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 abnormalelastin, tissue development and function are compromised. The component of arteries and the lung inhigher vertebrates that accounts for their elastic properties is the elastic fiber network. Ultrastructuralanalysis 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 weshowed that elastic fiber assembly is more complicated and the players more numerous than previouslythought. Thus, the overall objective of this renewal application is to better understand the assemblypathway and investigate the expanding list of molecules that participate in the process. The experimentalapproach will utilize in vitro assembly models supported by live cell imaging to identify the proteins involvedin elastin assembly. We will also utilize quick-freeze, deep-etch electron microscopy to characterize elasticfiber assembly at the tissue level. Finally, we will build upon results obtained during the previous fundingperiod 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 keyassembly proteins during the early stages of elastic fiber formation. 2) Investigate the underlyingmechanisms of autosomal dominant cutis laxa (ADCL) and the possibility that elastin assembly occursthrough different mechanisms in different tissues. 3) Characterize elastic fiber assembly and matrixultrastructure in intact tissues using DEEM. 4) Elucidate the molecular structure of fibrillin-containingmicrofibrils.

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 #
5R01HL053325-17
Application #
8089262
Study Section
Intercellular Interactions (ICI)
Program Officer
Postow, Lisa
Project Start
1994-12-20
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
17
Fiscal Year
2011
Total Cost
$458,429
Indirect Cost
Name
Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Luo, Yongfeng; Li, Nan; Chen, Hui et al. (2018) Spatial and temporal changes in extracellular elastin and laminin distribution during lung alveolar development. Sci Rep 8:8334
Craft, Clarissa S; Broekelmann, Thomas J; Mecham, Robert P (2018) Microfibril-associated glycoproteins MAGP-1 and MAGP-2 in disease. Matrix Biol 71-72:100-111
Mecham, Robert P (2018) Elastin in lung development and disease pathogenesis. Matrix Biol 73:6-20
Kabir, Ashraf Ul; Lee, Tae-Jin; Pan, Hua et al. (2018) Requisite endothelial reactivation and effective siRNA nanoparticle targeting of Etv2/Er71 in tumor angiogenesis. JCI Insight 3:
Turecamo, S E; Walji, T A; Broekelmann, T J et al. (2018) Contribution of metabolic disease to bone fragility in MAGP1-deficient mice. Matrix Biol 67:1-14
Kim, Jungsil; Staiculescu, Marius Catalin; Cocciolone, Austin J et al. (2017) Crosslinked elastic fibers are necessary for low energy loss in the ascending aorta. J Biomech 61:199-207
Panzer, Adam A; Regmi, Suk D; Cormier, DePorres et al. (2017) Nkx2-5 and Sarcospan genetically interact in the development of the muscular ventricular septum of the heart. Sci Rep 7:46438
Halabi, Carmen M; Broekelmann, Thomas J; Lin, Michelle et al. (2017) Fibulin-4 is essential for maintaining arterial wall integrity in conduit but not muscular arteries. Sci Adv 3:e1602532
Li, Rongbo; Herriges, John C; Chen, Lin et al. (2017) FGF receptors control alveolar elastogenesis. Development 144:4563-4572
Jiao, Yang; Li, Guangxin; Korneva, Arina et al. (2017) Deficient Circumferential Growth Is the Primary Determinant of Aortic Obstruction Attributable to Partial Elastin Deficiency. Arterioscler Thromb Vasc Biol 37:930-941

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