The affinity of integrins for extracellular ligands is tightly regulated in platelets. Upon disruption of vascular integrity, platelet integrins undergo conformational changes that result in increased affinity for ligand, termed integrin activation, thereby supporting platelet adhesion, aggregation, and thrombus formation necessary for hemostasis. Failure to properly regulate integrin activity in platelets can promote thrombotic disease. This project focuses on the regulation of talin-integrin interactions with the rationale that selectively modulating their interactions could provide a novel anti-thrombotic therapeutic strategy. This concept will be tested in Aim 1 by analyzing mice expressing talin1 mutants that selectively disrupt the capacity of talin to activate integrins without affecting the binding of tain to integrins or other known talin-binding proteins in vivo.
Aim 2 will investigate the cellular and molecular mechanisms, focused primarily on bidirectional integrin signaling, that underlie the phenotypes characterized in Aim 1.
In Aim 3, the cellular distribution of talin and kindlin will be examined in platelets by fluorescence microscopy and signaling pathways that regulate talin and kindlin redistribution to the plasma membrane will be dissected. Together, these studies will provide new information about the biological significance of integrin-talin interactions in hemostasis and thrombosis and provide insights into the signaling pathways that regulate the platelet agonist-induced dynamic redistribution of proteins that control integrin activation. Together our proposed experiments, consistent with the mission of the NHLBI, may point to novel therapies for the prevention and treatment of heart attack and stroke.

Public Health Relevance

Platelet aggregation is critical for hemostasis but can also lead to arterial thrombosis, a cause of heart attack and stroke. The studies proposed here will test how specific proteins function to regulate platelet aggregation. Insights gained into the regulation of platelet aggregation may provide new therapeutic targets for the prevention and treatment of arterial thrombosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL117061-02
Application #
8669821
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Kindzelski, Andrei L
Project Start
2013-06-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$341,775
Indirect Cost
$121,275
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093