Regulation of BMP2 in CKD Induced Calcification in the Klotho Aging Model

BMP2 在 Klotho 老化模型中 CKD 诱导钙化中的调节

• 批准号: 9349635
• 负责人: MELISSA B ROGERS
• 金额: $ 39.75万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349635
• 关键词: 3' Untranslated Regions; Adult; Age; Aging; Alleles; American Heart Association; Amputation; Angioplasty; Aorta; Arteries; Atherosclerosis; Cardiovascular Diseases; Cause of Death; Cells; Cessation of life; Chronic Kidney Failure; Coronary Arteriosclerosis; Diabetes Mellitus; Disease; Elderly; Event; Functional disorder; Gene Targeting; Goals; Health; Heart Diseases; Heart Valves; Human; Indium; Institutes; Kidney; Knockout Mice; Lead; Mediating; Mesenchymal; MicroRNAs; Modeling; Molecular; Mus; Outcome; Pathology; Premature aging syndrome; Protein Biosynthesis; Regulation; Renal function; Reporter; Repression; Research; Stroke; Testing; Therapeutic; Time; Tissues; Transcription Repressor/Corepressor; Transgenes; United States; Update; Vascular calcification; age related; aortic valve; aortic valve disorder; bone cell; bone morphogenetic protein 2; calcification; microRNA biomarkers; normal aging; novel; novel therapeutics; osteogenic; prevent; research clinical testing; restenosis; soft tissue; statistics; therapy design

 DESCRIPTION (provided by applicant): 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. 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 experimentally 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 designed to 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.

 描述（由申请人提供）：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，从而进一步促进心脏瓣膜和脉管系统的病理性钙化。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 BMP2 水平至关重要，并且 (2) 衰老和 CKD 等条件会损害介导健康心脏瓣膜和主动脉中这种抑制的因素的功能。我们将在老年正常小鼠（24 个月）和 Klotho 无效小鼠（模拟年龄相关疾病，包括 CKD）中测试这些假设。 Klotho 无效小鼠会过早衰老，并在 7-8 周龄时死亡。此时，心脏瓣膜、脉管系统和其他软组织已发生广泛钙化。目的1是测试有条件地删除Bmp2 3'非翻译区(UTR)中的强抑制元件对正常老年小鼠和早衰和衰老相关肾功能障碍的Klotho缺失小鼠钙化的影响。我们将使用最近开发的 Bmp2 等位基因来评估这种有效的转录后阻遏蛋白的缺失如何影响与衰老和肾功能障碍相关的钙化过程。 AIM 2 旨在识别年轻、健康的主动脉和主动脉瓣特有的 miRNA 特征，与正常衰老小鼠以及早衰和严重血管钙化的 Klotho 缺失小鼠的这些组织的特征进行比较。在这些概况中，我们将重点关注以 Bmp2 UCS 为目标并有助于健康组织中 3'UTR 介导的抑制的转录后抑制因子 (miRNA)。目的 3 是测试经过选择和实验验证的 miRNA 如何影响 Bmp2 的表达和下游成骨事件，从而导致携带我们独特转基因的 Klotho 无效小鼠钙化。我们的新型 Bmp2 报告小鼠将加快旨在预防病理性钙化的 miRNA 疗法的临床前测试。我们新开发的 Bmp2 等位基因（目标 1）将区分这些针对 Bmp2 的 miRNA 相对于脱靶基因造成的变化。拟议研究的结果将是（1）加深对 BMP2 如何影响病理钙化的了解，（2）潜在 miRNA 生物标志物的识别和分析，以及（3）控制病理钙化的新治疗线索。