Targeting fibrocytes in Duchenne muscular dystrophy

杜氏肌营养不良症中的靶向纤维细胞

• 批准号: 8423117
• 负责人: Lan Zhou
• 金额: $ 20.71万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8423117
• 关键词: Targeting; fibrocytes; Duchenne; muscular; dystrophy

DESCRIPTION (provided by applicant): Muscle fibrosis is a prominent pathological feature of chronic muscle diseases, including muscular dystrophies. It directly leads to muscle dysfunction and clinical muscle weakness. Duchenne muscular dystrophy (DMD) is the most common and lethal muscle disease with no cure at this point. Previous studies by our lab and others have demonstrated that ameliorating muscle fibrosis represents a viable therapeutic approach to improve muscular dystrophy phenotype in mdx mice, a mouse model for DMD. Fibrosis is caused by excessive deposition of extracellular matrix (ECM) proteins, which are primarily produced by tissue effector fibroblasts. Extensive research in fibrotic disease models of non-muscle tissues has shown that the circulation-derived fibrocyte is an important cellular mediator of tissue fibrogenesis by producing ECM proteins and profibrotic cytokines as well as differentiating into tissue effector fibroblasts. The chemokine system is essential to the recruitment and fibrogenic functions of fibrocytes. Our preliminary study showed that fibrocytes were also present in mdx diaphragm, the only muscle in mdx mice that undergoes progressive fibrosis. We further showed that mdx diaphragm fibrocytes expressed chemokine receptors CCR1, CCR2, CCR5, and CXCR4. This study is to address our central hypothesis that fibrocytes play a pathogenic role in skeletal muscle fibrogenesis associated with DMD, the chemokines and chemokine receptors are involved in skeletal muscle recruitment and fibrogenic functions of fibrocytes, and blocking relevant chemokine receptors and their ligands can inhibit fibrocyte recruitment and fibrogenic functions and ameliorate fibrosis in dystrophic muscles. We will address our hypothesis through three Specific Aims. Specific Aim 1 will characterize muscle recruitment and effector properties of mdx diaphragm fibrocytes. Specific Aim 2 will characterize the chemokine receptors and ligands involved in mdx diaphragm fibrocyte recruitment and fibrogenic functions. Specific Aim 3 will test therapeutic interventions to inhibit chemokine receptors and ligands identified in Aim 2 to establish novel therapeutic targets for DMD. Our long-term goal is to utilize the knowledge gained from these studies to develop novel antifibrotic therapies for DMD. PUBLIC HEALTH RELEVANCE: Duchenne muscular dystrophy (DMD) is the most common and lethal muscle disease with no cure at this point. Scar formation is evident and progressive in muscles of DMD patients which causes muscle dysfunction and weakness. Fibrocytes are cells that have been shown to contribute to scar formation in the disease mouse models of lung, kidney, and liver. We have found that fibrocytes were also present in the muscle which undergoes progressive scar formation in mdx mice, a mouse model for DMD. We thus propose this study to characterize the functions of muscle fibrocytes and their contribution to muscle scar formation in mdx mice. We will also determine which regulatory proteins, chemokines and chemokine receptors, regulate muscle fibrocyte functions, and test whether inhibit these proteins can suppress fibrocyte functions and reduce muscle scar formation. Our long-term goal is to utilize the knowledge gained from these studies to develop novel therapies to ameliorate scar formation and improve muscle functions for patients with DMD.

描述（由申请人提供）：肌肉纤维化是慢性肌肉疾病的重要病理特征，包括肌肉营养不良。它直接导致肌肉功能障碍和临床肌肉无力。 Duchenne肌肉营养不良（DMD）是最常见，最致命的肌肉疾病，目前尚无治愈。我们的实验室和其他人的先前研究表明，改善肌肉纤维化是一种可行的治疗方法，可改善MDX小鼠的肌肉营养不良表型，这是DMD的小鼠模型。纤维化是由细胞外基质（ECM）蛋白的过度沉积引起的，这些蛋白主要由组织效应子成纤维细胞产生。在非肌肉组织的纤维化疾病模型中进行了广泛的研究表明，循环衍生的纤维细胞是通过产生ECM蛋白和纤维化细胞因子并区分组织效应的成纤维细胞的重要细胞纤维发生的重要细胞介体。趋化因子系统对于纤维细胞的募集和纤维化功能至关重要。我们的初步研究表明，MDX隔膜也存在纤维细胞，MDX隔膜是MDX小鼠中唯一经历进行性纤维化的肌肉。我们进一步表明，MDX diaphragm纤维细胞表达趋化因子受体CCR1，CCR2，CCR5和CXCR4。这项研究是为了解决我们的中心假设，即纤维细胞在与DMD相关的骨骼肌纤维发生中起致病作用，趋化因子和趋化因子受体与骨骼肌募集有关，以及纤维细胞的纤维源性功能，以及与相关的趋化因子及其纤维纤维纤维纤维纤维的阻断，并具有障碍物的纤维细胞。在营养不良的肌肉中。我们将通过三个具体目标解决我们的假设。特定的目标1将表征MDX diaphragm纤维细胞的肌肉募集和效应特性。特定的目标2将表征参与MDX diaphragm纤维细胞募集和纤维化功能的趋化因子受体和配体。特定的目标3将测试治疗干预措施，以抑制AIM 2中鉴定的趋化因子受体和配体，以建立DMD的新型治疗靶标。我们的长期目标是利用从这些研究中获得的知识来开发DMD的新型抗纤维化疗法。 公共卫生相关性：Duchenne肌肉营养不良（DMD）是最常见，最致命的肌肉疾病，目前尚无治愈。在DMD患者的肌肉中，疤痕形成是显而易见的，会导致肌肉功能障碍和无力。纤维细胞是已证明在肺，肾脏和肝脏的疾病小鼠模型中造成疤痕形成的细胞。我们发现，肌肉也存在纤维细胞，该肌肉在MDX小鼠（DMD的小鼠模型）中经历了逐渐疤痕的形成。因此，我们建议这项研究表征肌肉纤维细胞的功能及其对MDX小鼠肌肉疤痕形成的贡献。我们还将确定哪些调节蛋白，趋化因子和趋化因子受体，调节肌肉纤维细胞功能，并测试抑制这些蛋白是否可以抑制纤维细胞功能并减少肌肉疤痕的形成。我们的长期目标是利用从这些研究中获得的知识来开发新的疗法来改善疤痕形成并改善DMD患者的肌肉功能。