Administrative Supplement - Novel Protein Aggregation Inhibitors and Upper Motor Neuron Stabilizers for ALS and other Neurodegenerative Diseases

行政补充 - 用于 ALS 和其他神经退行性疾病的新型蛋白质聚集抑制剂和上运动神经元稳定剂

• 批准号: 10451057
• 负责人: Pembe Hande Ozdinler
• 金额: $ 12万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451057
• 关键词: 3-Dimensional; Administrative Supplement; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Antioxidants; Attention; Basic Science; Biological Assay; Biological Process; Biology; Brain; Brain region; Cells; Characteristics; Cyclohexanes; Development; Disease; Disease model; Drug Kinetics; Electrophysiology (science); Equipment; FDA approved; Goals; Grant; Health; Hereditary Spastic Paraplegia; Homeostasis; Impairment; In Vitro; Investigation; Ion Channel; Label; Laboratories; Lead; Measures; Modeling; Motor; Motor Neuron Disease; Motor Neurons; Movement; Neurodegenerative Disorders; Neurons; Outcome; PC12 Cells; Parkinson Disease; Pathology; Pathway interactions; Penetration; Pharmaceutical Preparations; Photoaffinity Labels; Preclinical Drug Development; Preclinical Testing; Primary Lateral Sclerosis; Process; Proteasome Inhibition; Proteins; Pyrazolones; Reporter; Research; Resolution; Structure; Therapeutic; Toxic effect; Translations; Universities; Upper Motor Neuron Disease; age related neurodegeneration; analog; base; covalent bond; design; drug candidate; drug discovery; effective therapy; experimental study; frontotemporal lobar dementia-amyotrophic lateral sclerosis; improved; in vivo; inhibitor/antagonist; innovation; interest; motor neuron function; multicatalytic endopeptidase complex; mutant; neuron loss; novel; novel therapeutics; overexpression; phenylmethylpyrazolone; pre-clinical; preclinical evaluation; protein TDP-43; protein aggregation; response; scaffold; screening; small molecule; superoxide dismutase 1; treatment strategy

ABSTRACT Our collaborative efforts between the Ozdinler and Silverman Laboratories began to reveal the presence of small molecules that can reduce protein aggregation and improve the health of upper motor neurons that are diseased due to misfolded SOD1 toxicity and TDP-43 pathology. We are setting the stage for a cell-based and mechanism-focused drug discovery effort that utilizes upper motor neuron health as a readout. Recently, we also revealed the importance of ion channel homeostasis for upper motor neuron stability and how cortical connectivity is an important aspect of their health and function. Here, we apply to acquire a new equipment, which will allow us to assay and investigate potential improvements in cortical connectivity upon compound administration. Current studies investigate the stability and the cellular integrity of upper motor neurons by studying at cell/neuron structure. However, it is most desirable to reveal whether compound treatments also lead to improved cortical connectivity and function. Novel equipment, which measure field potentials, propagation of connectivity within different regions of the brain at a layer and even at a cellular level resolution has the potential to add tremendous impact to the RO1 grant we currently have. As we continue our investigations on small molecule controls over upper motor neuron health and stability, –via reduced protein aggregation–, we believe that investigation of their neuronal activity at a cellular level, and more broadly within the cortical network, will have an immense impact on our proposal.

摘要 我们在奥兹丁勒和西尔弗曼实验室之间的合作努力开始揭示 小分子的存在，可以减少蛋白质聚集，改善上 运动神经元由于错误折叠的SOD 1毒性和TDP-43病理学而患病。我们 为基于细胞和机制的药物发现工作奠定了基础， 运动神经元的健康状况最近，我们还揭示了离子通道的重要性， 上运动神经元稳定性的内稳态以及皮质连接如何是一个重要方面 他们的健康和功能。在这里，我们申请获得一个新的设备，这将使我们能够 测定并研究化合物对皮质连接的潜在改善 局目前的研究探讨了上运动神经元的稳定性和细胞完整性 通过研究细胞/神经元的结构来研究神经元。然而，最好能揭示出， 化合物治疗还导致皮层连接性和功能的改善。新型设备， 它测量场电位，大脑不同区域内的连通性传播， 一层，甚至在细胞水平的分辨率有可能增加巨大的影响， 我们目前拥有的RO 1赠款。 当我们继续研究小分子对上运动神经元的控制时， 通过减少蛋白质聚集，我们相信对它们的研究 在细胞水平上的神经元活动，以及更广泛地在皮质网络内的神经元活动，将具有 对我们的提案有很大的影响。