Unfolding the Link Between the Endoplasmic Reticulum, AIS Shortening, and Cognitive Impairment in Type 2 Diabetes

揭示内质网、AIS 缩短和 2 型糖尿病认知障碍之间的联系

• 批准号: 10314355
• 负责人: Jennae Nicolle Shelby
• 金额: $ 4.34万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10314355
• 关键词: ATF6 gene; Action Potentials; Address; Age; Alzheimer' s Disease; Animal Model; Apoptosis; Axon; Brain; Caring; Cell Death; Cell physiology; Cells; Chronic; Cognitive; Cognitive deficits; Data; Data Analyses; Dementia; Diabetes Mellitus; Diagnosis; Disease; Electrophysiology (science); Encephalopathies; Endoplasmic Reticulum; Family; Functional disorder; Future; Genetic; Goals; Grant; Hippocampus (Brain); Hour; Immunofluorescence Immunologic; Impaired cognition; In Vitro; Inflammation; Knowledge; Learning; Length; Link; Location; Mediator of activation protein; Memory; Modeling; Mus; National Research Service Awards; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; PPP3CA gene; Pathway interactions; Patient Care; Patient Representative; Patients; Pharmacology; Phosphoric Monoester Hydrolases; Physicians; Prefrontal Cortex; Prognosis; Proteins; Public Health; Pyruvaldehyde; Research; Research Design; Risk; Role; Scientist; Signal Transduction; Small Interfering RNA; Sodium phenylbutyrate; Streptozocin; Structure; Study Skills; Synapses; Synaptic Transmission; Techniques; Testing; Therapeutic Human Experimentation; Training; Tunicamycin; Western Blotting; Writing; career; career development; cognitive performance; comorbidity; db/db mouse; diabetic; diabetic rat; endoplasmic reticulum stress; experimental group; flexibility; improved; inhibitor/antagonist; mild cognitive impairment; morris water maze; mouse model; multi-electrode arrays; neurobehavioral test; neuronal excitability; new therapeutic target; non-diabetic; novel; post stroke; prevent; protein folding; response; sensor; targeted treatment; therapeutic target; training opportunity

Project Summary/Abstract The axon initial segment (AIS) is a critical mediator of neuronal function, and changes in its structure or location have been implicated in several neurodegenerative conditions. In diseases such as diabetes and Alzheimer's disease, there is a shortening of the AIS with cognitive impairment. Dementia and mild cognitive impairment are well recognized comorbidities of type 2 diabetes, termed diabetic encephalopathy, that lack in course modifying treatment options. AIS shortening may be reversible, hence investigating the mechanism responsible could address this significant gap in patient care by providing new therapeutic targets. The overall goal of this proposal is to examine the cellular mechanisms responsible for AIS shortening in these patients while providing the training necessary to support the career development of the applicant. Endoplasmic reticulum (ER) stress, a cellular condition that activates the unfolded protein response (UPR) has been implicated in diabetic encephalopathy. Preliminary studies show induction of ER stress induces AIS shortening, and inhibition of ER stress prevents AIS shortening in vitro. This NRSA F30 proposal will test the hypothesis that endoplasmic reticulum stress modulates the axon initial segment leading to cognitive impairment in type 2 diabetes utilizing two aims. Aim 1 will test the hypothesis that the UPR PERK pathway underlies ER stress- induced AIS shortening. The PERK pathway of the UPR activates calcineurin, a phosphatase associated with AIS shortening. This aim will pharmacologically and genetically inhibit PERK in mouse cortical neuron culture and evaluate changes in AIS structure and neuronal network activity following ER stress induction. Aim 2 will test the hypothesis that ER stress inhibition ameliorates AIS shortening and cognitive impairment in diabetes. This aim will inhibit ER stress in db/db mice, an established model of type 2 diabetes, and evaluate changes in cognitive performance and AIS structure. Confirmation of the central hypothesis in the proposed study will identify ER stress and AIS shortening as therapeutic targets to mitigate cognitive impairment in diabetic encephalopathy. Completion of this proposal will also provide opportunities for training key to the applicant's future research goal to be an independent physician scientist studying changes in neural transmission and cognitive defects caused by neurodegenerative diseases. This proposal is significant because completion will elucidate a target for therapeutic research to treat this condition in patients with type 2 diabetes while training a future physician scientist who will care for them.

项目总结/摘要 轴突起始段（AIS）是神经元功能的关键介质，其结构或功能的变化可能是神经元轴突起始段（AIS）的一个重要因素。 位置与几种神经退行性疾病有关。在糖尿病和 老年痴呆症，有一个缩短的AIS与认知功能障碍。痴呆和轻度认知 损伤是公认2型糖尿病的合并症，称为糖尿病脑病， 改变治疗方案。AIS缩短可能是可逆的，因此研究其机制 Responsible可以通过提供新的治疗靶点来解决患者护理中的这一重大差距。整体 这项计划的目的是研究这些患者AIS缩短的细胞机制 同时提供必要的培训，以支持申请人的职业发展。内质 内质网（ER）应激，一种激活未折叠蛋白反应（UPR）的细胞条件， 与糖尿病脑病有关初步研究表明，ER应激的诱导可诱导AIS缩短， 并且抑制ER应激防止体外AIS缩短。NRSA F30提案将检验这一假设 内质网应激调节轴突起始段，导致2型认知障碍 糖尿病有两个目的。目的1将检验UPR PERK通路是ER应激的基础的假设- 导致AIS缩短。UPR的PERK途径激活钙调神经磷酸酶，一种与 AIS缩短。这一目标将在药理学和遗传学上抑制小鼠皮质神经元培养物中的PERK 并评估ER应激诱导后AIS结构和神经元网络活性的变化。目标2将 测试ER应激抑制改善糖尿病患者AIS缩短和认知障碍的假设。 这一目标将抑制db/db小鼠（一种已建立的2型糖尿病模型）中的ER应激，并评估 认知性能和AIS结构。在拟议的研究中确认中心假设将 确定ER应激和AIS缩短作为治疗靶点以减轻糖尿病患者的认知障碍 脑病完成本建议书还将提供培训机会， 未来的研究目标是成为一名独立的医生科学家，研究神经传递的变化， 由神经退行性疾病引起的认知缺陷。这一建议意义重大，因为完成后， 阐明治疗研究的目标，以治疗2型糖尿病患者的这种情况，同时训练 未来的医生科学家来照顾他们。