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Creative biosynthesis mitigates pathogenesis in mdx mice

创造性生物合成减轻 mdx 小鼠的发病机制

基本信息

批准号：
7901052
负责人：
BRIAN S TSENG
金额：
$ 12.69万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7901052
关键词：
A Mouse Advisory Committees Anabolism Biochemical Biochemical Markers Bioinformatics Biological Assay Cell membrane Childhood Clinical Clinical Investigator Creatine Creatine Kinase Development Developmental Biology Disease Doctor of Philosophy Duchenne muscular dystrophy Dystrophin Enzyme Precursors Enzymes Exhibits Extravasation Fiber Functional disorder Gene Mutation Gene-Modified Genetic Goals Guanidinoacetate N-Methyltransferase Histology Histopathology Homologous Gene Human Imaging Techniques In Situ Hybridization Internet K-Series Research Career Programs Knockout Mice Lead Longevity Magnetic Resonance Imaging Measures Medical Membrane Mentors Messenger RNA Metabolic Methyltransferase Mining Mission Molecular Molecular Genetics Mus Muscle Muscle Fibers Muscle function Muscular Dystrophies Mutation Myopathy National Institute of Arthritis and Musculoskeletal and Skin Diseases Neurologist Pathogenesis Pathology Patients Phenotype Postdoctoral Fellow Principal Investigator Production Prognostic Marker Proteins Protons Reaction Research Research Personnel Resources Role Running Scientist Serum Skeletal Muscle Technology Testing Time Training Urine Utrophin amidinotransferase base boys career creatine transporter fitness gait examination graduate student improved in vivo insight interest mdx mouse multidisciplinary novel programs satellite cell skills

项目摘要

DESCRIPTION (provided by applicant): This proposal describes a 5 year Mentored Clinical Investigator Career Development Award in Muscle Diseases Research as detailed in the NIAMS mission statement. The MD/PhD principal investigator is a board-certified pediatric neurologist. He will now expand upon his scientific skills through a unique integration of interdepartmental resources and establish a scientific niche to construct an academic career. This program will promote the longstanding interest of the PI in Duchenne Muscular Dystrophy (DMD) by expanding into molecular and developmental biology and mouse molecular genetics. Dr. Lee Niswander will mentor the principal investigators scientific development. A Howard Hughes Medical Investigator, Dr. Niswander is a recognized leader in the field of developmental biology and mouse genetics and has trained numerous postdoctoral fellows, graduate students and clinical fellows. In addition, an advisory committee of highly-regarded muscle scientists will provide scientific, clinical and career advice to help the PI develop into an independent investigator. The PI is in an ideal setting to incorporate expertise from diverse resources and utilize multidisciplinary technologies. Research will focuses on the hypothesis of de novo creatine synthesis in dystrophin-deficient mdx mice. The PI has identified guanidineacetate methyltransferase (GAMT), the key enzyme for creatine synthesis as being differentially upregulated at both the mRNA and protein level in mdx skeletal muscle. Using an assortment of biochemical, molecular, cellular and magnetic resonance imaging techniques, the specific aims include: 1) As GAMT is upregulated in mdx mice, the end-product creatine should also be increased. However because of membrane leakage, increased creatine levels may be largely found in urine and serum, not muscle, 2) Determine if AGAT (the precursor enzyme with GAMT required for creatine synthesis), is also upregulated at the mRNA and protein level in mdx muscle, and 3) Determine the phenotype of a double-null GAMTimdx mouse. This will be the first detailed analysis of creatine biosynthesis in the mdx mouse. Objective is to determine if the mdx mouse synthesizes creatine de-novo as an adaptation to mitigate metabolic compromise caused by leaky membranes. Dystrophin is an important protein for normal muscle function. Boys with DMD do not make dystrophin and their muscles weaken over time. The mdx mice do not make dystrophin yet they do not become crippled. These studies may offer important clues that could help with new treatments for boys with DMD.

描述（由申请人提供）：该提案描述了肌肉疾病研究领域为期 5 年的指导临床研究者职业发展奖，详情请参阅 NIAMS 使命宣言。医学博士/博士首席研究员是一位经过委员会认证的儿科神经科医生。他现在将通过跨部门资源的独特整合来扩展他的科学技能，并建立一个科学领域来构建学术生涯。该项目将通过扩展到分子和发育生物学以及小鼠分子遗传学领域，促进 PI 对杜氏肌营养不良症 (DMD) 的长期兴趣。 Lee Niswander 博士将指导主要研究人员的科学发展。 Niswander 博士是霍华德·休斯 (Howard Hughes) 医学研究员，是发育生物学和小鼠遗传学领域公认的领导者，并培养了众多博士后研究员、研究生和临床研究员。此外，由备受推崇的肌肉科学家组成的咨询委员会将提供科学、临床和职业建议，帮助 PI 发展成为一名独立研究者。 PI 处于一个理想的环境中，可以整合来自不同资源的专业知识并利用多学科技术。研究将集中于肌营养不良蛋白缺陷 mdx 小鼠中肌酸从头合成的假设。 PI 已鉴定出乙酸胍甲基转移酶 (GAMT)（肌酸合成的关键酶）在 mdx 骨骼肌中的 mRNA 和蛋白质水平上均出现差异性上调。使用各种生化、分子、细胞和磁共振成像技术，具体目标包括：1) 由于 GAMT 在 mdx 小鼠中上调，最终产物肌酸也应增加。然而，由于膜渗漏，肌酸水平增加可能主要出现在尿液和血清中，而不是肌肉中，2) 确定 AGAT（肌酸合成所需的 GAMT 前体酶）是否也在 mdx 肌肉中的 mRNA 和蛋白质水平上调，以及 3) 确定双无效 GAMTimdx 小鼠的表型。这将是对 mdx 小鼠肌酸生物合成的首次详细分析。目的是确定 mdx 小鼠是否从头合成肌酸作为缓解膜渗漏引起的代谢损害的适应措施。肌营养不良蛋白是正常肌肉功能的重要蛋白质。患有 DMD 的男孩不会产生肌营养不良蛋白，他们的肌肉会随着时间的推移而减弱。 mdx 小鼠不会产生肌营养不良蛋白，但它们也不会致残。这些研究可能提供重要线索，有助于为患有 DMD 的男孩提供新的治疗方法。