Molecular Interactions Between Angiotensin and NMDA Receptors

血管紧张素是一种小肽，因其在调节血压、饮酒行为、神经内分泌功能和组织生长方面的作用而闻名，它至少部分通过激活特定的血管紧张素受体来实现，这些受体耦合到独特的细胞信号通路和基因表达模式。最近，Weyhenmeyer博士和其他人已经证明血管紧张素可以调节选定神经元的存活和/或死亡，因此可能在大脑发育、衰老和功能方面具有重要意义。事实上，这些初步研究表明，血管紧张素可能通过改变受N-甲基-D-天冬氨酸(NMDA)(谷氨酸)受体调控的死亡和生存基因的表达来影响神经细胞死亡。拟议中的研究将通过识别和表征血管紧张素调节NMDA受体诱导的细胞死亡程序能力的分子机制来扩展Weyhenmeyer博士的初步发现。这些研究将特别集中于确定血管紧张素和NMDA受体信号通路之间的汇合点，这些信号通路影响下游基因的表达(对于已知和新的死亡和生存基因)。拟议的研究对于我们理解程序性细胞死亡具有广泛的意义，程序性细胞死亡不仅是正常大脑发育和功能的一部分，而且似乎是老化神经系统退行性疾病(如中风、痴呆)的重要病理因素。

Angiotensin is a small peptide known for its role in regulating blood pressure, drinking behavior, neuroendocrine function, and tissue growth, which it accomplishes, at least in part, by activating specific Angiotensin receptors that are coupled to unique cell signaling pathways and gene expression patterns. Recently, Dr. Weyhenmeyer and others have shown that angiotensin can regulate the survival and/or death of selected neurons, and as such may have important implications in brain development, aging, and function. Indeed, these preliminary studies suggest that angiotensin may influence neuronal cell death by altering the expression of death and survival genes that are regulated by the N-methyl-D-aspartate (NMDA) (glutamate) receptor. The proposed studies will extend Dr. Weyhenmeyer preliminary findings by identifying and characterizing the molecular mechanisms that underlie angiotensin's ability to modulate the NMDA receptor-induced cell death programs. These studies will specifically focus on identifying points of convergence between the angiotensin and NMDA receptor signaling pathways that affect downstream gene expression (for both known and novel death and survival genes). The proposed studies have wide ranging implications regarding our understanding of the programmed cell death that is not only part of normal brain development and function, but also appears to be a significant contributor to the pathology in degenerative disorder (e.g., stroke, dementia) of the aging nervous system.