Gene Regulatory Mechanisms that Repress BMP2 in Pathological Calcification

病理钙化中抑制 BMP2 的基因调控机制

基本信息

批准号：
9216823
负责人：
MELISSA B ROGERS
金额：
$ 39.73万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9216823
关键词：
3&apos Untranslated Regions Adult Age Aging Alleles Amputation Angioplasty Aorta Arteries Atherosclerosis Calcified Calcinosis Cardiovascular Diseases Cardiovascular system Cause of Death Cells Cessation of life Chronic Kidney Failure Collection Complement Conserved Sequence Coronary Arteriosclerosis Dangerousness Data Diabetes Mellitus Disease Elderly Elements Event Functional disorder Gene Targeting Genetic Transcription Genetically Engineered Mouse Goals Heart Diseases Heart Valves Human Impairment Kidney Kidney Failure Knockout Mice LacZ Genes Lead Mediating Mesenchymal Messenger RNA Metabolism MicroRNAs Minerals Modeling Molecular Mus Muscle Cells Mutant Strains Mice Normal tissue morphology Outcome Pathologic Pathology Physiology Premature aging syndrome Protein Biosynthesis Publishing Reagent Regulator Genes Renal function Reporter Repression Research Research Design Signal Transduction Stroke Testing Therapeutic Time Tissues Transcription Repressor/Corepressor Transgenes United States Update Vascular Smooth Muscle Vascular calcification age related aged aortic valve aortic valve disorder bone cell bone morphogenetic protein 2 calcification calcium phosphate gene repression microRNA biomarkers novel novel therapeutics osteogenic pre-clinical prevent research clinical testing restenosis soft tissue statistics therapy design

项目摘要

The goal of this project is to understand how aging and chronic kidney disease (CKD) promote bone morphogenetic protein 2 (BMP2) synthesis that furthers pathological calcification of the heart valves and vasculature. Post-transcriptional regulatory mechanisms repress BMP2 in aorta and aortic valve. We hypothesize that (1) this repression is essential for controlling BMP2 levels in the adult and that (2) conditions such as aging and CKD impair the function of factors that mediate this repression in healthy heart valves and aorta. We will test these hypotheses in aged normal mice (24 months) and in the Klotho null mouse which models age-related disorders, including CKD. Klotho null mice suffer premature aging and death occurs at 7 - 8 weeks of age. At this time, extensive calcification of the heart valves, vasculature, and other soft tissues has occurred. AIM 1 is to test the influence of conditionally deleting a strong repressive element in the 3'untranslated region (UTR) of Bmp2 on calcification in normal aged mice and in Klotho null mice with premature aging and aging associated renal dysfunction. We will use recently developed Bmp2 alleles to assess how the deletion of this potent post-transcriptional repressor influences the course of calcification associated with aging and renal dysfunction. Preliminary results indicate that the UCS inhibits calcification. AIM 2 is to identify and compare miRNA signatures unique to young, healthy aorta and aortic valve to the signatures of these tissues from normal aged mice and in Klotho null mice with premature aging and severe vascular calcification. Within these profiles, we will focus on post- transcriptional repressive factors (miRNAs) that target the Bmp2 UCS and contribute to 3'UTR mediated repression in healthy tissues. AIM 3 is to test how selected and validated miRNAs influence the expression Bmp2 and downstream osteogenic events that lead to calcification in Klotho null mice bearing our unique transgenes. Our novel Bmp2 reporter mouse will expedite pre-clinical testing of miRNA therapies that prevent pathological calcification. Our newly developed Bmp2 allele (Aim 1) will differentiate changes due these miRNAs targeting Bmp2 relative to off-target genes. The outcomes of the proposed research will be (1) increased understanding of how BMP2 influences pathological calcification, (2) the identification and analyses of potential miRNA biomarkers, and (3) new therapeutic leads for controlling pathological calcification.

该项目的目标是了解衰老和慢性肾病 (CKD) 如何促进骨形态发生蛋白 2 (BMP2) 的合成，进一步促进骨的病理性钙化心脏瓣膜和脉管系统。转录后调节机制抑制主动脉和主动脉瓣中的 BMP2。我们假设 (1) 这种抑制对于控制成人的 BMP2 水平至关重要，并且 (2) 衰老和慢性肾病等疾病会损害介导此现象的因素的功能健康心脏瓣膜和主动脉的抑制。我们将在老年正常小鼠（24 个月）和 Klotho 无效小鼠中测试这些假设它模拟了与年龄相关的疾病，包括 CKD。 Klotho 缺失小鼠遭受过早衰老死亡发生在 7 - 8 周龄时。此时，心脏瓣膜广泛钙化，血管系统和其他软组织已发生。目的1是测试有条件删除强压制元素的影响 Bmp2 的 3' 非翻译区 (UTR) 对正常老年小鼠和 Klotho null 钙化的影响小鼠过早衰老和衰老相关的肾功能障碍。我们最近会用到开发了 Bmp2 等位基因来评估这种有效的转录后阻遏蛋白的缺失影响与衰老和肾功能障碍相关的钙化过程。初步的结果表明UCS抑制钙化。 AIM 2 是识别和比较年轻、健康主动脉和主动脉特有的 miRNA 特征正常老年小鼠和 Klotho 缺失小鼠的这些组织特征的阀门过早衰老和严重的血管钙化。在这些简介中，我们将重点关注后期靶向 Bmp2 UCS 并有助于 3'UTR 的转录抑制因子 (miRNA) 介导健康组织中的抑制。目标 3 是测试选定和验证的 miRNA 如何影响 Bmp2 和下游成骨事件导致携带我们独特的 Klotho 缺失小鼠钙化转基因。我们的新型 Bmp2 报告小鼠将加快 miRNA 的临床前测试预防病理性钙化的疗法。我们新开发的 Bmp2 等位基因（目标 1）将区分这些针对 Bmp2 的 miRNA 相对于脱靶基因的变化。拟议研究的结果将是 (1) 加深对 BMP2 如何影响病理钙化，（2）潜在miRNA的鉴定与分析生物标志物，以及（3）控制病理钙化的新治疗线索。