Targeting Nitrate-Nitrite-NO pathway for Ameliorating Muscle and Bone Comorbidities in Duchenne Muscular Dystrophy

靶向硝酸盐-亚硝酸盐-NO 途径改善杜氏肌营养不良症的肌肉和骨骼合并症

• 批准号: 10477446
• 负责人: Hongshuai Li
• 金额: $ 33.63万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10477446
• 关键词: Affect; Anions; Arginine; Attenuated; Biological Availability; Blood; Bone Tissue; Bypass; Cells; Clinical Trials; Cyclic GMP; Data; Dietary Nitrite; Disease; Disease Progression; Duchenne muscular dystrophy; Dystrophin; Genes; Guanosine Monophosphate; Hindlimb Suspension; Histologic; Homeostasis; Human; Hypoxia; Intervention; Investigation; Knock-out; Knowledge; Liver; Longevity; Measures; Mediating; Molecular; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle function; Muscular Dystrophies; Musculoskeletal; Mutation; Myocardium; Myoglobin; Myopathy; Neuromuscular Diseases; Nitrates; Nitric Oxide; Nitric Oxide Pathway; Nitric Oxide Signaling Pathway; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitrites; Nitrogen Dioxide; Oral; Oral Administration; Organ Culture Techniques; Osteoporosis; Outcome; Oxygen; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Periodicity; Pharmacology; Physiological; Production; Recombinant Fibroblast Growth Factor; Role; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Skeletal Muscle; Skeletal bone; Source; Testing; Therapeutic; Therapeutic Effect; Tissues; Utrophin; base; bone; bone cell; bone loss; bone quality; comorbidity; cost; cost effective; cranium; curative treatments; dietary nitrate; effective therapy; efficacy evaluation; efficacy study; efficacy testing; fibroblast growth factor 21; gain of function; improved; in vivo; inhibitor; innovation; insight; mechanical load; mouse model; neuron loss; neutralizing antibody; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; phosphoric diester hydrolase; potential biomarker; pre-clinical; preservation; skeletal muscle differentiation; therapeutic target; therapeutically effective

Abstract: Duchenne Muscular Dystrophy (DMD) is a severe, progressive muscular disease that affects both muscle and bone. To date, effective therapies for DMD are limited. Studies have shown that reduced nitric oxide (NO) bioavailability resulted from secondary loss of neuronal nitric oxide synthase (nNOS) in the absence of dystrophin is a key contributor to disease progression. Restoring NO homeostasis via dietary nitrite and nitrate representing a novel therapeutic approach due to its ability to be converted to NO in low oxygen and ischemic states that can bypass nNOS. The purpose of this study is to test the efficacy of inorganic nitrite and explore its mechanism of action on both skeletal muscle and bone. Our preliminary data, based on a severe dystrophic mouse model (dKO-dystrophin/utrophin double knock out), demonstrated disrupted NO homeostasis in dystrophic muscle and more excitingly, oral administration of nitrite significantly improved the life span and a series of pathological changes in dystrophic mice, both in skeletal muscle and bone tissues. The mechanisms underlying these improvements deserve further investigation to provide important preclinical and mechanistic information for identifying novel therapeutic targets. We hypothesize that inorganic nitrite administration improves both muscle and bone pathologies in DMD by enhancing NO signaling pathways in dystrophic muscle and by modulating the expression and secretion of bone- regulating myokines. We will test this hypothesis in three specific aims. Aim 1: To test the hypothesis that inorganic nitrite restores nitrate/nitrite pool in dystrophic mice and improves muscle/bone pathologies and preserves muscle function. Aim 2: To test the hypothesis that nitrite affects skeletal muscle via myoglobin-mediated NO-cGMP signaling pathway. Aim 3: To test the hypothesis that in addition to increased mechanical loading, nitrite affects bone homeostasis via modulating the expression and secretion of bone-regulating myokines from dystrophic muscle. We anticipate that these findings will provide a novel, safe and low-cost therapeutic approach benefiting both muscle and bone for the currently untreatable DMD. Completion of these aims will advance our knowledge of novel mechanisms for the pathogenesis of bone abnormalities in DMD through bone-regulating myokines as well; which may uncover new potential therapeutic targets. Importantly, our findings may have profound translational implications not only to DMD but also to other neuromuscular diseases that lack normal NO signaling pathway function.

摘要： 杜氏肌营养不良症（DMD）是一种严重的、进行性肌肉疾病，影响 肌肉和骨骼。迄今为止，DMD的有效疗法有限。研究表明 一氧化氮（NO）生物利用度的降低是由于神经元一氧化氮（NO）的继发性丢失， 在缺乏肌营养不良蛋白的情况下，氧化物合酶（nNOS）是疾病进展的关键因素。 通过膳食亚硝酸盐和硝酸盐恢复NO稳态代表一种新的治疗方法 由于其在低氧和缺血状态下转化为NO的能力， 旁路nNOS。本研究的目的是测试无机亚硝酸盐的功效，并探讨其 对骨骼肌和骨骼的作用机制。我们的初步数据，基于一个 严重营养不良小鼠模型（dKO-肌营养不良蛋白/肌营养不良蛋白双敲除），证实 破坏了营养不良肌肉中的NO稳态，更令人兴奋的是，口服 亚硝酸盐显著改善了营养不良小鼠的寿命和一系列病理变化 小鼠的骨骼肌和骨组织中。这些潜在的机制 这些改进值得进一步研究，以提供重要的临床前和机制 用于鉴定新的治疗靶点的信息。我们假设无机亚硝酸盐 给药通过增强NO信号传导改善DMD中的肌肉和骨骼病理 途径，并通过调节骨的表达和分泌， 调节肌因子。我们将在三个具体目标中检验这一假设。目标1：测试 假设无机亚硝酸盐恢复营养不良小鼠中硝酸盐/亚硝酸盐池并改善 肌肉/骨骼病理和保留肌肉功能。目的2：检验假设， 亚硝酸盐通过肌红蛋白介导的NO-cGMP信号通路影响骨骼肌。目标3： 测试假设，除了增加机械负荷，亚硝酸盐影响骨骼 通过调节骨调节肌因子的表达和分泌， 营养不良的肌肉我们预计，这些发现将提供一种新的，安全的，低成本的 对目前无法治疗的DMD的肌肉和骨骼都有益的治疗方法。 这些目标的完成将促进我们对新机制的了解， DMD中骨异常的发病机制也通过骨调节肌因子; 可能会发现新的潜在治疗靶点。重要的是，我们的发现可能会产生深远的影响。 不仅对DMD，而且对其他神经肌肉疾病， NO信号通路功能正常。