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: 10661717
• 负责人: Jennae Nicolle Shelby
• 金额: $ 5.27万
• 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/10661717
• 关键词: ATF6 gene; Action Potentials; Address; Age; Alzheimer' s Disease; Animal Model; Apoptosis; Axon; Brain; Calcineurin; Caring; Cell Death; Cell physiology; Cells; Chronic; Cognitive; Cognitive deficits; Data; Data Analyses; Dementia; Diabetes Mellitus; Diabetic mouse; Diagnosis; Disease; Electrophysiology (science); Encephalopathies; Endoplasmic Reticulum; Family; Functional disorder; Future; Genetic; Goals; Grant; Hippocampus; Hour; Immunofluorescence Immunologic; Impaired cognition; In Vitro; Inflammation; Knowledge; Learning; Length; Link; Location; Mediator; Memory; Modeling; Mus; National Research Service Awards; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; Pathway interactions; Patient Care; Patient Representative; Patients; Phosphoric Monoester Hydrolases; Physicians; Prefrontal Cortex; Proteins; Public Health; Pyruvaldehyde; Rattus; Research; Research Design; Risk; Role; Scientist; Signal Transduction; Small Interfering RNA; Sodium phenylbutyrate; Streptozocin; Structure; Study Skills; Synapses; Synaptic Transmission; Techniques; Testing; Therapeutic Research; Training; Transfection; Tunicamycin; Western Blotting; Writing; career; career development; cognitive performance; comorbidity; db/db mouse; diabetic; diabetic rat; endoplasmic reticulum stress; experimental group; flexibility; improved; inhibitor; meter; mild cognitive impairment; morris water maze; mouse model; multi-electrode arrays; neurobehavioral test; neuronal excitability; new therapeutic target; non-diabetic; novel; patient prognosis; pharmacologic; 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.

项目摘要/摘要 轴突初始段（AIS）是神经元功能的关键介体，其结构或 位置已与几种神经退行性条件有关。在糖尿病等疾病中 阿尔茨海默氏病，有认知障碍的AI缩短了AIS。痴呆和温和认知 损害是2型糖尿病的合并症，称为糖尿病性脑病，缺乏 课程修改治疗选择。 AIS缩短可能是可逆的，因此研究机制 负责通过提供新的治疗靶标可以解决患者护理中的这一重大差距。总体 该提案的目标是检查这些患者中AIS缩短的细胞机制 在提供支持申请人职业发展所必需的培训的同时。内质 网状（ER）应力，一种激活未折叠蛋白反应（UPR）的细胞状况已有 与糖尿病性脑病有关。初步研究表明，ER应力的诱导诱导AIS缩短， ER应力的抑制可防止AIS在体外缩短。该NRSA F30提案将检验假设 内质网应力调节轴突初始段，导致2型认知障碍 利用两个目标的糖尿病。 AIM 1将检验以下假设：UPR PERK途径是ER应力的基础 诱导AIS缩短。 UPR的PERK途径激活钙调神经蛋白酶，这是一种与 AIS缩短。该目标将在药理和遗传上抑制小鼠皮质神经元培养的PERK 并评估ER应力诱导后AIS结构和神经元网络活性的变化。 AIM 2意志 测试以下假设，即ER应激抑制可改善糖尿病中的AIS缩短和认知障碍。 该目标将抑制DB/DB小鼠的ER应力，这是一种已建立的2型糖尿病模型，并评估了变化的变化。 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应力和AIS缩短为治疗靶标，以减轻糖尿病的认知障碍 脑病。该提案的完成还将为申请人的培训密钥提供机会 未来的研究目标是成为一个独立的医师科学家，研究神经传播的变化和 由神经退行性疾病引起的认知缺陷。该提议很重要，因为完成将 阐明训练2型糖尿病患者的治疗研究的靶标，以治疗这种疾病 未来的医师科学家会照顾他们。