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.
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.
|Kozel, Beth A; Su, Chi-Ting; Danback, Joshua R et al. (2014) Biomechanical properties of the skin in cutis laxa. J Invest Dermatol 134:2836-8|
|Siefring, Mark L; Lawrence, Elizabeth C; Nguyen, Tom C et al. (2014) A novel elastin gene mutation in a Vietnamese patient with cutis laxa. Pediatr Dermatol 31:347-9|
|Urban, Zsolt; Davis, Elaine C (2014) Cutis laxa: intersection of elastic fiber biogenesis, TGF* signaling, the secretory pathway and metabolism. Matrix Biol 33:16-22|
|Uitto, Jouni; Li, Qiaoli; Urban, Zsolt (2013) The complexity of elastic fibre biogenesis in the skin--a perspective to the clinical heterogeneity of cutis laxa. Exp Dermatol 22:88-92|
|Callewaert, Bert; Su, Chi-Ting; Van Damme, Tim et al. (2013) Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa. Hum Mutat 34:111-21|
|Willaert, Andy; Khatri, Sandeep; Callewaert, Bert L et al. (2012) GLUT10 is required for the development of the cardiovascular system and the notochord and connects mitochondrial function to TGF? signaling. Hum Mol Genet 21:1248-59|
|Berk, David R; Bentley, Danette D; Bayliss, Susan J et al. (2012) Cutis laxa: a review. J Am Acad Dermatol 66:842.e1-17|
|Brunetti-Pierri, Nicola; Piccolo, Pasquale; Morava, Eva et al. (2011) Cutis laxa and fatal pulmonary hypertension: a newly recognized syndrome? Clin Dysmorphol 20:77-81|
|Callewaert, Bert; Renard, Marjolijn; Hucthagowder, Vishwanathan et al. (2011) New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations. Hum Mutat 32:445-55|