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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.

摘要这个项目的目标是了解衰老和慢性肾脏疾病（CKD）如何促进骨骼形态发生蛋白2（BMP 2）的合成，促进心脏瓣膜的病理性钙化，脉管系统转录后调节机制抑制主动脉和主动脉瓣中的BMP 2。我们假设（1）这种抑制对于控制成人中的BMP 2水平是必不可少的，并且（2）诸如衰老和CKD的状况损害了在健康人中介导这种抑制的因子的功能，心脏瓣膜和主动脉。我们正在正常老年小鼠（24个月）和 Klotho突变小鼠，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是测试有条件地删除一个强抑制因素的影响， Bmp 2的3 '非翻译区（UTR）对正常老年小鼠和患有过早衰老和衰老相关的肾功能不全。最近开发的Bmp 2等位基因用于评估这种有效的转录后抑制因子的缺失如何影响钙化过程与衰老和肾功能不全有关。初步结果表明，UCS抑制了钙化目的2是鉴定和比较年轻健康主动脉和主动脉瓣的这些组织的签名来自正常老年小鼠和Klotho敲除小鼠，过早衰老和严重的血管钙化在这些配置文件中，我们将重点放在后- 靶向Bmp 2 UCS并有助于3 'UTR介导的转录抑制因子（miRNA）在健康组织中的抑制。目的3是测试选择和验证的miRNAs如何影响 Klotho基因敲除小鼠中导致钙化的Bmp 2表达和下游成骨事件携带着我们独特的转基因建议的研究成果将（1）增加了解BMP 2如何影响病理性钙化，（2）识别和分析潜在的miRNA生物标志物，和（3）用于控制病理性钙化的新治疗线索。这一修订的目的是要求补充资金，以支持一位名叫Lindsey埃尔南德斯的妇女，西班牙裔妇女，在研究补充，以促进健康的多样性的主持下，相关研究（公告编号PA-18-906）。埃尔南德斯女士的目标是进入博士学位遗传学计划建议的研究经验将直接提高陈女士的竞争力。埃尔南德斯申请研究生。如研究计划所述，埃尔南德斯女士将直接参与父母补助金的目标，并为她的培训制定了具体的实验。