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.
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.
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|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|