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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Intercellular Interactions (ICI)
Program Officer
Postow, Lisa
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Anatomy/Cell Biology
Schools of Medicine
Saint Louis
United States
Zip Code
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
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
Kim, Dongjoon; Mecham, Robert P; Trackman, Philip C et al. (2017) Downregulation of Lysyl Oxidase Protects Retinal Endothelial Cells From High Glucose-Induced Apoptosis. Invest Ophthalmol Vis Sci 58:2725-2731
Munjal, Charu; Jegga, Anil G; Opoka, Amy M et al. (2017) Inhibition of MAPK-Erk pathway inĀ vivo attenuates aortic valve disease processes in Emilin1-deficient mouse model. Physiol Rep 5:
Kugler, Matthias C; Loomis, Cynthia A; Zhao, Zhicheng et al. (2017) Sonic Hedgehog Signaling Regulates Myofibroblast Function during Alveolar Septum Formation in Murine Postnatal Lung. Am J Respir Cell Mol Biol 57:280-293
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
Staiculescu, Marius Catalin; Kim, Jungsil; Mecham, Robert P et al. (2017) Mechanical behavior and matrisome gene expression in the aneurysm-prone thoracic aorta of newborn lysyl oxidase knockout mice. Am J Physiol Heart Circ Physiol 313:H446-H456
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
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

Showing the most recent 10 out of 42 publications