This collaboration between experiment and theory will provide a physics-based understanding on how cells withstand mechanical stress and maintain homeostasis. The main hypothesis is that adherent cells resist mechanical failure in two ways: by switching the conformations of their adhesive proteins and by clustering them together at sites of cell-cell contact. The PI will test this hypothesis on multiple length scales, ranging from single molecules to live cells, by using an integrated approach that uniquely and innovatively combines predictive computer simulations and quantitative single molecule experiments. This research will be integrated with an education plan to attract undergraduate students, particularly under-represented minorities from local community colleges, into physics by motivating them with hands-on research experiences, by offering one-on-one mentorship, and by developing new inquiry-based courses that integrate research into teaching. The goals of the educational plan are to (i) Provide hands-on research experience to underrepresented minority students from local community colleges by partnering with the Iowa Illinois Nebraska STEM Partnership for Innovation in Research and Education (IINSPIRE) (ii) Collaborate with the Iowa State University Freshman Honors Program (FHP) to provide research experiences for undergraduates early in their academic careers. (iii) Collaborate with colleges serving underrepresented minorities to improve their science curricula (iv) Increase knowledge of biological physics by developing new courses that integrate research and teaching. A critical barrier to the success of underrepresented minorities majoring in physics is the lack of direct exposure to research and the absence of personalized mentoring. The partnership with IINSPIRE and with colleges serving underrepresented minorities will eliminate these barriers. With FHP, the PI will identify undergraduate talent early and nurture their scientific potential and guide them into research-strong careers. New courses are being developed by the investigators that will directly encourage and foster student interest in biological physics research.

Cadherins are prototypical adhesion proteins that mediate the integrity of all soft tissue. Their principal role is to bind cells together to survive mechanical perturbations. However, the mechanisms by which cadherins resist mechanical stress, are not understood. Based upon extensive preliminary experimental and simulation data, the PI hypothesizes that mechanical force triggers a feedback loop to establish adhesive equilibrium. Two key mechanisms are involved in this feedback: (i) force-induced switching between alternate cadherin conformations and (ii) force-induced clustering of cadherin at cell-cell contacts. To test this hypothesis, the PI will measure how force induces shuttling of cadherins between alternate conformations, both in vitro and on live cells, using single molecule force measurements. The PI will also measure force-induced cadherin clustering, on the millisecond timescale, using single molecule force microscope-fluorescence microscope, an innovation that this group recently developed. Specific molecular interpretations of experiments will be provided by a variety of multi-scale molecular simulations that will be carried out in parallel with the experiments. The project is organized around two specific aims: Aim 1: How does cadherin conformational shuttling establish mechanical feedback? Aim 2: How does mechanical force promote cadherin clustering? This project will provide a deep, physics-based understanding of the force-induced response of cadherin within the context of fully functional cell-cell adhesion junctions and provide molecular mechanisms for these processes. The approaches developed in this project will have transformative applications in numerous areas of mechano-biology, including studies of stem cell differentiation and tissue remodeling.

This project is being jointly supported by the Physics of Living Systems program in the Division of Physics and the Cellular Cluster in the Division of Molecular and Cellular Biosciences.

Agency
National Science Foundation (NSF)
Institute
Division of Physics (PHY)
Application #
1607550
Program Officer
Krastan Blagoev
Project Start
Project End
Budget Start
2016-09-01
Budget End
2020-08-31
Support Year
Fiscal Year
2016
Total Cost
$480,000
Indirect Cost
Name
Iowa State University
Department
Type
DUNS #
City
Ames
State
IA
Country
United States
Zip Code
50011