前棘手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，以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.