Integrins are proteins important for integrating signals from cell to cell and for interpreting cues from their microenvironment that greatly influencing cell behavior. Integrins are broadly expressed in hematopoietic and non-hematopoietic cells alike and they have proven to be important players in the cells migratory behavior throughout development and in adulthood. In addition, integrins, because of their ability to serve as bidirectional signaling machines and because of their "cross talk" with other integrins, or growth factor receptors and signaling mediators, can induce changes in gene expression and other cellular responses. The role of integrins in early primitive normal hematopoietic cells is well established and accumulating evidence suggests that they also have important roles in neoplastic cells. However, their role in Erythropoiesis has been largely descriptive, and most importantly inconsistent in data presentation, using either antibodies (Abs) or genetic models. In our recent work we have attempted to clarify some of the previous ambiguities regarding the loss of ?1 integrin partners in Hematopoiesis/Erythropoiesis by comparing relevant genetic murine models. Although novel and important information was gained, the data generated fresh questions. In this grant, capitalizing on our experience with the prior integrin genetic models, we hope to provide definitive data about the distinct roles of a and a4 integrins in terminal E-differentiation at homeostasis and in response to stress using innovative genetic model combinations (SA 1). Furthermore, there is only fragmentary information about the integrin-dependent molecular mediators and a lot of molecular links are missing. How the information from other important players in Erythropoiesis is intercepted through integrins on erythroid cells for addressing stress responses is unclear and will be addressed in SA2. Finally, incorporation of state of the art genomic tools in our studies with our new genetic models (SA 3) should shed further light on the complex and combinatorial interplay of certain integrins controlling terminal steps in Erythropoiesis, especially under stress. Experiments described in this Grant not only would establish the ?1 integrins as a novel and unexplored player in oxidative stress response and anti-oxidant homeostasis of erythroid cells, but will provide an enhanced view on the contribution of single or combinatorial action of integrins in Erythropoiesis. Furthermore, long term studies in our animal models should provide essential biological knowledge needed when integrins are used as targets in cancer therapeutics.

Public Health Relevance

In Hematopoiesis integrins are important for migration of cells to inflammatory sites to fight infection and for the retention, survival and development of immature cells in BM. What we are studying in this Grant is the role of ?1 integrins in Erythropoiesis;a largely unexplored issue. As now integrins have been targeted for inhibition in cancer patients, their effects on normal cells on long term basis is necessary and it is the main goal of our Grant application.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK094702-03
Application #
8536283
Study Section
Special Emphasis Panel (ZRG1-VH-F (02))
Program Officer
Bishop, Terry Rogers
Project Start
2011-09-30
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$324,277
Indirect Cost
$114,389
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195