CALCIUM SIGNALING AND CELL DEATH IN CELLULAR MODELS OF ALZHEIMER AND PARKINSON'S

神经退行性综合征，如阿尔茨海默病（AD）和帕金森病（PD） 疾病的特点是选择性的，不适当的死亡， 特定的中枢神经元这种疾病流行， 毁灭性的，昂贵的人类生命和医疗保健资金。电流 治疗主要是对症治疗， 进展理解选择性神经元的细胞基础 脆弱性将加速新疗法的发现。这个项目 研究线粒体DNA（mtDNA）缺陷的生物学后果 的AD，比较他们与PD，通过研究模型神经细胞与 患者的mtDNA这是一个项目的一部分，组织检查 AD和线粒体功能与阿尔茨海默病的关系 疾病 选择性神经脆弱性意味着死亡是由一种独特的侮辱造成的 对人群来说，一个特殊的表型易感性， 侮辱，或者两者兼而有之。AD和PD患者的线粒体 可能与特定神经元表型结合联合收割机的电子链缺陷 和/或环境以产生对细胞死亡的增强的脆弱性。的 AD和PD mtDNA对诱导细胞死亡敏感性的影响将 在胞质杂种模型和原代神经元培养物中进行检查和比较。 大多数细胞死亡事件都具有某些特征。细胞凋亡是一个过程 通过转录依赖性细胞死亡去除神经。诱导 将区分凋亡过程与坏死序列， 在模型文化中进行了研究。细胞内Ca/2+和Ca ~（2+）的调节 活性氧（ROS）的产生在生物体内起着重要作用 唱歌引发细胞死亡。AD和PD线粒体DNA对细胞的影响 将研究Ca/2+、Ca/2+缓冲性能和ROS产生， 使用荧光测定法和比率荧光测定法， 细胞和单个识别的神经元中。神经营养生长因子具有 在某些情况下可以保护神经元免于细胞死亡。 这些信号分子对Ca/2+处理和ROS产生的影响 将在从细胞死亡中拯救时进行检查。研究目标是 通过衡量ETC的项目间合作和比较得到加强 活性，胞质杂种模型神经元中的细胞死亡遗传程序， 体内自由基生成的改变。的结果予以 研究将确定线粒体DNA缺陷的具体细胞后果， 患者对模型神经元背景中细胞死亡的调节。 线粒体DNA赋予神经脆弱性的知识将预测 最好的治疗，以克服缺陷，规避或延迟神经 死亡

Neurodegenerative syndromes such as Alzheimer's (AD) and Parkinson's (PD) diseases are characterized by the selective, inappropriate death of specific central neurons. The disease are prevalent, progressively devastating, and costly of human lives and health care dollars. Current treatments are primarily symptomatic and do not health disease progression. Understanding the cellular basis of selective neuronal vulnerability will hasten discovery of novel treatments. This project examines the biological consequences of mitochondrial DNA (mtDNA) defects of AD, comparing them to those of PD, by studying a model neural cell with mtDNA from patients. It is part of a Program Project organized to examine aspects of AD and mitochondrial function in relation to Alzheimer's disease. Selective neural vulnerability implies death results from an unique insult to the population, an exceptional phenotypic susceptibility to a general insult, or a combination. Mitochondria from AD and PD patients have electron chain defects that may combine with specific neuronal phenotypes and/or circumstances to yield enhanced vulnerability to cell death. The influence of AD and PD mtDNA upon sensitivity to induced cell death will be examined and compared in cybrid models and primary neuronal cultures. Most cell death events share certain features. Apoptosis is a process for neural removal via transcription-dependent cell death. Induction of apoptotic processes versus necrotic sequences will be distinguished and examined in the model cultures. The regulation of cytosolic Ca/2+ and generation of reactive oxygen species (ROS) are known to play central role sin triggering cell death. The influence of AD and PD mtDNA upon cell Ca/2+, Ca/2+ buffering performance and ROS production will be studied, using fluorescence assays and ratio fluorimetry in groups of cultured cells and in single, identified neurons. Neurotrophic growth factors have been shown to protect neurons from cell death in certain circumstances. The effects of these signal molecules on Ca/2+ handling and ROS production will be examined during rescue from cell death. The research goals are enhanced by inter-projected collaborations and comparisons measuring ETC activity, the cell death genetic program in the cybrid model neurons and alterations in free-radical generation in vivo. The results of these studies will define the specific cellular consequences of mtDNA defects in patients to the regulation of cell death in a model neuron background. Knowledge of the neural vulnerability conferred by the mtDNA will predict the best therapy to overcome the defects and circumvent or delay neural death.