Summary
Research project investigating the structural and functional roles of integrins α3β1 and αvβ3, and tetraspanin CD151, in maintaining or disrupting the glomerular filtration barrier in the kidney, particularly in disease states.
Structure and Function of Integrins in the Kidney
US · IL
NIH
grant
awarded
#nih-5R01DK088327-12
What they want
The project aims to test the hypothesis that activation of αvβ3 in disease states sequesters CD151 away from binding to α3β1, thus impairing optimal α3β1 function and disrupting the glomerular filtration barrier (GFB). This involves determining the structural basis of active integrin conformation with CD151 using cryo-EM and examining the glomerular response to injury when αvβ3 is inactivated genetically or pharmacologically in rodent models of proteinuric kidney disease.
Deliverables
- Data on the interaction between αvβ3 and CD151, and its impact on α3β1 function and GFB integrity.
- Cryo-EM structure of an integrin in an inactive conformation in complex with a tetraspanin.
- Cryo-EM structure of the active integrin conformation that forms the complex with CD151.
- Data on glomerular response to injury in mice with podocyte-specific deletion of αv.
- Data on glomerular response to injury in rodent models treated with novel αvβ3 inhibitors.
Technical requirements
- Cryo-EM structure determination of integrin-tetraspanin complexes.
- Generation of mice with podocyte specific deletion of αv.
- Development and application of novel αvβ3 inhibitors.
- Use of rodent models of proteinuric kidney disease.
