This proposal describes a five year training program for development of an independent research career in academic medicine. The principle investigator is board certified in Internal Medicine with a PhD degree in Pharmacology. The Pi's long term goal is to become an independent physician-scientist in biomedical research. Heart failure (HF) is a very serious problem of chronic kidney disease (CKD) patients. The Pi's research plan is directed at identifying cellular and molecular mechanisms causing cardiac fibrosis and HF in a murine model of CKD. Mark Entman, MD, an authority on inflammation and cardiac remodeling will mentor the Pi's scientific development while William Mitch, MD, an expert on CKD and its consequences will serve as a co-mentor. Both have outstanding records of training young investigators. To broaden the Pi's training, an Advisory Committee of established investigators has been organized. Furthermore, Baylor and the Department of Medicine have extensive resources providing an ideal training environment for junior physician-scientists. Epidemiologically, CKD patients have marked susceptibility for developing cardiac fibrosis and HF. However, the mechanisms causing cardiac fibrosis are unknown and there is no effective therapy. Our Preliminary Results demonstrate that high angiotensin II (Ang II) level (as found in CKD/HF) leads to accumulation of bone marrow-derived fibroblasts in the heart, which challenge the paradigm that cardiac fibrosis arises from fibroblasts residing in the heart and lead us to hypothesize that bone marrow- derived fibroblast precursor cells migrate into the heart to produce cardiac fibrosis. To test this hypothesis, the following specific aims will be pursued.
Specific Aim 1 is to determine whether uremia stimulates chemokine production followed by accumulation of fibroblast precursors in the heart.
Specific Aim 2 is to examine whether bone marrow-derived fibroblast precursors are recruited into the heart via chemokines (e.g. MCP-1) which are also high in CKD. Since ACEi &ARB's are widely used in CKD patients and since Ang II is high in CKD, Specific Aim 3 is to evaluate whether inhibition of Ang II will block the recruitment of fibroblast precursors into the heart in response to uremia.

Public Health Relevance

The proposed studies could lead to a new paradigm that bone marrow-derived fibroblast precursors contribute to the pathogenesis of cardiac fibrosis. Understanding the triggering events that lead to the recruitement of bone marrow-derived fibroblast precursors into the heart could reveal why CKD is linked to cardiac fibrosis and heart failure and may lead to novel therapy for the treatment of heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL092958-05
Application #
8496574
Study Section
Special Emphasis Panel (ZHL1-CSR-O (F1))
Program Officer
Carlson, Drew E
Project Start
2009-08-04
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$131,084
Indirect Cost
$9,710
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Xia, Yunfeng; Yan, Jingyin; Jin, Xiaogao et al. (2014) The chemokine receptor CXCR6 contributes to recruitment of bone marrow-derived fibroblast precursors in renal fibrosis. Kidney Int 86:327-37
Chen, Jiyuan; Xia, Yunfeng; Lin, Xia et al. (2014) Smad3 signaling activates bone marrow-derived fibroblasts in renal fibrosis. Lab Invest 94:545-56
Xia, Yunfeng; Jin, Xiaogao; Yan, Jingyin et al. (2014) CXCR6 plays a critical role in angiotensin II-induced renal injury and fibrosis. Arterioscler Thromb Vasc Biol 34:1422-8
Xia, Yunfeng; Entman, Mark L; Wang, Yanlin (2013) CCR2 regulates the uptake of bone marrow-derived fibroblasts in renal fibrosis. PLoS One 8:e77493
Jin, Xiaogao; Chen, Jiyuan; Hu, Zhaoyong et al. (2013) Genetic deficiency of adiponectin protects against acute kidney injury. Kidney Int 83:604-14
Xia, Yunfeng; Entman, Mark L; Wang, Yanlin (2013) Critical role of CXCL16 in hypertensive kidney injury and fibrosis. Hypertension 62:1129-37
Yang, Jun; Lin, Song-Chang; Chen, Gang et al. (2013) Adiponectin promotes monocyte-to-fibroblast transition in renal fibrosis. J Am Soc Nephrol 24:1644-59
Chen, Gang; Lin, Song-Chang; Chen, Jiyuan et al. (2011) CXCL16 recruits bone marrow-derived fibroblast precursors in renal fibrosis. J Am Soc Nephrol 22:1876-86
Xu, Jing; Lin, Song-Chang; Chen, Jiyuan et al. (2011) CCR2 mediates the uptake of bone marrow-derived fibroblast precursors in angiotensin II-induced cardiac fibrosis. Am J Physiol Heart Circ Physiol 301:H538-47