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）：该提案描述了一项为期五年的培训计划，以开发独立的学术医学研究职业。该主要研究人员获得了内科董事会认证，并获得了药理学博士学位。 PI的长期目标是成为生物医学研究的独立医师科学家。心力衰竭（HF）是慢性肾脏疾病（CKD）患者的一个非常严重的问题。 PI的研究计划旨在鉴定在CKD的鼠模型中引起心脏纤维化和HF的细胞和分子机制。医学博士马克·恩特曼（Mark Entman），关于炎症和心脏重塑的权威，将指导PI的科学发展，而CKD专家William Mitch及其后果将担任同事。两者都有培训年轻调查人员的出色记录。为了扩大PI的培训，已经组织了一个成熟的研究人员的咨询委员会。此外，贝勒和医学系拥有丰富的资源，为初级医师科学家提供理想的培训环境。从流行病学上讲，CKD患者对发展心脏纤维化和HF的敏感性明显。但是，引起心脏纤维化的机制尚不清楚，没有有效的治疗。我们的初步结果表明，高血管紧张素II（ANG II）水平（在CKD/HF中发现）导致心脏中骨髓衍生的成纤维细胞的积累，这挑战了心脏纤维化的范式，该范式由心脏中的成纤维细胞产生并导致骨骼的骨骼造型，使骨骼的骨髓延伸到骨骼中。纤维化。为了检验这一假设，将追求以下具体目标。具体目的1是确定尿毒症是否刺激趋化因子产生，然后刺激成纤维细胞前体在心脏中积累。具体目的2是检查骨髓衍生的成纤维细胞前体是否通过趋化因子（例如MCP-1）募集到心脏中，而CKD也很高。由于ACEI和ARB的CKD患者广泛使用，并且ANG II在CKD中很高，因此特定的目标3是评估ANG II的抑制是否会阻止成纤维细胞前体募集到心脏中，以响应尿emia。相关性（请参阅说明）：拟议的研究可能导致新的范式，即骨髓衍生的成纤维细胞前体有助于心脏纤维化的发病机理。了解导致骨髓衍生的成纤维细胞前体募集到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，并可能导致新的治疗心脏衰竭治疗。