Chronic kidney disease (CKD) affects over 26 million Americans. Agents that can directly halt the progression of CKD at the cellular and molecular level are much needed but lacking. The common pathway of CKD is renal fibrosis. Fibroblasts are key effectors of fibrosis by mediating aberrant remodeling of extracellular matrix (ECM). The epithelium-restricted v integrin, v 6 directly activates latent TGF which in turn regulates fibroblast activity. Until recently much less was known about renal fibroblast v integrins. Our laboratory deleted all v integrins from activated myofibroblasts and found that these mice were dramatically protected from renal fibrosis following unilateral ureteral obstruction (UUO), an established model of tubulointerstitial fibrosis. Integrins are a family of transmemebrane cell-matrix receptors consisting of a and a subunit. In contrast to v 6 whose expression is restricted to the epithelium, the other four v integrins, v 1, v 3, v 5 and v 8 can be expressed in fibroblasts. All can bind and/or activate TGF , a central fibrogenic factor, in vitro.Moreover, v integrins have been shown to work synergistically with growth factor receptors to initiate common downstream signaling pathways to regulate cell growth. The goal of this research is to determine which v integrins are expressed on pathologic renal myofibroblasts and how one or more of these integrins modulates the behavior of myofibroblasts to cause renal fibrosis. We will examine 3 interrelated candidate mechanisms - direct activation of latent TGF , enhancement of fibroblast proliferation and/or enhancement of differentiation into pathologic myofibroblasts. We will determine whether any of these effects of integrin signaling are regulated by its association with growth factor receptors. We also seek to identify which specific v integrin(s) contributes to the renal protective effects we saw in conditional v null mice. Global genetic deletion of 3 and 5 or fibroblast specific 8 deletion did not protect mice from liver fibrosis, suggesting that in that model either multiple fibroblast v integrins contribute orfibrosis depends on v 1. Until now it was not possible to study the in vivo role of v 1 since mice lacking 1 on myofibroblasts do not survive. To address this problem we have recently developed a highly potent and specific small molecule inhibitor of v 1. We will take advantage of this novel compound as well as lines of mice that have already been generated in the laboratory to determine the identity of the critical v integrins that contribute to renal fibrosisin vivo. In summary, through this study, we will identify specific fibroblast v integrins and their signaling pathways essential for renal fibroblast activation. The experience and track record I gain from these studies, together with planned coursework and participation in external training programs should provide me with the skill set required to launch a successful academic career as a nephrology physician-scientist.

Public Health Relevance

Chronic kidney disease (CKD) and eventual organ failure is a major health care concern in the U.S. underscoring the urgent need for therapies to directly halt disease progression before organ failure. This research proposal stems from our recent exciting findings that blocking proteins called v integrins in mice protected them from kidney failure. Here; we propose to characterize the underlying mechanisms and test compounds we generated that specifically block these integrins to see if they protect mice from kidney failure. f so; these compounds may give rise to novel treatments for CKD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32DK100084-01
Application #
8594625
Study Section
Special Emphasis Panel (ZDK1-GRB-G (M1))
Program Officer
Rankin, Tracy L
Project Start
2014-01-01
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
Fiscal Year
2014
Total Cost
$66,530
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143