The mechanical properties and gas exchange units of the lung are determined by the extracellular matrix (ECM) network laid down during development. The macromolecules most important for lung mechanics and structural integrity are collagen, elastin, and proteoglycans. The importance of elastin to lung development and homeostasis is evident from the consequences of elastin gene mutation. When elastin is not expressed because of loss of function mutations, the lung does not develop normally and the organism does not survive. With abnormal elastin or lower than normal elastin levels, lung function is compromised and susceptibility to diseases is enhanced. Elastin degradation is a key step in the pathogenesis of chronic obstructive pulmonary disease and elastin misassembly is associated with lung disease in several forms of cutis laxa. Exacerbating the disease process is the inability of lung cells to repair damaged elastic fibers, which leads to permanently compromised lung function and ongoing degenerative disease. Given the importance of elastin to lung development and homeostasis, it is surprising that our understanding of elastic fiber synthesis and repair remains incomplete. The work outlined in this project continues our studies of elastic fiber biology. New findings are presented that call into question existing paradigms about elastin assembly requirements and the involved players. To better understand how elastin assembly occurs during normal development and why elastin repair doesn't happen in disease, we propose to take a fresh look at elastic fiber organization based on new structural and genetic information that suggests a novel way of thinking about this complicated process. We will pursue the hypothesis that the initial stages of elastin assembly occur in a specialized intracellular compartment and that lipids contribute to elastic fiber formation both inside and outside the cell. We will also reevaluate several long-held ideas about the role of microfibrils in elastic fiber formation and growth.
Our specific aims are:
Aim #1 : Elucidate the temporal and spatial relationship of proteins involved in elastin synthesis and elastic fiber formation;
Aim #2 : Investigate a role for cellular lipids in elastin assembly;
Aim #3 : Characterize intracellular trafficking of elastic fiber proteins and determine how this defines elastic fiber assembly;
and Aim #4 : Understand how elastin gain-of-function mutations lead to human disease.

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 #
5R01HL053325-22
Application #
9418519
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Postow, Lisa
Project Start
1994-12-20
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
22
Fiscal Year
2018
Total Cost
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
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 in 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