The long-range objectives of these studies are to elucidate the functions of the elastic extracellular matrix in human development and physiology, to uncover the molecular mechanisms of disease caused by elastic fiber (EF) dysfunction and to develop novel treatment strategies for these diseases. Several lines of recent evidence highlight the complexity of EF assembly. Cell biological and biochemical studies illustrate the dynamic, hierarchical and cell mediated nature of EF biogenesis. However, key molecular determinants of this process have remained elusive. Molecular genetic studies of patients with vascular anomalies, emphysema and cutis laxa (CL) show that multiple genes are required for distinct steps of the EF formation. These studies identified mutations in the genes for elastin, fibulin-4, fibulin-5, the a2 subunit of the v- type H+-ATPase, and the latent transforming growth factor beta-binding protein 4 (LTBP4), highlighting the existence of a network of molecules required for elastogenesis. New preliminary data from our studies now demonstrate the existence of new CL genes and show that a downstream effect of different cutis laxa mutations includes dysregulation of transforming growth factor beta (TGF) signaling through novel mechanisms. Based on these results we hypothesize that cutis laxa is caused by the disruption of EF biogenesis at multiple levels leading to both structural disruption of elastic fibers and by altere storage and release of growth factors in the extracellular matrix and by affecting the stability an activity of growth factor receptors. To address these hypotheses we propose (1) to investigate the genetic program of human EF formation by in-depth phenotyping and identifying disease-causing mutations in patients with CL, emphysema and vascular anomalies. In addition to mutational profiling of recently discovered genes, we will use whole exome sequencing, RNA sequencing and array comparative genomic hybridization to identify novel genes for these disorders.
In aim 2, we will use in vitro models of EF assembly to identify the sequence of molecular interactions between extracellular matrix molecules impacted by cutis laxa mutations. We will also study the mechanisms by which EF dysfunction leads to dysregulation of growth factor activity.
In aim 3, we intend to investigate dissect the role of cutis laxa genes in early cardiovascular and connective tissue development. We will use genetics and small molecule drugs to identify the contribution of EF dysfunction and altered growth factor signaling to developmental lesions.
Common age-related diseases of the blood vessels and lungs including arteriosclerosis, aneurysms and emphysema are associated with the loss of elastic fibers. Although repair mechanisms are initiated in damaged tissues, adult organisms appear to be unable to regenerate functional elastic tissue. Understanding the processes of elastic fiber formation through development is essential to develop new ways for tissue regeneration or to protect against deterioration associated with age and disease.
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