Personalized diagnosis - defining how glycogen metabolism and proteostasis impact LD

个性化诊断 - 定义糖原代谢和蛋白质稳态如何影响 LD

• 批准号: 9309107
• 负责人: Matthew S. Gentry
• 金额: $ 42.79万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9309107
• 关键词: Acute; Address; Affect; Antiepileptic Agents; Apoptosis; Area; Astrocytes; Autophagocytosis; Biochemical; Biochemistry; Biochemistry and Cellular Biology; Biological Assay; Brain; Cell Culture Techniques; Cell physiology; Cells; Cessation of life; Clinical; Collaborations; Cystic Fibrosis; Data; Defect; Development; Diagnosis; Disease; Disease Progression; Energy Metabolism; Epilepsy; Event; Family; Functional disorder; Genes; Glucans; Glycogen; Goals; Homeostasis; International; Intervention; Ion Channel; Knowledge; Lafora Disease; Life; Metabolic; Modeling; Molecular; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotransmitters; Outcome; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phosphoric Monoester Hydrolases; Production; Program Research Project Grants; Progressive Myoclonic Epilepsies; Proteins; Recovery; Research; Role; Sampling; Stress; Structural Biochemistry; Structure; Symptoms; Terminator Codon; Testing; Therapeutic; Toxic effect; Translating; Translations; Water; clinical application; design; disease-causing mutation; disorder subtype; drug efficacy; endoplasmic reticulum stress; glycogen metabolism; in vitro Model; induced pluripotent stem cell; insight; member; misfolded protein; molecular subtypes; mouse model; neuron apoptosis; neurotoxicity; new therapeutic target; novel; novel therapeutic intervention; overexpression; particle; personalized approach; personalized diagnostics; personalized therapeutic; potency testing; premature; protein degradation; protein expression; proteostasis; receptor; restoration; small molecule; symptom treatment; tool; trafficking; ubiquitin-protein ligase

Lafora disease (LD) is a fatal, recessive neurodegenerative disorder that presents as an epileptic event in the 2nd decade of life. A hallmark of LD is the accumulation of cytoplasmic, hyperphosphorylated, water- insoluble glycogen-like particles called Lafora bodies (LBs). LD results from mutations in either of the genes encoding laforin, a glycogen phosphatase, or malin, an E3 ubiquitin ligase, and mutations in either gene results in development of LD. LBs cause disease from acute neurotoxicity due to the sensitivity of neurons to energy perturbations. Associated with LB formation, cells display multiple markers indicating perturbations in critical cellular pathways, including increased endoplasmic reticulum stress, autophagy, ROS production, and others. The overall focus of this Program Project Grant is to facilitate the Lafora Epilepsy Cure Initiative (LECI): which is an international collaboration devoted to the Diagnosis, Treatment, and Cure of LD. The goals of this project are to define the clinical biochemistry of LD mutations to provide a personalized diagnosis and establish therapeutic options. To achieve these goals, we will define the molecular basis of LD utilizing structural biochemistry, cellular biology, and mouse models and translate our insights into mutation-specific diagnoses and novel therapeutic approaches to ameliorate LD induced epilepsy and cure LD. We will first utilize integrated structural and functional tools to define the physical and cellular perturbations caused by LD mutations in both laforin and malin. These approaches will allow us to define the basis of neuronal-specific toxicity leading to disease. We will then develop personalized approaches to diagnosis and treat LD patients. We will define the role of neurotransmitter transporters affected in LD. Further, we will determine how laforin and malin affect transporter homeostasis and how LD mouse models respond to treatment of symptoms with antiepileptic drugs. Lastly, we will establish the beneficial effect of pharmacological intervention novel compounds that promote read-through of premature termination codons. Embedded in these approaches is the development of a novel bioassay will allow patient-specific diagnosis and definition of molecular sub-types of the disease, key to each of the LECI Center projects. Further, these results have significant broader implications since LD is one of five major progressive myoclonic epilepsies, and the connection between metabolic dysfunction and epilepsy is an emerging theme. Cumulatively, these results will allow personalized therapeutic options that are developed to promote recovery of molecular and cellular function as a means of treating and curing LD.

拉福拉病 (LD) 是一种致命的隐性神经退行性疾病，表现为癫痫事件 生命的第二个十年。 LD 的一个标志是细胞质、过度磷酸化、水- 不溶性糖原样颗粒称为拉福拉体 (LB)。 LD 由任一基因突变引起 编码 laforin（一种糖原磷酸酶）或 malin（一种 E3 泛素连接酶）以及任一基因结果的突变 LD的开发中。由于神经元对能量的敏感性，LBs 会因急性神经毒性而引起疾病 扰动。与 LB 形成相关，细胞显示多个标记，表明关键的扰动 细胞途径，包括内质网应激增加、自噬、ROS 产生等。 该计划项目拨款的总体重点是促进拉福拉癫痫治愈计划 (LECI)： 这是一项致力于 LD 诊断、治疗和治愈的国际合作项目。本次活动的目标 该项目旨在定义 LD 突变的临床生物化学，以提供个性化诊断并建立 治疗选择。为了实现这些目标，我们将利用结构定义 LD 的分子基础 生物化学、细胞生物学和小鼠模型，并将我们的见解转化为突变特异性诊断 以及改善 LD 诱发的癫痫和治愈 LD 的新治疗方法。 我们将首先利用集成的结构和功能工具来定义物理和细胞扰动 由 laforin 和 malin 的 LD 突变引起。这些方法将使我们能够定义的基础 导致疾病的神经元特异性毒性。然后我们将开发个性化的诊断方法和 治疗 LD 患者。我们将定义神经递质转运蛋白在 LD 中的作用。此外，我们将 确定 laforin 和 malin 如何影响转运蛋白稳态以及 LD 小鼠模型如何响应 用抗癫痫药物治疗症状。最后，我们将确定药理学的有益作用 干预促进提前终止密码子通读的新型化合物。嵌入在这些 方法是开发一种新型生物测定法，将允许对患者进行特定诊断和定义 该疾病的分子亚型是 LECI 中心每个项目的关键。此外，这些结果还 由于 LD 是五种主要进行性肌阵挛性癫痫之一，并且 代谢功能障碍与癫痫之间的联系是一个新兴的主题。 累积起来，这些结果将允许开发出个性化的治疗方案来促进 恢复分子和细胞功能作为治疗和治愈 LD 的一种手段。