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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：肌萎缩性侧面硬化症（ALS）是一种进行性且最终致命的疾病，可杀死脊髓，脑皮质和脑干的运动神经元。在诊所中，零星和家族性ALS在提示常见病理机制的诊所中是无法区分的。因此，发现家族性ALS的患者通常在编码CU/Zn超氧化物歧化酶（SOD1）的基因中具有优势获得功能的毒性突变是主要机械线索。 mutsod1错误折叠和骨料形成神经元包容物体。尽管它们的作用尚未完全定义，但这些聚集体出现在动物模型中的神经元死亡之前，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应力触发展开的蛋白质反应（UPR）途径，该途径减慢了翻译并在转录上上调基因，从而增强了ER蛋白质折叠能力和与ER相关的蛋白质降解。如果无法通过这些输出恢复体内平衡，则UPR会触发凋亡。我们的团队最近发现，UPR IRE1A的关键组成部分是稳态和凋亡输出之间的切换开关，最终控制了细胞命运。该STTR的项目目标是开发小分子，使IRE1A的输出偏向稳态，并证明ALS中这些化合物的治疗潜力。我们已经开发了一种新型的生化测定方法来检测此类化合物，并确定了药物化学的良好起点。一种新型的Mutsod1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，将有助于我们推动这些化合物的功能效力。拟议研究的结果将指导我们选择铅化合物，以在MutSOD1 ALS小鼠模型中验证这种方法。最终，这些努力是朝着为ALS和相关ND的新型治疗开发的重要一步。公共卫生相关性：肌萎缩性侧索硬化症（ALS）是一种进行性且最终是致命的神经退行性疾病（ND），通常在40至70岁之间罢工。大脑皮层和脑干。这些越来越多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年内瘫痪和呼吸道死亡。 ALS患者几乎没有治疗方案，仅提供有限的有效性。我们正在设计一类新的口服药物，以在保留功能的同时对抗运动神经元死亡。我们的努力代表着为ALS和相关ND的新型治疗而开发的重要步骤。