Development of a novel HIBM2 mouse model and therapy

新型 HIBM2 小鼠模型和疗法的开发

• 批准号: 8808258
• 负责人: PAUL Taylor MARTIN
• 金额: $ 19.73万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-13 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8808258
• 关键词: Acetylglucosamine; Alleles; Anabolism; Asialoglycoprotein Receptor; Breeding; Clinic; Cytidine Monophosphate N-Acetylneuraminic Acid; Data; Development; Disease; Distal Muscular Dystrophies; Effectiveness; Essential Genes; Genes; Genetic; Glycoproteins; Grant; Half-Life; Hereditary Disease; Human; Inclusion Bodies; Inherited; Liver; Mammals; Modeling; Mus; Muscle; Muscle Weakness; Mutate; Myopathy; N-acetylmannosamine; Oral; Pathogenesis; Pathology; Patients; Phosphotransferases; Polysaccharides; Proteins; Replacement Therapy; Role; Serum; Sialic Acids; Skeletal Muscle; Testing; Thinking; Tissues; Transgenic Mice; Translating; Vacuole; adeno-associated viral vector; base; effective therapy; epimerase; fascinate; gene replacement; gene therapy; human disease; human tissue; mouse model; mutant; novel; public health relevance; quadriceps muscle; research study; sialylation; skeletal; tool

DESCRIPTION (provided by applicant): Hereditary Inclusion Body Myopathy Type II (HIBM2), also called Nonaka distal myopathy, quadriceps sparing myopathy and distal myopathy with rimmed vacuoles, is an autosomal genetic disorder that results in progressive muscle weakness and is associated with the development of inclusion bodies within skeletal myofibers. The gene responsible for HIBM2 has been identified as GNE, which encodes the UDP-N-acetylglucosamine epimerase/N- acetylmannosamine-6 kinase. GNE is gene required for biosynthesis of sialic acid, an essential glycan found in all human tissues. Despite the identification of the genetic basis for HIBM2, no effective therapies are currently available for this disease. This proposal will accomplish two specific aims. First, it will create a new mouse model for HIBM2 where the mouse sialic acid repertoire reflects the sialic acid repertoire normally found in humans. Humans lack the ability to synthesize certain forms of sialic acid that are present in all lower mammals. HIBM2 is a disease related to defective sialic acid biosynthesis, and CMP-sialic acid also negatively regulates GNE activity. Therefore, creating a mouse model that mimics human glycans is essential to understanding the role of human sialic acids in the disease. This new model will also provide a tool that will allow easier assessment of potential glycan therapies. Second, this grant will directly test a novel hypothesis regarding HIBM2 pathogenesis and develop a novel gene therapy that, if successful, could be applied to patients.

描述（由申请人提供）：遗传性包涵体肌病II型（HIBM2），也称为Nonaka远端肌病，四头肌保留肌病和远端肌病伴边缘空泡，是一种常染色体遗传疾病，导致进行性肌肉无力，与骨骼肌纤维内包涵体的发育有关。与HIBM2有关的基因已被确定为GNE，该基因编码udp -N-乙酰氨基葡萄糖烯丙基酶/N-乙酰甘露糖胺-6激酶。GNE是生物合成唾液酸所需的基因，唾液酸是一种存在于所有人体组织中的必需聚糖。尽管确定了HIBM2的遗传基础，但目前尚无有效的治疗方法。这项建议将实现两个具体目标。首先，它将为HIBM2创建一个新的小鼠模型，其中小鼠唾液酸库反映了通常在人类中发现的唾液酸库。人类缺乏合成某些形式唾液酸的能力，而这些唾液酸存在于所有低等哺乳动物中。HIBM2是一种与唾液酸生物合成缺陷相关的疾病，cmp -唾液酸也会负向调节GNE活性。因此，创建一个模拟人类多糖的小鼠模型对于理解人类唾液酸在疾病中的作用至关重要。这个新模型也将提供一种工具，可以更容易地评估潜在的聚糖疗法。其次，这笔拨款将直接测试一个关于HIBM2发病机制的新假设，并开发一种新的基因疗法，如果成功，可以应用于患者。