ER stress mediates methylglyoxal-evoked AIS shortening and neuronal dysfunction

项目摘要/摘要(多样性补编) 轴突起始节段(AIS)的改变是各种神经退行性变的关键病理生理机制 疾病，包括糖尿病。AIS长度的缩短已被证明降低了神经元的兴奋性，并 也与2型糖尿病和阿尔茨海默病的认知障碍有关。然而，蜂窝和 这些结构域在疾病条件下如何改变的分子机制仍然知之甚少。这 知识的严重差距限制了该领域操纵AIS进行治疗的能力。为了填补这个空白 在我们知识上的重大差距，父母资助(R01 NS107398)检验了甲基乙二醛的假设 (Mg)通过激活钙蛋白来破坏AIS蛋白复合体，并抑制神经系统功能。海流 多样性补充提案旨在阐明导致AIS缩短的更详细的机制。这个 这个应用程序的总体目标是确定一个关键的细胞机制，该机制激活钙调蛋白来响应 对MG的增加。以前的研究和这里提供的初步数据已经确定了内质网 (3)应激可能是MG引起的钙蛋白激活和AIS缩短的潜在中介。这个 假说是MG的亚致死性增加导致内质网应激，导致钙蛋白激活和AIS缩短。 我们将通过两个具体目标来检验这一假设。目标1：检验假设，与MG增加无关， 亚致死水平的内质网应激可导致钙蛋白酶激活、AIS缩短和神经元网络功能障碍。目标 2：验证内质网应激抑制可阻止MG诱导的钙蛋白酶激活、AIS缩短和 神经网络功能障碍。这个应用程序在概念上是创新的，因为我们提出ER压力是一种 MG致AIS缩短和神经元功能障碍的关键介质。多电极的创新使用 阵列将确定诱导的内质网应激和增加的MG以及内质网应激抑制的影响 神经网络功能。这项拟议的研究意义重大，因为AIMS的完成将验证ER 应激作为翻译研究的潜在靶点，旨在治疗儿童并存的认知障碍 2型糖尿病。这些结果也有可能影响各种各样的神经退行性疾病， 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 支持一名非裔美国女性医学博士/博士学生的职业发展。她的职业目标是 独立内科科学家研究神经传递和认知缺陷的变化 神经退行性疾病。认知障碍对非裔美国人的影响不成比例，但非洲人 美国人在科学劳动力中的代表性不足。为了解决卫生研究中的不公平问题， 对于诊所来说，使这一领域多样化至关重要。因此，在这一多样性中拟议的工作和指导活动 补充剂最终将对神经退行性疾病领域产生持续而强大的影响 疾病。

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.