NADPH Oxidase and Autophagic Dysfunction in Duchenne Muscular Dystrophy

杜氏肌营养不良症中的 NADPH 氧化酶和自噬功能障碍

基本信息

批准号：
9174359
负责人：
George G Rodney
金额：
$ 34.87万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9174359
关键词：
Age Age-Years Autophagocytosis Autophagosome Biogenesis Cell physiology Cessation of life Clinical Treatment Clinical Trials Connective Tissue Cytoskeletal Proteins Dasatinib Data Defect Deposition Disease Down-Regulation Duchenne muscular dystrophy Dystrophin Equilibrium Event Excision Exercise Functional disorder Future Generations Genes Genetic Goals Heart failure Histologic Homeostasis Hyperactive behavior Impairment In Vitro Incidence Inflammation Life Link Lysosomes Mediating Microtubules Modeling Molecular Mus Muscle Muscle Fibers Muscle Weakness Muscle function Muscular Atrophy Muscular Dystrophies Mutation NADPH Oxidase Natural regeneration Oxidation-Reduction Oxidative Stress Oxides Pathologic Pathology Pathway interactions Patients Pharmacology Phosphorylation Play Predisposition Principal Investigator Process Production Proteins Publishing Reactive Oxygen Species Regulation Research Respiratory Failure Role Skeletal Muscle Stretching Testing Therapeutic Therapeutic Agents Transgenic Organisms Translating Tubulin Walking Work cancer therapy clinical development density disease-causing mutation experience feeding genetic approach improved in vivo inhibition of autophagy inhibitor/antagonist kinase inhibitor male mdx mouse muscle degeneration muscular dystrophy mouse model new therapeutic target novel peptidomimetics polymerization prevent programs response skeletal src-Family Kinases therapeutic target

项目摘要

Project Summary Duchenne muscular dystrophy (DMD) is a devastating type of muscular dystrophy, with an incidence of 1 in every 3500 males. DMD is an X-linked, muscle-wasting disease caused by mutations in the cytoskeletal protein dystrophin. Young DMD patients experience muscle damage that is followed by regeneration; however, as the disease progresses regeneration is impeded and muscle fibers are progressively replaced by connective tissue and fatty deposits. Profound muscle weakness results in decreased mobility by 10 to 12 year of age and eventually death by the age of 20 to 30 due to respiratory and/or cardiac failure. While there is currently no treatment for the disease, many different therapeutic approaches for DMD are entering clinical trials. Accumulating evidence supports the idea that the elevated susceptibility to damage in mdx muscles correlates with the presence of increased sarcolemmal Ca2+ influx and increased production of reactive oxygen species (ROS). Impaired autophagy, a cellular process to clear damaged constituents, has recently been implicated in the disease process. Ongoing work by our group has found that increased ROS generation from Nox2 contributes to altered redox balance and Ca2+ homeostasis in skeletal muscle from the mouse model of muscular dystrophy (Mdx). We have recently shown that Src, a non-receptor tyrosine kinase, acts as a redox switch to activate Nox2. Genetic inhibition of Nox2 decreases the exuberant ROS generation, decreases Src kinase activity, and rescues the defective autophagy in skeletal muscle from Mdx mice. Furthermore, we have shown that inhibiting Src kinase in-vitro decreases oxidative stress and improves autophagy. In preliminary data we have recently found that treating Mdx mice with the Src kinase inhibitor dasatinib improves autophagic flux and skeletal muscle function. The overall goal of this proposal is to test whether inhibition of Src kinase can prevent oxidative stress, impaired autophagic flux, and muscle pathology in Mdx mice. If successful, the proposed research will provide a novel therapeutic target, Src kinase, for DMD. Given that Src kinase inhibitors are in clinical development for the treatment of cancer, results from these studies will be valuable for future clinical trials for the treatment of DMD.

项目摘要 Duchenne肌肉营养不良症（DMD）是肌肉营养不良的毁灭性类型，发生率为1 每3500名男性。 DMD是由细胞骨架突变引起的X连锁的，挥发肌肉的疾病蛋白质肌营养不良蛋白。年轻的DMD患者遭受肌肉损伤，随后再生。然而，随着疾病的进展，再生受到阻碍，肌肉纤维逐渐取代结缔组织和脂肪沉积。深刻的肌肉无力导致迁移率降低10至12 年龄，最终由于呼吸道和/或心脏衰竭而在20至30岁时死亡。而有目前尚未治疗该疾病，DMD的许多不同治疗方法正在进入临床试验。积累的证据支持了以下观点，即MDX肌肉的易感性升高与存在增加的肌膜Ca2+流入和活性氧的产生增加有关物种（ROS）。自噬受损是一种清除受损成分的细胞过程，最近是与疾病过程有关。我们小组正在进行的工作发现，ROS的产生增加了 NOX2有助于改变的氧化还原平衡和骨骼肌中Ca2+稳态的改变。肌肉营养不良（MDX）。我们最近表明，非受体酪氨酸激酶SRC充当氧化还原切换到激活NOX2。 NOX2的遗传抑制减少了旺盛的ROS的产生，降低了SRC 激酶活性，并从MDX小鼠的骨骼肌中挽救了自噬的缺陷。此外，我们还有表明，抑制SRC激酶内外会减少氧化应激并改善自噬。在初步我们最近发现的数据，用SRC激酶抑制剂Dasatinib治疗MDX小鼠可改善自噬通量和骨骼肌功能。该建议的总体目标是测试抑制SRC激酶可以预防MDX小鼠中的氧化应激，自噬通量受损和肌肉病理。如果成功，拟议的研究将为DMD提供一种新型的治疗靶标SRC激酶。鉴于SRC激酶抑制剂正在临床发展以治疗癌症，这些研究的结果对于 DMD治疗的未来临床试验。