Developing UPR Modulators as Novel Therapeutics for Neurodegeneration

开发 UPR 调节剂作为神经退行性疾病的新型疗法

• 批准号: 8057686
• 负责人: Bradley J Backes
• 金额: $ 19.67万
• 依托单位: METAFOLD THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8057686
• 关键词: Affect; Age; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Model; Apoptosis; Apoptotic; Astrocytes; Autopsy; Biochemical; Biological Assay; Brain Stem; Cell Culture System; Cell Culture Techniques; Cell Fate Control; Cell Line; Cell Survival; Cells; Cerebral cortex; Cessation of life; Clinic; Coupled; Cuprozinc Superoxide Dismutase; Development; Disease; Disease Progression; Effectiveness; Employee Strikes; Endoplasmic Reticulum; FDA approved; Familial Amyotrophic Lateral Sclerosis; Genes; Goals; Homeostasis; Human; Huntington Disease; Imatinib; Inclusion Bodies; Integral Membrane Protein; Interneurons; Lead; Messenger RNA; Modeling; Monitor; Motor Neurons; Movement; Mus; Muscle; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Oral; Output; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phosphorylation; Phosphotransferases; Play; Population; Proteins; RNA Splicing; Reporter; Resistance; Respiratory Paralysis; Ribonucleases; Role; Sampling; Signal Pathway; Signal Transduction; Small Business Technology Transfer Research; Source; Spinal Cord; Stress; Supporting Cell; Testing; Therapeutic; Tissues; Toxic effect; Translations; Withdrawal; base; combat; design; drug development; embryonic stem cell; endoplasmic reticulum stress; gain of function; human disease; immortalized cell; improved; inhibitor/antagonist; killings; kinase inhibitor; mRNA Decay; mouse model; neuronal survival; neuroprotection; neurotoxicity; novel; novel therapeutics; oxidative damage; programs; protein aggregate; protein degradation; protein folding; protein misfolding; response; self-renewal; small molecule

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a progressive and ultimately fatal disease that kills motor neurons of the spinal cord, cerebral cortex and brainstem. Sporadic and familial ALS are indistinguishable in the clinic suggesting common pathological mechanisms. Thus, the discovery that patients with familial ALS often harbor dominant gain-of-function toxic mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) is a major mechanistic clue. mutSOD1 misfolds and aggregates to form neuronal inclusion bodies. While their role is not fully defined, these aggregates appear before neuronal death in animal models and strongly correlate with disease progression. Furthermore, evidence suggests that these aggregates cause endoplasmic reticulum (ER) stress-induced neurotoxicity that plays a central role in disease pathology. ER stress triggers the unfolded protein response (UPR) pathway, which slows translation and transcriptionally upregulates genes that enhance ER protein-folding capabilities and ER-associated protein degradation. If homeostasis is not restored through these outputs, the UPR triggers apoptosis. Our team recently discovered that a key component of the UPR, IRE1a, acts as a toggling switch between homeostatic and apoptotic outputs, ultimately controlling cell fate. The project goal of this STTR is to develop small molecules that bias IRE1a's outputs towards homeostasis and to demonstrate the therapeutic potential of these compounds in ALS. We have developed a novel biochemical assay to detect such compounds, and have identified good starting points for medicinal chemistry. A novel mutSOD1 embryonic stem cell-derived cell culture model of neurodegeneration designed to evaluate UPR mechanism-based neuroprotection will help us drive the functional potency of these compounds. Results from the proposed studies will guide our selection of lead compounds to validate this approach in the mutSOD1 ALS mouse model. Ultimately, these efforts represent a significant step towards the development of a novel treatment for ALS and related NDs. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a progressive and ultimately fatal neurodegenerative disease (ND) that typically strikes between the ages of 40 and 70. The central pathological hallmark of ALS is the selective loss of motor neurons of the spinal cord, cerebral cortex and brainstem. These mounting losses destroy the patient's ability to initiate and control muscle movements and ultimately result in paralysis and respiratory death within 3-5 years. Patients with ALS have few treatment options that offer only limited effectiveness. We are designing a new class of oral drugs to combat motor neuron death while preserving function. Our efforts represent significant steps towards the development of a novel treatment for ALS and related NDs.

描述（由申请人提供）：肌萎缩侧索硬化症（ALS）是一种进行性和最终致命的疾病，可杀死脊髓、大脑皮层和脑干的运动神经元。散发性和家族性ALS在临床上难以区分，提示共同的病理机制。因此，发现家族性ALS患者通常在编码Cu/Zn超氧化物歧化酶（SOD 1）的基因中具有显性功能获得性毒性突变是一个主要的机制线索。mutSOD 1错误折叠并聚集形成神经元包涵体。虽然它们的作用尚未完全确定，但这些聚集体在动物模型中出现在神经元死亡之前，并且与疾病进展密切相关。此外，有证据表明，这些聚集体引起内质网（ER）应激诱导的神经毒性，在疾病病理学中起着核心作用。ER应激触发未折叠蛋白反应（UPR）途径，其减慢翻译并转录上调增强ER蛋白折叠能力和ER相关蛋白降解的基因。如果体内平衡没有通过这些输出恢复，UPR触发细胞凋亡。我们的团队最近发现，UPR的一个关键组成部分IRE 1a作为稳态和凋亡输出之间的切换开关，最终控制细胞命运。该STTR的项目目标是开发使IRE 1a的输出偏向稳态的小分子，并证明这些化合物在ALS中的治疗潜力。我们已经开发了一种新的生化检测方法来检测这些化合物，并确定了药物化学的良好起点。一种新的mutSOD 1胚胎干细胞衍生的神经变性细胞培养模型，旨在评估基于UPR机制的神经保护作用，这将有助于我们推动这些化合物的功能潜力。来自所提出的研究的结果将指导我们选择先导化合物以在mutSOD 1 ALS小鼠模型中验证该方法。最终，这些努力代表了开发ALS和相关ND的新治疗方法的重要一步。 公共卫生关系：肌萎缩侧索硬化症（ALS）是一种进行性的，最终致命的神经退行性疾病（ND），通常在40至70岁之间发作。ALS的中心病理学标志是脊髓、大脑皮层和脑干的运动神经元的选择性丧失。这些不断增加的损失破坏了患者启动和控制肌肉运动的能力，并最终导致3-5年内的瘫痪和呼吸死亡。ALS患者的治疗选择很少，效果有限。我们正在设计一种新的口服药物，以对抗运动神经元死亡，同时保留功能。我们的努力代表了为ALS和相关ND开发新治疗方法的重要步骤。