Gene Regulatory Mechanisms That Repress Bmp2 In Pathological Calcification

Description

The goal of this project is to understand how aging and chronic kidney disease (CKD) promotebone morphogenetic protein 2 (BMP2) synthesis that furthers pathological calcification of theheart valves and vasculature.Post-transcriptional regulatory mechanisms repress BMP2 in aorta and aortic valve. Wehypothesize 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 thisrepression in healthy heart valves and aorta.We will test these hypotheses in aged normal mice (24 months) and in the Klotho null mousewhich models age-related disorders, including CKD. Klotho null mice suffer premature agingand 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 the3'untranslated region (UTR) of Bmp2 on calcification in normal aged mice and in Klotho nullmice with premature aging and aging associated renal dysfunction. We will use recentlydeveloped Bmp2 alleles to assess how the deletion of this potent post-transcriptional repressorinfluences the course of calcification associated with aging and renal dysfunction. Preliminaryresults indicate that the UCS inhibits calcification.AIM 2 is to identify and compare miRNA signatures unique to young, healthy aorta and aorticvalve to the signatures of these tissues from normal aged mice and in Klotho null mice withpremature 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'UTRmediated repression in healthy tissues.AIM 3 is to test how selected and validated miRNAs influence the expression Bmp2 anddownstream osteogenic events that lead to calcification in Klotho null mice bearing our uniquetransgenes. Our novel Bmp2 reporter mouse will expedite pre-clinical testing of miRNAtherapies that prevent pathological calcification. Our newly developed Bmp2 allele (Aim 1) willdifferentiate changes due these miRNAs targeting Bmp2 relative to off-target genes.The outcomes of the proposed research will be (1) increased understanding of how BMP2influences pathological calcification, (2) the identification and analyses of potential miRNAbiomarkers, and (3) new therapeutic leads for controlling pathological calcification.
StatusActive
Effective start/end date8/15/177/31/20

Funding

  • National Institutes of Health (NIH)

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Regulator Genes
MicroRNAs
Chronic Renal Insufficiency
Aorta
Heart Valves
Alleles
Untranslated Regions
Premature Aging
Vascular Calcification
Kidney
Premature Mortality
Aortic Valve