ER stress mediates methylglyoxal-evoked AIS shortening and neuronal dysfunction

内质网应激介导甲基乙二醛诱发的 AIS 缩短和神经元功能障碍

• 批准号: 10055833
• 负责人: Keiichiro Susuki
• 金额: $ 4.06万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055833
• 关键词: Action Potentials; Address; Affect; African American; Alzheimer' s Disease; Applications Grants; Axon; Behavior; Biological Assay; Brain; Butyric Acids; Calcium; Calpain; Caspase; Cell Death; Cell Survival; Characteristics; Clinic; Clinical; Cognition Disorders; Cognitive deficits; Communities; Coupled; Data; Data Analyses; Diabetes Mellitus; Disease; Endoplasmic Reticulum; Exposure to; Fellowship; Female; Functional disorder; Future; GRP78 gene; Genes; Glucose; Goals; Grant; Hippocampus (Brain); Hour; Immunofluorescence Immunologic; Impaired cognition; Knowledge; Lead; Length; Life; Measures; Mediating; Mediator of activation protein; Mentors; Modeling; Molecular; Mus; National Institute of Neurological Disorders and Stroke; National Research Service Awards; Nerve Degeneration; Nervous System Physiology; Nervous system structure; Neurodegenerative Disorders; Neurologic; Neuronal Dysfunction; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Parents; Patients; Pharmaceutical Preparations; Physicians; Positioning Attribute; Process; Proteins; Public Health; Pyruvaldehyde; Research; Research Design; Research Personnel; Resources; Scientist; Structure; Study Skills; Synaptic Transmission; Techniques; Testing; Training; Translational Research; Tunicamycin; Western Blotting; Woman; Work; career; career development; comorbidity; cytotoxicity; db/db mouse; diabetic; doctoral student; endoplasmic reticulum stress; experience; glucose metabolism; inhibitor/antagonist; innovation; multi-electrode arrays; network dysfunction; neural network; neuronal excitability; novel; parent grant; prevent; protein complex; response; success

PROJECT SUMMARY/ABSTRACT (Diversity Supplement) Alterations in the axon initial segment (AIS) are key pathophysiologies in various neurodegenerative diseases, including diabetes. Shortening of AIS length has been shown to lower neuronal excitability and is also implicated in cognitive impairment in type 2 diabetes and Alzheimer's disease. However, the cellular and molecular mechanisms of how these domains are altered in disease conditions remain poorly understood. This critical gap in knowledge limits the field's ability to manipulate the AIS for treatment. In order to fill this significant gap in our knowledge, the parent grant (R01 NS107398) tests the hypothesis that methylglyoxal (MG) disrupts AIS protein complexes via calpain activation and inhibits nervous system function. The current diversity supplement proposal seeks to elucidate more detailed mechanisms that lead to AIS shortening. The overall objective of this application is to identify a critical cellular mechanism that activates calpains in response to MG increase. The prior studies and preliminary data provided here have identified endoplasmic reticulum (ER) stress as a potential mediator for calpain activation and AIS shortening induced by MG increase. The hypothesis is that sublethal increase of MG induces ER stress, leading to calpain activation and AIS shortening. We will test this hypothesis via two Specific Aims. Aim 1: Test the hypothesis that, independent of MG increase, sublethal levels of ER stress cause calpain activation, AIS shortening, and neuronal network dysfunction. Aim 2: Test the hypothesis that inhibition of ER stress prevents MG-induced calpain activation, AIS shortening, and neuronal network dysfunction. This application is conceptually innovative, as we propose that ER stress is a key mediator of AIS shortening and neuronal dysfunction induced by MG. Innovative use of multi-electrode arrays will determine the effects of induced ER stress and increased MG together with ER stress inhibition on neural network function. The proposed research is significant, because completion of the aims will validate ER stress as potential targets for translational research aimed at treatments for comorbid cognitive impairment in type 2 diabetes. These results also have potential to impact a wide variety of neurodegenerative conditions, such as Alzheimer's. In addition to the scientific work, the important aspect of this diversity supplement is to support the career development of an African American female MD/PhD student. Her career goal is an independent physician scientist studying changes in neural transmission and cognitive defects caused by neurodegenerative diseases. Cognitive disorders disproportionately affect African Americans, yet African Americans are underrepresented in the scientific workforce. To address the inequity in heath research and clinics, it is critical to diversify the field. Thus, the proposed work and mentoring activities in this diversity supplement will ultimately provide a sustained and powerful influence on the field of neurodegenerative diseases.

项目摘要/摘要（多样性补充） 轴突初始段（AI）的改变是各种神经退行性的关键病理生理学 疾病，包括糖尿病。 AIS长度的缩短已显示为降低神经元兴奋性，为 还与2型糖尿病和阿尔茨海默氏病的认知障碍有关。但是，细胞和 在疾病条件下如何改变这些结构域的分子机制仍然很少了解。这 知识的关键差距限制了该领域操纵AIS治疗的能力。为了填补这个 我们所知的显着差距，父授予的赠款（R01 NS107398）检验了甲基糖的假设 （mg）通过钙蛋白酶激活破坏AIS蛋白复合物并抑制神经系统功能。电流 多样性补充提案旨在阐明导致AIS缩短的更详细的机制。这 该应用的总体目的是确定一种关键的细胞机制，该机制激活钙蛋白酶以响应 毫克增加。此处提供的先前研究和初步数据已经确定了内质网 （ER）应力作为calpain激活和AIS缩短的潜在介体。这 假设是，MG的余量增加会诱导ER应力，从而导致钙蛋白酶的激活和AIS缩短。 我们将通过两个具体目标检验这一假设。目标1：检验以下假设：与MG增加无关， 亚致死水平的ER应力会导致钙蛋白酶激活，AIS缩短和神经元网络功能障碍。目的 2：检验抑制ER应力的假设可防止MG诱导的钙蛋白酶激活，AIS缩短和 神经元网络功能障碍。该应用在概念上是创新的，因为我们建议AR压力是一种 MG诱导的AIS缩短和神经元功能障碍的关键介质。多电极的创新使用 阵列将确定诱导的ER应力和增加MG的影响以及ER应力抑制对 神经网络功能。拟议的研究很重要，因为目标的完成将验证ER 压力是转化研究的潜在目标，旨在处理合并症的认知障碍 2型糖尿病。这些结果也有可能影响多种神经退行性条件， 例如阿尔茨海默氏症。除了科学工作外，这种多样性补充的重要方面是 支持非裔美国女性医学博士/博士生的职业发展。她的职业目标是 独立的医师科学家研究神经传播的变化和由 神经退行性疾病。认知障碍不成比例地影响非洲裔美国人，但非洲人 美国人在科学劳动力中的人数不足。解决Heath Research和 诊所，使该领域多样化至关重要。因此，拟议的工作和指导活动在这种多样性中 补充最终将对神经退行性领域产生持续和强大的影响 疾病。