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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

基本信息

批准号：
10684206
负责人：
Hongshuai Li
金额：
$ 33.29万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
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/10684206
关键词：
Affect Anions Arginine Attenuated Biological Availability Blood Bone Tissue Brain Hypoxia-Ischemia Bypass Cells Clinical Trials Combined Modality Therapy Cyclic GMP Data Dietary Nitrite Disease Disease Progression Duchenne muscular dystrophy Dystrophin Genes Hindlimb Suspension Histologic Homeostasis Human Intervention Investigation Ischemia 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 Physiological Production Proliferating Recombinant Fibroblast Growth Factor Role Series Signal Pathway Signal Transduction Signaling Molecule Skeletal Muscle Skeletal bone Source Testing Therapeutic Therapeutic Effect Tissues Utrophin bone bone cell bone loss bone quality comorbidity cost cost effective cranium curative treatments dietary nitrate effective therapy efficacy evaluation 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 pharmacologic phosphoric diester hydrolase potential biomarker pre-clinical preservation skeletal muscle differentiation therapeutic target therapeutically effective

项目摘要

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.

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