Role of Bone Marrow-Derived Fibroblast Precursors in Cardiac Fibrosis

描述（由申请人提供）：该提案描述了一个为期五年的培训计划，以发展学术医学的独立研究事业。主要研究者是董事会认证的内科与药理学博士学位。Pi的长期目标是成为生物医学研究领域的独立内科科学家。心衰（HF）是慢性肾脏疾病（CKD）患者非常严重的问题。PI的研究计划旨在确定CKD小鼠模型中引起心脏纤维化和HF的细胞和分子机制。炎症和心脏重塑方面的权威医学博士Mark Entman将指导Pi的科学发展，而CKD及其后果方面的专家医学博士William Mitch将担任联合导师。这两家公司在培养年轻调查人员方面都有出色的记录。为了扩大PI的培训，已组织了一个由既定调查员组成的咨询委员会。此外，贝勒和医学系拥有丰富的资源，为初级医师和科学家提供了理想的培训环境。在流行病学上，CKD患者对发生心脏纤维化和心衰有明显的易感性。然而，引起心脏纤维化的机制尚不清楚，也没有有效的治疗方法。我们的初步结果表明，高水平的血管紧张素II (Ang II)（如在CKD/HF中发现的）导致心脏中骨髓源性成纤维细胞的积累，这挑战了心脏纤维化由居住在心脏中的成纤维细胞引起的模式，并使我们假设骨髓源性成纤维细胞前体细胞迁移到心脏中产生心脏纤维化。为了验证这一假设，将追求以下具体目标。特异性目的1是确定尿毒症是否刺激趋化因子的产生，随后在心脏中积累成纤维细胞前体。特异性目的2是检查骨髓来源的成纤维细胞前体是否通过趋化因子（如MCP-1）被募集到心脏，这在CKD中也很高。由于ACEi和ARB在CKD患者中被广泛使用，并且由于Ang II在CKD中含量高，特异性Aim 3是评估抑制Ang II是否会在尿毒症时阻断成纤维细胞前体进入心脏的募集。相关性（见说明）：提出的研究可能导致一个新的范式，即骨髓来源的成纤维细胞前体有助于心脏纤维化的发病机制。了解导致骨髓源性成纤维细胞前体进入心脏的触发事件可以揭示CKD与心脏纤维化和心力衰竭相关的原因，并可能导致心力衰竭治疗的新疗法。

DESCRIPTION (provided by applicant): 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. RELEVANCE (See instructions): 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.