This proposal outlines a three year program of research and training td establish the principal investigator (PI) as a biomedical engineering professor studying develqpmeiital cardiovascular mechanics. A postdoctoi-al year has been completed In Dr. Robert Mecham's laboratory at Washington University, where the PI expanded her knowledge of cell biology and physiology and practiced communication and management skills. The PI has accepted a tenure-track assistant professorship at Saint Louis University and plans to continue'her previous research. She will establish her independence by combining the cell biology and physiology with her expertise in biomechanics and mechanical modeling. Career training w/lir include teaching, mentorship by established professors and exposure at national meetings: During cardiovascular development, blood pressure and flow increase and smooth muscle cells produce extracellular matrix proteins, such as collagen and elastin. that define the mechanical behavior of the vessel wall. A mouse .model o( supravalvular aortic stenosis, an elastin-associated disease in humans, showed that elastin haploinsufficiency (eln+/-) results in altered vessel wall structure, decreased compliance and Increased blood pressure. Despite these features. eInW- mice live a normal life span, suggesting that they adjust to reduced elastin amounts and the resulting changes Iri rriechanicat stimuli. The hypothesis of this proposal is that developing vessels remodel to optimize mechanical stresses in the wall and that these stresses, provide a key signal for cellular differentiation. This remodeling will be described and predicted by a mathematical model in which pertiirbations cause grovi/th of various components, returning the stresses near homeostatic values. Because of the unique developmental remodeling in the eln+/-.cardiovascular system, these mice provide an Ideal tool to investigate the hypothesis and validate the mechanical model.
The specific aims are: 1) To detennine hemodynamic, mechanical and geometric parameters In developing vessels. 2) To determine how changes in elastin amount alter mechanical sigriats in developing vessels. 3) To develop a constrained mixture model lo predict the growth of developing vessels.

Public Health Relevance

Mechanical signals play a significant role in defining the structure and function of developing blood vessels. Understanding and predicting the growth and remodeling process is critical for determining possible treatments and preventative measures in developmental cardiovascular diseases

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
5R00HL087563-03
Application #
7760875
Study Section
Special Emphasis Panel (NSS)
Program Officer
Evans, Frank
Project Start
2009-02-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
3
Fiscal Year
2010
Total Cost
$248,999
Indirect Cost
Name
Saint Louis University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Cheng, Jeffrey K; Stoilov, Ivan; Mecham, Robert P et al. (2013) A fiber-based constitutive model predicts changes in amount and organization of matrix proteins with development and disease in the mouse aorta. Biomech Model Mechanobiol 12:497-510
Huang, Jianbin; Yamashiro, Yoshito; Papke, Christina L et al. (2013) Angiotensin-converting enzyme-induced activation of local angiotensin signaling is required for ascending aortic aneurysms in fibulin-4-deficient mice. Sci Transl Med 5:183ra58, 1-11
Wagenseil, Jessica E; Mecham, Robert P (2012) Elastin in large artery stiffness and hypertension. J Cardiovasc Transl Res 5:264-73
Le, Victoria P; Kovacs, Attila; Wagenseil, Jessica E (2012) Measuring left ventricular pressure in late embryonic and neonatal mice. J Vis Exp :
Sather, Bradley A; Hageman, Daniel; Wagenseil, Jessica E (2012) Murray's Law in elastin haploinsufficient (Eln+/-) and wild-type (WT) mice. J Biomech Eng 134:124504
Cheng, Jeffrey K; Wagenseil, Jessica E (2012) Extracellular matrix and the mechanics of large artery development. Biomech Model Mechanobiol 11:1169-86
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
Le, Victoria P; Wagenseil, Jessica E (2012) Echocardiographic Characterization of Postnatal Development in Mice with Reduced Arterial Elasticity. Cardiovasc Eng Technol 3:424-438
Amin, Mazyar; Le, Victoria P; Wagenseil, Jessica E (2012) Mechanical testing of mouse carotid arteries: from newborn to adult. J Vis Exp :
Le, Victoria P; Knutsen, Russell H; Mecham, Robert P et al. (2011) Decreased aortic diameter and compliance precedes blood pressure increases in postnatal development of elastin-insufficient mice. Am J Physiol Heart Circ Physiol 301:H221-9

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