Function and Property of Extrasynaptic NMDAR in Neuronal Cell Death

描述(由申请人提供)：在急性脑损伤期间，N-甲基-D-天冬氨酸受体(NMDAR)因大量释放谷氨酸而过度激活，是缺血性中风和脑创伤中神经元丢失的主要机制。虽然NMDAR的适当激活是细胞生存所必需的，但过度激活NMDAR会刺激细胞死亡信号，导致钙稳态的丧失。人们对将NMDAR作为治疗缺血性中风和其他形式的神经变性的干预措施的兴趣和需求很大。由于全面抑制所有NMDAR功能可能损害正常的脑功能，针对特定的NMDAR池或亚型可能会提高治疗价值。例如，抑制突触外NMDAR可能会减弱受体的过度激活，而不会破坏正常的突触功能。我们假设突触和突触外NMDAR的药理特性有很大的不同。为了验证这一假说并更好地了解突触外NMDAR的功能，我们将追求三个具体目标：目的1)确定突触外NMDAR在细胞死亡中的功能；目的2)确定突触外NMDAR在钙调节异常中的作用；目的3)确定突触外NMDAR与突触NMDAR之间的药理特性的差异。这项应用建议使用钙成像和分子表征来鉴定突触外NMDAR的功能和特性。这项提议的结果有望为未来通过特定阻断突触外NMDAR来减轻神经退行性变(如中风)的治疗策略奠定基础。 公共卫生相关性：在美国，中风是导致死亡和成人残疾的主要原因之一。我们研究的长期目标是开发治疗中风的分子疗法。此外，我们对分子和细胞机制的研究也可能导致其他形式的神经退行性变的治疗开发。

DESCRIPTION (provided by applicant): Overactivation of N-methyl D-aspartate receptor (NMDAR) by massive glutamate release during acute brain insults represents a major mechanism for neuronal loss in ischemic stroke and brain trauma. While proper activation of NMDAR is required for cell survival, overactivation of NMDAR stimulates cell death signaling and causes the loss of calcium homeostasis. There are significant interests and needs to target NMDAR as therapeutic interventions for ischemic stroke and other forms of neurodegeneration. Because general suppression of all NMDAR function may be detrimental to normal brain functions, targeting specific pools or subtypes of NMDAR may improve the therapeutic values. For example, inhibiting extrasynaptic NMDAR may attenuate receptor overactivation without disrupting normal synaptic functions. We hypothesize that the pharmacological property is dramatically different between synaptic and extrasynaptic NMDAR. To test the hypothesis and better understand the function of extrasynaptic NMDAR function, we will pursue 3 specific aims: Aim 1) Determine the function of extrasynaptic NMDAR in cell death; Aim 2) Determine the function of extrasynaptic NMDAR in Ca dysregulation; Aim 3) Determine the difference in pharmacological property between extrasynaptic and synaptic NMDAR. This application proposes to use calcium imaging and molecular characterization to identify the function and property of extrasynaptic NMDAR. The outcome of this proposal is expected to set the foundation for future therapeutic strategies to attenuate neurodegeneration, such as stroke, via specific blockade of extrasynaptic NMDAR. PUBLIC HEALTH RELEVANCE: Stroke is one of the major causes of mortality and adult disability in the United States. The long-term goal of our research is to develop molecular therapies for stroke. In addition, our study on molecular and cellular mechanisms may also lead to therapeutic development for other forms of neurodegeneration.