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

项目摘要/摘要 轴突起始段(AIS)是神经元功能的重要中介，其结构或功能的改变 位置与几种神经退行性疾病有关。在糖尿病和其他疾病中 阿尔茨海默病，有一种缩短的AIS，伴有认知障碍。痴呆症与轻度认知障碍 损害是公认的2型糖尿病的合并症，称为糖尿病脑病，缺乏 修改疗程治疗方案。AIS缩短可能是可逆的，因此研究了其机制 负责任可以通过提供新的治疗靶点来解决患者护理方面的这一重大缺口。整体而言 这项建议的目的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 网织应激(ER)是一种激活未折叠蛋白反应(UPR)的细胞状态，已被 与糖尿病脑病有关。初步研究表明，内质网应激诱导AIS缩短， 在体外，抑制内质网应激可阻止AIS缩短。这份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 糖尿病利用两个目的。目标1将检验UPR PERK通路是内质网应激的基础的假设- 诱发AIS缩短。UPR的PERK途径激活钙调神经磷酸酶，这是一种与 人工智能在缩写。这一目标将在药物和遗传上抑制小鼠皮质神经元培养中的PERK 并评价内质网应激诱导后AIS结构和神经元网络活动的变化。目标2将 检验内质网应激抑制改善糖尿病患者AIS缩短和认知损害的假设。 这一目标将抑制db/db小鼠的内质网应激，这是一种已建立的2型糖尿病模型，并评估 认知表现与AIS结构。对拟议研究中的中心假设的确认将 确定内质网应激和AIS缩短作为减轻糖尿病患者认知损害的治疗靶点 脑病。这项提案的完成还将为申请人提供培训关键 未来的研究目标是成为一名独立的内科科学家，研究神经传递和 由神经退行性疾病引起的认知缺陷。这项提议意义重大，因为完成后 阐明治疗研究的目标，以治疗2型糖尿病患者，同时训练 未来的内科科学家会照顾他们。

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.