INJURY RESPONSES IN ALZHEIMER DISEASE AND OTHER HUMAN CONDITIONS

阿尔茨海默病和其他人类疾病的损伤反应

• 批准号: 5204959
• 负责人: Sue Tilton Griffin
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5204959
• 关键词: Alzheimer's disease; amyloid proteins; amyloidosis; apolipoproteins; astrocytes; cellular pathology; coronary artery; coronary disorder; gene expression; glia; head /neck injury; human genetic material tag; human tissue; immunocytochemistry; interleukin 1; messenger RNA; microglia; molecular pathology; neural degeneration; neuritic plaques; neurofibrillary tangles; neurotrophic factors; partial seizure; pathologic process; temporal lobe /cortex disorder

The objective of Project One is to address the idea that overexpression of glia-derived cytokines, especially interleukin-1 (IL-1), is a seminal event in the pathogenesis of Alzheimer's disease (AD), giving rise to a two-armed cascade of cellular and molecular events that lead to neuron cell dysfunctions, including accumulation of neurofibrillary tangles and overgrowth of neurites, and eventually death which induces further overexpression of IL-1 in what becomes then a self-propagating "system" or cascade. In AD, we seek evidence of the involvement of cascade-related cellular and molecular events in the presumed neuropathological progression that accounts for the progressive nature of the dementia by determining their interrelationships with regard to: (i) specific plaque types and (ii) the recognized regional distribution of neuropathological changes in AD. In head injury, a recently established risk factor for later development of AD, we can know the time and age at onset, severity, and clinical course and thus relate these parameters to the distribution of plaques according to type within as well as across brain regions. In non-demented critical coronary artery disease (cCAD) patients where significant AD-like neuropathological changes have been observed, we seek to clarify the relationship of these changes to AD as we: (i) compare their regional distribution to that in AD and (ii) assess the potential involvement of cascade-related cellular and molecular events in specific plaque types within and across brain regions. In refractory temporal epilepsy, where we have evidence that some cascade-related cellular and molecular events occur, we seek to: (i) evaluate spatial relationships between defined epileptogenic foci and these events and (ii) compare these with those occurring in AD, head injury, and cCAD. A number of molecular techniques routine to our laboratory will be used to address our specific aims, which at successful completion will provide information regarding the generalizability of our proposed cascade--a necessity if it is to be useful in developing rational therapeutic strategies.

项目一的目标是解决过度表达 胶质细胞源性细胞因子，特别是白细胞介素-1（IL-1）， 阿尔茨海默病（AD）发病机制中的事件，引起 细胞和分子事件的双臂级联， 细胞功能障碍，包括神经纤维缠结的积累， 神经突的过度生长，最终导致死亡， IL-1的过度表达，然后变成一个自我繁殖的“系统”， 或级联。 在AD中，我们寻找级联相关细胞参与的证据， 以及假定的神经病理学进展中的分子事件， 解释了痴呆症的进展性质， 关于以下方面的相互关系：（i）特定斑块类型和（ii） 公认的AD神经病理学改变的区域分布。 在头部受伤，最近建立的风险因素，为以后的发展 AD的发病时间、发病年龄、严重程度、临床表现等， 并因此将这些参数与斑块的分布相关联 根据大脑区域内和跨区域的类型。 在非痴呆重症冠心病（cCAD）患者中， 已经观察到显著的AD样神经病理学变化，我们寻求 为了澄清这些变化与AD的关系，我们：（i）比较 它们的区域分布与AD中的分布，以及（ii）评估 级联相关的细胞和分子事件参与特定的 大脑区域内和跨大脑区域的斑块类型。 在难治性颞叶癫痫中，我们有证据表明， 级联相关的细胞和分子事件发生时，我们寻求：（i） 评价明确的致痫灶之间的空间关系， 这些事件和（ii）比较这些与发生在AD，头部 损伤和cCAD。 我们实验室的一些常规分子技术将被使用 实现我们的具体目标，这些目标在成功完成后将提供 关于我们提出的级联的普遍性的信息-a 如果要在开发合理的治疗方法中发挥作用， 战略布局