This project targets the challenge of connecting genetics theory with multi-scale physiological models, to address and understand physiological genomics in a population context. Many challenges in personalized medicine reflect a lack of understanding of the genotype-to-phenotype (GP) map (see Figure 1.1), i.e. the aggregated phenotypic effects across different length and time scales of different constellations of genetic variation (genotypes). Our approach is motivated by the fact that understanding the GP map for a complex trait is likely to require mechanistic model descriptions of the phenotypic effects of genetic variation, i.e. advanced multiseale physiological models with an explicit link to genetic information. We use the term causally cohesive genotype-phenotype models for models describing how genetic variation manifests in phenotypic variation at various systemic levels up to the tissue, organ and whole-organism level [19]. Causally cohesive genotype phenotype models are in silico representations that emerge from a composite mapping, first from genotypes to model parameters, and second from models to phenotypes, which may in turn be parameters in overlying model structures. (See Figure 1.1.) This approach makes it possible to address a whole range of complex phenomena, like genetic dominance, epistasis, penetrance, plelotropy, cryptic variation and genotype/environment interactions in ways that are beyond reach of classical statistical approaches [16-22]. In combination with the very advanced models to be developed in this project, this approach will provide novel and important information about the relationships between genetic variation and complex diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM094503-05
Application #
8727597
Study Section
Special Emphasis Panel (ZGM1-CBCB-2)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
$89,763
Indirect Cost
$14,083
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Lee, Pilhwa; Carlson, Brian E; Chesler, Naomi et al. (2016) Heterogeneous mechanics of the mouse pulmonary arterial network. Biomech Model Mechanobiol 15:1245-61
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Lee, Pilhwa; Wolgemuth, Charles W (2016) Physical Mechanisms of Cancer in the Transition to Metastasis. Biophys J 111:256-66
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Lee, Pilhwa; Wolgemuth, Charles W (2016) An immersed boundary method for two-phase fluids and gels and the swimming of Caenorhabditis elegans through viscoelastic fluids. Phys Fluids (1994) 28:011901
Zhang, Yanhang; Barocas, Victor H; Berceli, Scott A et al. (2016) Multi-scale Modeling of the Cardiovascular System: Disease Development, Progression, and Clinical Intervention. Ann Biomed Eng 44:2642-60

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