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 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 and the a2 subunit v- type H+ATPase, highlighting the existence of a network of molecules required for elastogenesis. New preliminary data from our studies now suggest that a downstream effect of different cutis laxa mutations includes dysregulation of transforming growth factor beta (TGFb) signaling. 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 altered storage and release of TGFb in the extracellular matrix. To address these hypotheses we propose (1) to investigate the genetic program of human EF formation by identifying disease-causing mutations in patients with cutis laxa, emphysema and vascular anomalies. In addition to mutational profiling of recently discovered genes, we will use candidate gene analysis 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 test if EF dysfunction leads to inappropriate TGFb release by destabilizing the large latent complex of TGFb.
In aim 3, we intend to dissect the role of fibulin-4 and related molecules in early vascular patterning and subsequent blood vessel maturation using zebrafish as a model. We will use genetics and small molecule drugs to identify the contribution of EF dysfunction and altered TGFb signaling to developmental lesions.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Genetics of Health and Disease Study Section (GHD)
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Tolunay, Eser
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University of Pittsburgh
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