Sialic acid has putative signaling roles in muscle disorders of aging

描述(申请人提供)：散发性包涵体肌炎(SIBM)是最常见的与年龄相关的获得性肌肉疾病。SIBM困扰着50岁以上的个人。虽然肌肉无力逐渐发展，但疾病是无情的进展，导致严重萎缩和严重的远端和近端肌肉无力。患者在发病后5-10年内被绑在轮椅上。对患者肌肉活检的病理分析揭示了两种病理变化：(1)炎性细胞的渗透和(2)肌肉退行性改变，包括边缘空泡形成、蛋白质聚集物和肌核破裂。尽管有这些知识，但导致肌肉退化和肌肉无力的确切致病级联却知之甚少。此外，sIBM的炎性成分和退行性成分之间的关系仍然是一个谜。因此，目前还没有针对sIBM的有效治疗方法。唾液酸生物合成失调与包涵体肌病(IBM)的发病机制有关。遗传性包涵体肌病是一种常染色体隐性遗传病，其编码催化唾液酸生物合成第一步的酶的UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine激酶基因(GNE)发生突变。HIBM的病理模拟了sIBM。此外，像sIBM一样，hIBM也是一种衰老疾病；尽管在出生时就有突变基因，但在gne中携带hIBM突变的人直到达到一定的年龄，通常是25岁左右，才会出现肌肉无力。了解GNOE的突变和随后唾液酸稳态的破坏如何影响转录和信号网络，将有助于深入了解IBM中调控失调的途径。这项建议的目标1是确定唾液酸作为信号分子的能力。这将揭示IBM肌肉中不受调控的通路。目标2是确定作为信号分子的唾液酸代谢产物(S)，并发现作为唾液酸感受器的蛋白质。这项工作的结果将揭示IBM病的新治疗目标。目标3的目的是确定唾液酸信号对亚细胞定位的依赖性。综上所述，这些实验将揭示糖代谢的新角色，并提供对IBM这一常见的毁灭性疾病的机械性洞察。 公共卫生相关性：散发性包涵体肌炎是一种无情的进行性肌肉疾病，会导致严重的虚弱，是最常见的与衰老相关的获得性肌肉疾病。一种独特的糖-唾液酸的调节失调与这种疾病的遗传形式有关。我将进行实验，以了解唾液酸如何影响信号和转录网络，当受到干扰时，这些网络将导致疾病。

DESCRIPTION (provided by applicant): Sporadic inclusion body myositis (sIBM) is the most common acquired muscle disease associated with aging. sIBM afflicts individuals older than 50 years of age. While muscle weakness develops gradually, the disease is relentlessly progressive, leading to gross atrophy and severe weakness of both the distal and proximal muscles. Afflicted individuals are wheelchair bound within 5-10 years of onset. Pathologic analyses of patient muscle biopsies reveal two pathologies: (1) infiltration of inflammatory cells and (2) muscle degenerative changes consisting of rimmed vacuole formation, protein aggregate inclusions, and myonuclear breakdown. Despite this knowledge, the exact pathogenic cascade that leads to muscle degeneration and muscle weakness is poorly understood. Furthermore, the relationship between the inflammatory and degenerative components of sIBM remains a mystery. As a result, no effective treatment for sIBM exists. Dysregulation of sialic acid biosynthesis is implicated in inclusion body myopathy (IBM) pathogenesis. Mutations in UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase gene (GNE), which encodes the enzyme that catalyzes the first committed step of sialic acid biosynthesis, have been found in patients suffering from hereditary inclusion body myopathy (hIBM), an autosomal recesive disease. The pathology of hIBM mimics sIBM. Additionally, like sIBM, hIBM is a disease of aging; despite having a mutant gene at birth, humans harboring hIBM mutations in GNE do not develop muscle weakness until they reach a certain age, typically their mid-20s. Understanding how mutations in GNE and subsequent disruption of sialic acid homeostasis affects transcriptional and signaling networks will provide insight into pathways dysregulated in IBM. Aim 1 of this proposal is to ascertain the ability of sialic acid to act as a signaling molecule. This will reveal pathways dysregulated in IBM muscle. Aim 2 is to determine the sialic acid metabolite(s) that is acting as a signaling molecule and to discover the protein that is acting as a sialic acid sensor. The results of this work will reveal new therapeutic targets for IBM disease. The purpose of aim 3 is to determine the dependence of sialic acid signaling on subcellular localization. Taken together, these experiments will reveal novel roles for sugar metabolism and provide mechanistic insight into IBM, a common, devastating disease. PUBLIC HEALTH RELEVANCE: Sporadic inclusion body myositis is a relentlessy progressive muscle disorder that leads to severe weakness and it is the most common acquired muscle disease associated with aging. Dysregulation of a unique sugar, sialic acid, is implicated in hereditary forms of this disease. I will perform experiments to understand how sialic acid affects signaling and transcriptional networks which when disturbed would lead to disease.