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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090648-03
Application #
8300926
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Tolunay, Eser
Project Start
2010-09-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$369,121
Indirect Cost
$121,621
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Public Health
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Minster, Ryan L; Hawley, Nicola L; Su, Chi-Ting et al. (2016) A thrifty variant in CREBRF strongly influences body mass index in Samoans. Nat Genet 48:1049-54
Su, Chi-Ting; Huang, Jenq-Wen; Chiang, Chih-Kang et al. (2015) Latent transforming growth factor binding protein 4 regulates transforming growth factor beta receptor stability. Hum Mol Genet 24:4024-36
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
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
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
Berk, David R; Bentley, Danette D; Bayliss, Susan J et al. (2012) Cutis laxa: a review. J Am Acad Dermatol 66:842.e1-17
Sugitani, Hideki; Hirano, Eiichi; Knutsen, Russell H et al. (2012) Alternative splicing and tissue-specific elastin misassembly act as biological modifiers of human elastin gene frameshift mutations associated with dominant cutis laxa. J Biol Chem 287:22055-67
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 TGFβ signaling. Hum Mol Genet 21:1248-59

Showing the most recent 10 out of 13 publications