Valve related congenital heart defects (CHD) are a major cause of preterm and infant death. Despite considerable research progress uncovering important genetic regulators of cardiac morphogenesis, translation to clinical benefit has been hampered by a lack of understanding of how these pathways coordinate to drive valve formation and remodeling. The embryonic valves are exposed to an increasingly demanding mechanical environment as they grow and mature, but the functional consequences of these forces are far less understood. Valvulogenesis can alternatively be considered an engineering process rather than a purely genetic program. Uncovering these new governing relationships is therefore essential but has been challenging because of the lack of analytical tools and experimental approaches that can isolate and quantify mechanical effects in live embryonic valves. First, we have developed unique biomechanical testing devices that can quantify embryonic cushion and valve biomechanics. Second, we have created a novel speckle tracking algorithm in conjunction with high frequency ultrasound that can non-invasively quantify dynamic tissue strains within the embryonic valves. Third, we developed a unique finite element simulation strategy that iterates with in vivo measurements to map local biomechanical parameters in anatomically precise geometries. Fourth, we have created the first experimental strategy to create locally isolated intracardiac defects in live avian embryos non-invasively through femtosecond laser photoablation (FLP). Using these enabling technologies, our objective for this proposal is to identify and characterize mechano-genetic relationships that guide the formation of the embryonic valves. Our overall hypothesis is that mechanical signaling orchestrates the sculpting and strengthening of the embryonic valves through simultaneous regulation of multiple valvulogenic signaling pathways. We will first quantify the changing in vivo mechanical environments surrounding the valves and their biomechanical adaptation (Aim 1). We will next determine how the network of known molecular regulators of valvulogenesis is modulated by mechanical stimulation in vitro (Aim 2). Then we test the mechano-genetic mechanisms suggested by the previous experiments in vivo using locally controlled photoablations to avian embryonic valves (Aim 3). This proposal will generate significant quantitative detail of the in vivo biomechanical environment during embryonic valvulogenesis and how this regulates local gene expression to promote valve formation and maturation. This novel information will complement existing datasets from genetic manipulation studies and guide new interpretations of these results. A better understanding of the mechanobiological relationships guiding valve formation and remodeling significantly broadens the array of mechanisms to explain the pathogenesis of CHD and tools to enable new clinical strategies to prevent or repair CHD.

Public Health Relevance

This proposal will implement new technologies to quantify the biomechanical environment surrounding developing embryonic heart valves. We will then determine how specific mechanical forces simultaneously regulate multiple genes to control heart valve formation and remodeling. By confirming these relationships in vivo, we will uncover a natural heart valve engineering paradigm that can inform new regenerative strategies for heart valve disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL110328-03
Application #
8500438
Study Section
Special Emphasis Panel (ZRG1-CB-P (55))
Program Officer
Evans, Frank
Project Start
2011-08-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$368,863
Indirect Cost
$130,863
Name
Cornell University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Gould, Russell A; Yalcin, Huseyin C; MacKay, Joanna L et al. (2016) Cyclic Mechanical Loading Is Essential for Rac1-Mediated Elongation and Remodeling of the Embryonic Mitral Valve. Curr Biol 26:27-37
Farrar, Emily J; Pramil, Varsha; Richards, Jennifer M et al. (2016) Valve interstitial cell tensional homeostasis directs calcification and extracellular matrix remodeling processes via RhoA signaling. Biomaterials 105:25-37
Kang, Laura Hockaday; Armstrong, Patrick A; Lee, Lauren Julia et al. (2016) Optimizing Photo-Encapsulation Viability of Heart Valve Cell Types in 3D Printable Composite Hydrogels. Ann Biomed Eng :
Gregg, Chelsea L; Butcher, Jonathan T (2016) Comparative analysis of metallic nanoparticles as exogenous soft tissue contrast for live in vivo micro-computed tomography imaging of avian embryonic morphogenesis. Dev Dyn 245:1001-10
Sung, Derek C; Bowen, Caitlin J; Vaidya, Kiran A et al. (2016) Cadherin-11 Overexpression Induces Extracellular Matrix Remodeling and Calcification in Mature Aortic Valves. Arterioscler Thromb Vasc Biol 36:1627-37
Duan, Bin; Hockaday, Laura A; Das, Shoshana et al. (2015) Comparison of Mesenchymal Stem Cell Source Differentiation Toward Human Pediatric Aortic Valve Interstitial Cells within 3D Engineered Matrices. Tissue Eng Part C Methods 21:795-807
Bowen, Caitlin J; Zhou, Jingjing; Sung, Derek C et al. (2015) Cadherin-11 coordinates cellular migration and extracellular matrix remodeling during aortic valve maturation. Dev Biol 407:145-57
Gregg, Chelsea L; Recknagel, Andrew K; Butcher, Jonathan T (2015) Micro/nano-computed tomography technology for quantitative dynamic, multi-scale imaging of morphogenesis. Methods Mol Biol 1189:47-61
Cheung, Daniel Y; Duan, Bin; Butcher, Jonathan T (2015) Current progress in tissue engineering of heart valves: multiscale problems, multiscale solutions. Expert Opin Biol Ther 15:1155-72
Farrar, Emily J; Huntley, Geoffrey D; Butcher, Jonathan (2015) Endothelial-derived oxidative stress drives myofibroblastic activation and calcification of the aortic valve. PLoS One 10:e0123257

Showing the most recent 10 out of 43 publications