Role of Bone Marrow-Derived Fibroblast Precursors in Cardiac Fibrosis

该提案描述了一个为期五年的培训计划，以发展独立的研究事业， 学术医学主要研究者获得内科学委员会认证，并获得以下方面的博士学位： 药理学。Pi的长期目标是成为生物医学领域的独立医生科学家。 research.心力衰竭（HF）是慢性肾脏病（CKD）患者的一个非常严重的问题。Pi的 一项研究计划旨在确定导致心脏纤维化和HF的细胞和分子机制， CKD的鼠模型。Mark Entman，医学博士，炎症和心脏重塑的权威将指导 而威廉米奇，医学博士，CKD及其后果的专家将服务于 作为共同导师两人都有培训年轻调查员的出色记录。为了扩大派的训练范围， 已组织了一个常设调查员咨询委员会。此外，贝勒和 医学系拥有丰富的资源，为年轻人提供理想的培训环境。 物理科学家在流行病学上，CKD患者具有发生心脏病的显著易感性， 纤维化和HF。然而，引起心脏纤维化的机制尚不清楚， 疗法我们的初步结果表明，高血管紧张素II（Ang II）水平（如CKD/HF） 导致骨髓来源的成纤维细胞在心脏中积聚，这挑战了 心脏纤维化是由心脏中的成纤维细胞引起的，并使我们假设骨髓- 衍生的成纤维细胞前体细胞迁移到心脏中以产生心脏纤维化。为了验证这个假设， 将努力实现以下具体目标。具体目标1是确定尿毒症是否刺激 趋化因子的产生，随后是心脏中成纤维细胞前体的积累。具体目标二是 检查骨髓来源的成纤维细胞前体是否通过趋化因子（例如， MCP-1），其在CKD中也是高的。由于ACEi和ARB广泛用于CKD患者，并且由于Ang II 在CKD患者中，血管紧张素II的水平较高，具体目的3是评估是否抑制血管紧张素II将阻断成纤维细胞的募集 前体进入心脏以应对尿毒症。 相关性（参见说明）： 这项研究可能会导致一种新的范式，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 骨髓来源的成纤维细胞前体进入心脏的募集可能揭示为什么CKD与 心脏纤维化和心力衰竭，并可能导致治疗心力衰竭的新疗法。

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.