Hypertensive kidney disease: Novel pathogenic and therapeutic pathway

描述（由申请人提供）：CHGA（嗜铬粒蛋白A）通路的紊乱与高血压肾病相关，高血压肾病是一种主要在非裔美国人中发现的毁灭性疾病。在对非裔美国人CHGA基因的研究中，我们已经发现了一种新的连续事件途径的证据，即mRNA的3 '-UTR中的常见遗传变异引发了致病性级联反应：CHGA 3 '-UTR C+87 T（rs7610）破坏小/非编码RNA识别基序（micro-RNA hsa-miR-107），以改变CHGA mRNA翻译，最终导致与高血压ESRD相关的catestatin（儿茶酚胺释放抑制）肽形成减少。最近，我们已经能够稳定合成catestatin对降解，使用反向（R-I）拟肽策略。 策略在这个提议中，我们将探索这个顺序途径中的两个点-CHGA 3 '-UTR多态性和catestatin肽-试图开发可能最终导致新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反驳。 目的-1：CHGA mRNA 3 '-UTR micro-RNA基序。我们将描述人类3 '-UTR CHGA多态性C+87 T（rs7610）及其如何破坏micro-RNA（hsa-miR-107）识别。我们预计这一步将阐明catestatin形成下降的触发因素，并建议合理的干预措施。 目的-2：CHGA片段catestatin肽模拟物。我们将表征级联反应的阳性（或“救援”）特征的稳定合成变体：CHGA肽catestatin，包括其最近合成的稳定的反向反转（R-I）模拟物。在这里，我们期望实现增强的活性、稳定性和作用持续时间。 这两个目标的意义来自于一种新的致病途径，该途径是为NIDDK的重要疾病状态而开发的。因此，我们预计，我们的研究应该提供新的进展到目前棘手的健康差距的治疗方法。因此，该提案代表了一个机会，以确定致病途径的遗传基础，其机械后果，以及其在发展重要人类疾病的风险中的作用。 公共卫生相关性：该提案代表了一个机会，以确定的chromogranin/secretogranin系统的一个主要的临床问题的贡献：高血压肾病在少数民族人口，如非洲裔美国人。我们的研究探讨了遗传变异可能导致这种疾病的机制，以及一种新的潜在的治疗方法进入综合征;我们的初步结果表明，肾上腺素能基因的遗传变异与高血压肾硬化症风险之间存在新的病理生理学联系。这些发现应该提出新的策略，以接近这种常见但迄今为止知之甚少的疾病的机制，诊断，治疗和并发症。

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. PUBLIC HEALTH RELEVANCE: The proposal represents an opportunity to define the contribution of the chromogranin/secretogranin system to a major clinical problem: hypertensive kidney disease in minority populations such as African Americans. Our studies probe the mechanism whereby genetic variation may eventuate in the disease, and a novel potential therapeutic inroad into the syndrome; our initial results suggest novel pathophysiological links between genetic variation at an adrenergic gene, and risk for hypertensive nephrosclerosis. The findings should suggest new strategies to approach the mechanism, diagnosis, treatment, and complications of this common yet so far poorly understood disorder.