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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要/摘要轴突初始段 (AIS) 是神经元功能的关键介质，其结构或变化位置与多种神经退行性疾病有关。在糖尿病等疾病中阿尔茨海默病，AIS 缩短并伴有认知障碍。痴呆症和轻度认知障碍损伤是 2 型糖尿病公认的合并症，称为糖尿病脑病，缺乏课程修改治疗方案。 AIS 缩短可能是可逆的，因此研究其机制负责人可以通过提供新的治疗目标来解决患者护理方面的这一重大差距。整体该提案的目标是检查导致这些患者 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。内质网状（ER）应激是一种激活未折叠蛋白反应（UPR）的细胞状况与糖尿病脑病有关。初步研究表明 ER 应激的诱导会导致 AIS 缩短，抑制 ER 应激可防止体外 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标。目标 1 将检验以下假设：UPR PERK 通路是 ER 应激的基础引起 AIS 缩短。 UPR 的 PERK 通路激活钙调神经磷酸酶，这是一种与 AIS 缩短。这一目标将从药理学和遗传学上抑制小鼠皮层神经元培养物中的 PERK 并评估 ER 应激诱导后 AIS 结构和神经元网络活动的变化。目标2将检验 ER 应激抑制可改善糖尿病患者 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）的 ER 应激，并评估认知表现和 AIS 结构。拟议研究中中心假设的确认将确定 ER 应激和 AIS 缩短作为减轻糖尿病认知障碍的治疗目标脑病。完成该提案还将为申请人提供关键的培训机会未来的研究目标是成为一名独立的医师科学家，研究神经传递和神经传递的变化神经退行性疾病引起的认知缺陷。该提案意义重大，因为完成后将阐明治疗研究的目标，以治疗 2 型糖尿病患者的这种情况，同时培训未来的医学科学家将照顾他们。