Role of Skeletal Muscle Lymphatics in Duchenne Muscular Dystrophy Regulation

骨骼肌淋巴管在杜氏肌营养不良症调节中的作用

• 批准号: 10345958
• 负责人: MARIAPPAN MUTHUCHAMY
• 金额: $ 52万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-24 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10345958
• 关键词: Affect; Animal Housing; Animal Model; Animal Muscular Dystrophy; Animals; Anti-Inflammatory Agents; Attenuated; Biopsy; Calcium Channel Blockers; Canis familiaris; Chronic; Clinical Trials; Collection; Consequentialism; Data; Dependovirus; Development; Disease; Distal; Duchenne muscular dystrophy; Dystrophin; Exhibits; Forelimb; Functional disorder; Gene Mutation; Genetic; Hand Strength; Health; Human; Hypertension; Inflammation; Inflammation Process; Inflammatory; Inflammatory Bowel Diseases; Limb structure; Link; Lower Extremity; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic Capillaries; Lymphatic System; Lymphatic function; Lymphedema; Medical Imaging; Modeling; Molecular; Mus; Muscle; Muscle Fibers; Muscle Weakness; Muscle function; Muscular Atrophy; Muscular Dystrophies; Myopathy; Nuclear; Pathogenesis; Pathologic; Pathology; Patients; Pelvis; Pharmaceutical Preparations; Play; Psoriasis; Reactive Oxygen Species; Regulation; Reporting; Research Personnel; Resolution; Rheumatoid Arthritis; Role; Scientist; Skeletal Muscle; Skin; Structure; Texas; Therapeutic; Universities; Vascular Endothelial Growth Factor D; Weight; X Chromosome; age group; boys; canine model; clinically relevant; density; experience; experimental study; healing; imaging facilities; improved; in vivo; inhibitor; lymphatic vessel; mdx mouse; mouse model; multidisciplinary; muscle strength; muscular dystrophy mouse model; next generation; novel; overexpression; response; skeletal muscle wasting; tibialis anterior muscle; trend

Duchenne muscular dystrophy (DMD) is an incurable, X chromosome-linked muscle disease that exhibits skeletal muscle wasting/weakness and the associated inflammation and dysfunction. Though available data on anti-inflammatory drugs in DMD patients and animal models are promising in diminishing inflammation and promoting muscle healing in patients, further understanding the inflammatory mechanisms and DMD pathogenesis is critical to develop the next generation of DMD drugs. The lymphatics have emerged as a central player in the process of inflammation and play active roles in both the resolution and progression of inflammation. This proposal brings a novel perspective for treatment of DMD. Since the lymphatic system plays active roles in both the resolution and progression of inflammation, the idea is that further increasing lymphangiogenesis in muscle tissues will augment lymph transport, and consequently, lessen inflammation and improve muscle health in DMD muscle. Preliminary data demonstrate: i) lymph transport in the distal pelvic limb is decreased while lymphatic vessel density is increased in tibialis anterior muscle from the severely affected, D2mdx mice; ii) skeletal muscle-specific overexpression of vascular endothelial growth factor (VEGF)-D increases lymphangiogenesis in normal muscle, with an increase in muscle weight and a positive trend in improving forelimb grip strength and iii) augments lymph transport in denervated muscle. Hence, central hypotheses are: 1) Inflammatory lymphangiogenesis combined with a decrease in lymphatic contractile activity cause a decrease in lymph transport, thereby causing chronic inflammatory status in muscles of DMD animals and 2) further augmenting lymphangiogenesis with VEGF-D overexpression beyond the level of inflammatory lymphangiogenesis observed in dystrophic muscle will improve lymph transport in skeletal muscle, and consequently, resolve the inflammation and attenuate muscle weakness and dysfunction in DMD animals. Specific Aims are: 1) To determine the changes in lymphatic structure and function in skeletal muscle of DMD mouse and canine models and 2) To determine whether experimentally increasing lymphangiogenesis in skeletal muscle improves muscle health in D2.mdx mice and golden retriever muscular dystrophy (GRMD) dogs. Different age groups of D2.mdx mice and wildtype control DBA/2J mice will be used. GRMD dogs and muscle biopsy collections from muscle dystrophy patients of various dog breeds will also be used. Overexpression of VEGF-D in D2.mdx mice and in GRMD will be achieved by genetic or adeno-associated virus approaches. Lymphangiogenesis, inflammation, lymphatic contractility and lymph transport, muscle health and function will be evaluated in controls and experimental animals. This proposal will provide novel information regarding the therapeutic role of lymphangiogenesis in improving muscle health in DMD animal models.

杜氏肌营养不良症 (DMD) 是一种无法治愈的 X 染色体连锁肌肉疾病， 骨骼肌消耗/无力以及相关的炎症和功能障碍。尽管现有数据 DMD 患者和动物模型中的抗炎药物有望减少炎症和 促进患者肌肉愈合，进一步了解炎症机制和DMD 发病机制对于开发下一代 DMD 药物至关重要。淋巴管已成为中枢 炎症过程中的重要参与者，并在炎症的消退和进展中发挥积极作用。 该提议为 DMD 的治疗带来了新的视角。由于淋巴系统起着积极的作用 无论是炎症的消退还是进展，其想法是进一步增加淋巴管生成 肌肉组织将增强淋巴运输，从而减轻炎症并改善肌肉健康 在 DMD 肌肉中。初步数据表明： i) 远端骨盆肢体的淋巴转运减少，同时 严重受影响的 D2mdx 小鼠胫骨前肌的淋巴管密度增加；二） 骨骼肌特异性血管内皮生长因子 (VEGF)-D 过度表达增加 正常肌肉中的淋巴管生成，伴随着肌肉重量的增加和改善的积极趋势 前肢握力，并且 iii) 增强去神经肌肉中的淋巴运输。因此，中心假设 是： 1) 炎症性淋巴管生成与淋巴管收缩活性降低相结合，导致 淋巴运输减少，从而导致 DMD 动物肌肉慢性炎症状态；2) VEGF-D 过表达超出炎症水平，进一步增强淋巴管生成 在营养不良的肌肉中观察到的淋巴管生成将改善骨骼肌中的淋巴运输，并且 因此，可以解决 DMD 动物的炎症并减轻肌肉无力和功能障碍。 具体目标是： 1) 确定DMD骨骼肌淋巴结构和功能的变化 小鼠和犬模型以及 2) 确定实验是否可以增加骨骼中的淋巴管生成 肌肉可改善 D2.mdx 小鼠和金毛肌营养不良症 (GRMD) 狗的肌肉健康。不同的 将使用 D2.mdx 小鼠和野生型对照 DBA/2J 小鼠的年龄组。 GRMD 狗和肌肉活检 还将使用来自各种犬种的肌肉营养不良患者的收集品。 VEGF-D 过度表达 在 D2.mdx 小鼠和 GRMD 中，将通过遗传或腺相关病毒方法实现。 淋巴管生成、炎症、淋巴收缩力和淋巴运输、肌肉健康和功能将 在对照和实验动物中进行评估。该提案将提供有关 淋巴管生成在改善 DMD 动物模型肌肉健康中的治疗作用。