The proposed research pioneers the study of the dynamic interrelationship between in vivo heterogeneous individual cell behavior and systems-level tissue properties. The project employs multiplex in vivo single cell imaging and computational analyses of tailbud cell motion to elucidate the mechanical basis of both normal vertebrate body elongation and structural musculoskeletal defects such as scoliosis. A central hypothesis of this proposal is that key systems properties of developing tissues, such as the correlation length of cell motion and cell packing, are under genetic regulation to enable robust control of symmetry maintenance and symmetry breaking. To uncover the general design principles of such regulation, the team will combine zebrafish genetics and live imaging with single cell resolution with analytical and computational tools from fluid mechanics and soft matter physics. Using this interdisciplinary approach, the team will create a 4D computational model (3D with time evolution) of the extending zebrafish tailbud incorporating cell-cell interactions, cell motion, cell packing and dynamic tissue boundaries. By comparing and contrasting the wild-type cell flow and contorted phenotypes, the team will produce a better understanding of the physical parameters that must be genetically regulated for linear body elongation. In other words, the experimental and computational systems analysis of cell motion will integrate genetics and multi-scale mechanics (i.e. molecular, cell and tissue level) into a unified ontogeny of abnormal curvatures of the spina column.

Public Health Relevance

This proposal combines multiplex in vivo measurements of single cell behavior and 4D computational modeling of the extending vertebrate body axis to explore the mapping between, distributions of single cell behavior, systems tissue properties and molecular parameters underlying abnormal spinal column curvature.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
1R33GM114257-01
Application #
8831966
Study Section
Special Emphasis Panel (ZRG1-BST-A (50))
Program Officer
Gindhart, Joseph G
Project Start
2014-09-30
Project End
2017-08-31
Budget Start
2014-09-30
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$416,248
Indirect Cost
$166,249
Name
Yale University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06510