Hypertensive kidney disease: Novel pathogenic and therapeutic pathway

高血压肾病：新的致病和治疗途径

基本信息

批准号：
8270931
负责人：
DANIEL T O'CONNOR
金额：
$ 33.69万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-15 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8270931
关键词：
Adrenergic Agents African American Alleles Amino Acids Binding Biological CHGA gene Catecholamines Chromogranin A Chromogranins Clinical Data Development Diagnosis Disease Disease susceptibility End stage renal failure Event Frequencies Functional RNA Genes Genetic Genetic Polymorphism Genetic Translation Genetic Variation Genotype Goals Haplotypes Human Hypertension Intervention Kidney Diseases Link Messenger RNA MicroRNAs Minority Molecular National Institute of Diabetes and Digestive and Kidney Diseases Nephrosclerosis Pathway interactions Patients Peptides Phenotype Physiological Plasma Population RNA RNA Recognition Motif Reagent Renal function Retro-Inverso Peptide Risk Role Series Single Nucleotide Polymorphism Syndrome System Therapeutic Translations Untranslated Regions Variant Vesicle adrenergic analog autocrine base cholinergic chromogranin A (344-364)defined contribution health disparity human disease mimetics novel novel therapeutic intervention patient population peptidomimetics research study secretogranins

项目摘要

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.

描述（由申请人提供）：CHGA中的危险（Chromogranin a）途径与高血压肾脏疾病有关，这是非裔美国人主要发现的毁灭性疾病。在对非裔美国人的CHGA基因的研究期间，我们为事件的新型，顺序的途径开发了证据，使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+87T（ RS7610）破坏一个小/非编码RNA识别基序（Micro-RNA HSA-MIR-107），以改变Chga mRNA翻译，在Catestatin（Catestatin抑制性抑制性cate胺抑制）肽的形成下降低，与高血压ESRD相关。最近，我们已经能够使用复古插入术（R-I）肽型策略来稳定合成猫蛋白降解。在此提案中，我们将在此顺序途径中探索两个点-CHGA 3' -UTR多态性和Catestatin肽 - 试图开发可以在新型治疗方法中发生的药理探针。我们已经为每个目标开发了引人注目的初步数据（原理证明）。目的产生了可检验的假设，这些假设可以通过概述的实验确认或驳斥。 AIM-1：CHGA mRNA 3'-UTR微RNA图案。我们将表征人类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，这一步骤将阐明猫蛋白形成下降的触发因素以及逻辑干预措施。 AIM-2：CHGA碎片catestatin肽仪。我们将表征喀斯喀特阳性（或“救援”）特征的稳定合成变体：CHGA肽catestatin，包括其最近合成的，稳定的稳定的恢复（R-I）模拟物。在这里，我们预计可以增强活动，稳定性和作用持续时间。意义上这两个目标是从一种为NIDDK重要的疾病状态而开发的新型致病途径中出现的。因此，我们预计我们的研究应该为目前棘手的健康差异提供新的治疗方法。因此，该提案代表了定义致病途径的遗传基础，其机械后果以及其在重要人类疾病发展风险中的作用的机会。公共卫生相关性：该提案代表了定义铬烷蛋白/分泌蛋白系统对主要临床问题的贡献的机会：非裔美国人等少数群体中的高血压肾脏疾病。我们的研究探究了遗传变异可能在疾病中发生的机制，以及综合征的新型潜在治疗方法。我们的最初结果表明，肾上腺素能基因的遗传变异与高血压性肾硬化的风险之间存在新的病理生理联系。这些发现应提出新的策略，以应对这种常见但迄今为止理解不足的疾病的机制，诊断，治疗和并发症。