Role of Bone Marrow-Derived Fibroblast Precursors in Cardiac Fibrosis

骨髓来源的成纤维细胞前体在心脏纤维化中的作用

• 批准号: 7660604
• 负责人: YANLIN WANG
• 金额: $ 13.11万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-04 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660604
• 关键词: Advisory Committees; Angiotensin II; Biomedical Research; Bone Marrow; CCL2 gene; Cardiac; Chronic; Chronic Kidney Failure; Development; Doctor of Philosophy; Environment; Event; Extracellular Matrix; Fibroblasts; Fibrosis; Figs - dietary; Functional disorder; Goals; Heart; Heart failure; Inflammation; Infusion procedures; Instruction; Internal Medicine; Junior Physician; Lead; Link; Medicine; Mentors; Modeling; Molecular; Mus; Pathogenesis; Pathologic; Patients; Pharmacology; Physicians; Predisposition; Production; Program Development; Public Health; Records; Recruitment Activity; Reporting; Research; Research Personnel; Resources; Risk Factors; Role; Scientist; Source; Stem cells; Testing; Tissues; Training; Training Programs; United States; Uremia; authority; career; chemokine; effective therapy; interstitial; novel; precursor cell; programs; response; uptake

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.

描述（由申请人提供）：本提案描述了一个为期五年的培训计划，用于发展学术医学的独立研究事业。主要研究者是内科委员会认证，拥有药理学博士学位。Pi的长期目标是成为生物医学研究领域的独立医生科学家。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的研究计划旨在确定CKD小鼠模型中导致心脏纤维化和HF的细胞和分子机制。炎症和心脏重塑方面的权威Mark Entman医学博士将指导Pi的科学发展，而CKD及其后果方面的专家William Mitch医学博士将担任共同导师。两人都有培训年轻调查员的出色记录。为了扩大对PI的培训，成立了一个由资深调查员组成的咨询委员会。此外，贝勒大学和医学系拥有丰富的资源，为初级医生科学家提供了理想的培训环境。在流行病学上，CKD患者具有发展为心脏纤维化和HF的显著易感性。然而，导致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，高血管紧张素II（Ang II）水平（如在CKD/HF中发现的）导致骨髓来源的成纤维细胞在心脏中的积累，这挑战了心脏纤维化由驻留在心脏中的成纤维细胞引起的范例，并使我们假设骨髓来源的成纤维细胞前体细胞迁移到心脏中以产生心脏纤维化。为了检验这一假设，将追求以下具体目标。具体目标1是确定尿毒症是否刺激趋化因子的产生，然后在心脏中积累成纤维细胞前体。具体目标2是检查骨髓来源的成纤维细胞前体是否通过在CKD中也很高的趋化因子（例如MCP-1）募集到心脏中。由于ACEi和ARB广泛用于CKD患者，并且由于Ang II在CKD中较高，因此具体目标3是评估Ang II的抑制是否会阻断成纤维细胞前体响应于尿毒症而募集到心脏中。相关性（参见说明）：这些研究可能会导致一个新的范式，即骨髓来源的成纤维细胞前体细胞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细胞进入心脏的触发事件可以揭示为什么CKD与心脏纤维化和心力衰竭有关，并可能导致治疗心力衰竭的新疗法。