Elastin is the extracellular matrix protein that imparts the property of elasticity to the lung and blood vessels. Its importance to both tissues is absolute. Without elastin the organism does not survive. With abnormal elastin, tissue development and function are compromised. The component of arteries and the lung in higher vertebrates that accounts for their elastic properties is the elastic fiber network. Ultrastructural analysis of elastic fibers identified two components: the protein elastin and fibrillin-containing microfibrils. Understanding how elastic fibers are formed, however, has been difficult. During the past funding period we showed that elastic fiber assembly is more complicated and the players more numerous than previously thought. Thus, the overall objective of this renewal application is to better understand the assembly pathway and investigate the expanding list of molecules that participate in the process. The experimental approach will utilize in vitro assembly models supported by live cell imaging to identify the proteins involved in elastin assembly. We will also utilize quick-freeze, deep-etch electron microscopy to characterize elastic fiber assembly at the tissue level. Finally, we will build upon results obtained during the previous funding period to better understand the molecular organization of fibrillin-containing microfibrils.
Our specific aims are: 1) Identify the spatial and temporal appearance and functional interactions of key assembly proteins during the early stages of elastic fiber formation. 2) Investigate the underlying mechanisms of autosomal dominant cutis laxa (ADCL) and the possibility that elastin assembly occurs through different mechanisms in different tissues. 3) Characterize elastic fiber assembly and matrix ultrastructure in intact tissues using DEEM. 4) Elucidate the molecular structure of fibrillin-containing microfibrils.

Public Health Relevance

This project seeks to elucidate the molecular basis of elastic fiber assembly. These studies are important for understanding how mutations in elastic fiber genes lead to vascular and pulmonary disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL053325-19
Application #
8502731
Study Section
Intercellular Interactions (ICI)
Program Officer
Postow, Lisa
Project Start
1994-12-20
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
19
Fiscal Year
2013
Total Cost
$436,818
Indirect Cost
$149,438
Name
Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Jarad, George; Knutsen, Russell H; Mecham, Robert P et al. (2016) Albumin contributes to kidney disease progression in Alport syndrome. Am J Physiol Renal Physiol 311:F120-30
Walji, Tezin A; Turecamo, Sarah E; DeMarsilis, Antea J et al. (2016) Characterization of metabolic health in mouse models of fibrillin-1 perturbation. Matrix Biol 55:63-76
Walji, Tezin A; Turecamo, Sarah E; Sanchez, Alejandro Coca et al. (2016) Marrow Adipose Tissue Expansion Coincides with Insulin Resistance in MAGP1-Deficient Mice. Front Endocrinol (Lausanne) 7:87
Balestrini, Jenna L; Gard, Ashley L; Gerhold, Kristin A et al. (2016) Comparative biology of decellularized lung matrix: Implications of species mismatch in regenerative medicine. Biomaterials 102:220-30
Lee, Vivian S; Halabi, Carmen M; Hoffman, Erin P et al. (2016) Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans. Proc Natl Acad Sci U S A 113:8759-64
Ferruzzi, J; Bersi, M R; Mecham, R P et al. (2016) Loss of Elastic Fiber Integrity Compromises Common Carotid Artery Function: Implications for Vascular Aging. Artery Res 14:41-52
Balestrini, Jenna L; Liu, Angela; Gard, Ashley L et al. (2016) Sterilization of Lung Matrices by Supercritical Carbon Dioxide. Tissue Eng Part C Methods 22:260-9
Walker, Ashley E; Henson, Grant D; Reihl, Kelly D et al. (2015) Greater impairments in cerebral artery compared with skeletal muscle feed artery endothelial function in a mouse model of increased large artery stiffness. J Physiol 593:1931-43
Guzy, Robert D; Stoilov, Ivan; Elton, Timothy J et al. (2015) Fibroblast growth factor 2 is required for epithelial recovery, but not for pulmonary fibrosis, in response to bleomycin. Am J Respir Cell Mol Biol 52:116-28
Mecham, Robert P; Gibson, Mark A (2015) The microfibril-associated glycoproteins (MAGPs) and the microfibrillar niche. Matrix Biol 47:13-33

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