Understanding the Molecular Mechanisms of Fibromuscular Dysplasia

Project Details

Description

PROJECT SUMMARY Fibromuscular dysplasia (FMD) is an understudied and sometimes fatal medical enigma that can cause arterial fibrosis, stenosis, dissection, tortuosity, aneurysm and occlusion, throughout the body. Mean age at diagnosis is 50- 55 yrs and 94% are female. Although it has a prevalence of up to 5% in females, there is no specific treatment, and very little is known about its etiology. In the press, this lack of knowledge, underappreciated prevalence and sometimes fatal outcomes have led to FMD being called “The Rare Disease That Isn’t” (WSJ, June 27, 2009). Our team, world leaders in FMD, have advanced our knowledge of its clinical features. To address the lack of understanding about its cause, in 2013 we initiated the DEFINE-FMD study - a large, functional ‘omics study of the genetic and molecular basis of FMD. Already, DEFINE-FMD has helped provide important insights into the cause of FMD, showing that it has a complex (non-Mendelian) genetic basis. Here, we propose detailed functional and mechanistic studies to understand a top causal candidate for FMD that was identified in the DEFINE-FMD study – a critical regulatory gene network (RGN) we refer to as the “FMD-RGN.” Using differing approaches, we have repeatedly validated the association of this RGN with FMD, with P values consistently less than 1 x 10-16. In addition, we have identified that one of the top key drivers of the FMD-RGN is UBR4 (ubiquitin protein ligase E3 component n- recognin 4). UBR4 is a strong causal candidate for FMD, and we have already confirmed that it exerts strong effects on modulating the expression levels of other genes in the FMD-RGN. As our overall goals we aim to determine the specific effects of the FMD-RGN on the vascular cell and arterial phenotypes, and to understand the role of UBR4 in governing the FMD-RGN and in causing FMD. • In Specific Aim 1 we will undertake detailed analyses of the impact of UBR4 and the FMD-RGN on the cellular phenotype. We will perform a series of in vitro studies using human fibroblasts with knockdown and overexpression of UBR4 to understand the role of this gene and the FMD- RGN in FMD. • In Specific Aim 2 we will characterize the in vivo cardiovascular effects of cell-specific Ubr4 deletion. We will perform a series of in vivo studies in mice with endothelial-, smooth muscle cell-, and fibroblast- specific Ubr4 deletion. We will provide a detailed characterization of the cardiovascular phenotypes of these mouse lines, including histopathology, biomechanical properties by atomic force microscopy, and proteomics using liquid chromatography tandem mass spectrometry. • In Specific Aim 3 we will perform further studies to understand the in vivo fate and function of vascular cells expressing UBR4. We will apply single cell RNA sequencing and other cutting edge techniques to freshly obtained mouse and human artery samples to provide a decisive in vivo characterization of human UBR4-expressing vascular cells, and the cell-specific phenotypic effects of Ubr4 deletion in mice. Collectively, using these integrated but independent approaches, this R01 will fully dissect the molecular mechanisms of UBR4 and the FMD-RGN, to build a holistic functional picture of the vascular pathobiology of FMD. As a disease first reported in 1938, we believe these proposed studies on FMD are imperative, and long overdue.
StatusActive
Effective start/end date15/05/2030/04/23

Funding

  • National Heart, Lung, and Blood Institute: $719,179.00
  • National Heart, Lung, and Blood Institute: $683,402.00
  • National Heart, Lung, and Blood Institute: $647,260.00

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