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：
9922580
负责人：
MELISSA B ROGERS
金额：
$ 5.8万
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 2021-07-31
项目状态：
已结题

项目摘要

Abstract 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 are testing these hypotheses in aged normal mice (24 months) and in the Klotho mutant mouse which models age-related disorders, including extensive calcification of the heart valves and vasculature. 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 mice with premature aging and aging associated renal dysfunction. Recently developed Bmp2 alleles are used 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. 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. The purpose of this revision is to request supplemental funds to support Ms. Lindsey Hernandez, a Hispanic woman, under the auspices of the Research Supplement to Promote Diversity in Health- Related Research (Announcement Number PA-18-906). Ms. Hernandez goal is to enter a doctoral program in genetics. The proposed research experience will directly improve the competitiveness of Ms. Hernandez applications to graduate school. As described in the Research Plan, Ms. Hernandez will be directly involved in the goals of the parent grant, with specific experiments delineated for her training.

抽象的该项目的目标是了解衰老和慢性肾病 (CKD) 如何促进骨骼健康形态发生蛋白 2 (BMP2) 的合成进一步促进心脏瓣膜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。坚持认为 (1) 这种抑制对于控制成人 BMP2 水平至关重要，并且 (2) 衰老和慢性肾病等疾病会损害健康人体内介导这种抑制的因素的功能。我们正在老年正常小鼠（24 个月）和小鼠身上测试这些假设。 Klotho 突变小鼠可模拟年龄相关疾病，包括心脏广泛钙化瓣膜和脉管系统。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 小鼠钙化的影响最近开发的 Bmp2 等位基因用于治疗过早衰老和衰老相关的肾功能障碍。评估这种有效的转录后阻遏蛋白的缺失如何影响钙化过程初步结果表明，UCS 与衰老和肾功能障碍有关。 AIM 2 旨在识别和比较年轻、健康主动脉和钙化所特有的 miRNA 特征。主动脉瓣对正常老年小鼠和 Klotho 缺失小鼠的这些组织的特征的影响在这些概况中，我们将重点关注后期。靶向 Bmp2 UCS 并有助于 3'UTR 介导的转录抑制因子 (miRNA) AIM 3 是为了测试选定和验证的 miRNA 如何影响健康组织。 Bmp2 的表达和导致 Klotho 缺失小鼠钙化的下游成骨事件承载我们独特的转基因。拟议研究的成果将是（1）增加。了解 BMP2 如何影响病理性钙化，(2) 的识别和分析潜在的 miRNA 生物标志物，以及 (3) 控制病理钙化的新治疗线索。此次修订的目的是请求补充资金来支持 Lindsey Hernandez 女士，她是一名西班牙裔妇女，在促进健康多样性研究增刊的赞助下- 相关研究（公告号 PA-18-906）。 Hernandez 女士的目标是攻读博士学位。遗传学项目。所提出的研究经验将直接提高女士的竞争力。正如研究计划中所述，埃尔南德斯女士将申请研究生院。直接参与家长补助金的目标，并为她的培训制定了具体的实验。