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：
8520582
负责人：
DANIEL T O'CONNOR
金额：
$ 4.37万
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/8520582
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.

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，这是一种主要见于非裔美国人的毁灭性疾病。在对非裔美国人的 CHGA 基因进行研究期间，我们发现了一种新的、连续的事件途径的证据，通过该途径，mRNA 3'-UTR 中的常见遗传变异引发了致病级联：CHGA 3'-UTR C+87T（ rs7610) 破坏小/非编码 RNA 识别基序 (micro-RNA hsa-miR-107)，以改变 CHGA mRNA 翻译，最终导致儿茶素 (儿茶酚胺释放) 形成减少抑制）肽，与高血压 ESRD 相关。最近，我们已经能够使用逆向逆 (R-I) 拟肽策略来稳定合成儿茶素，防止降解。在本提案中的策略中，我们将探索该连续途径中的两个点 - CHGA 3'-UTR 多态性和儿茶素肽 - 试图开发最终可能产生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。 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 micro-RNA (hsa-miR-107) 识别。我们预计这一步骤将阐明儿科蛋白形成下降的触发因素，并建议合理的干预措施。 Aim-2：CHGA 片段 catestatin 肽模拟物。我们将表征级联的积极（或“救援”）特征的稳定合成变体：CHGA 肽 catestin，包括其最近合成的稳定的 Retro-Inverso (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。这两个目标的意义源于针对 NIDDK 重要疾病状态开发的新型致病途径。因此，我们预计我们的研究将为当前棘手的健康差距的治疗方法提供新的进展。因此，该提案提供了一个机会来定义致病途径的遗传基础、其机制后果及其在重要人类疾病发展风险中的作用。