Roles of Astrocytic G Protein-Coupled Signaling in Memory

描述（由申请人提供）：记忆丧失在老年人群中普遍存在，并且是阿尔茨海默病（AD）的关键特征，AD是最常见的年龄相关神经退行性疾病。随着全球人口的老龄化，我们必须确定记忆的机制，并找到有效的策略来防止记忆丧失。星形胶质细胞在记忆中的作用知之甚少。这位候选人的初步研究结果表明，星形胶质细胞中的G蛋白偶联信号会影响长期记忆。在小鼠中，星形胶质细胞GS偶联受体的激活干扰了长期记忆，而星形胶质细胞GS偶联腺苷受体表达的减少增强了长期记忆。在AD患者的死后人脑组织中发现这种受体的水平增加。这些发现提出了一种有趣的可能性，即星形胶质细胞的GS偶联受体调节长期的细胞周期。 导致记忆力减退。然而，目前还不知道这些星形胶质细胞受体如何调节记忆。这项研究的主要目的是确定星形胶质细胞的Gs-coupled信号如何影响记忆的神经过程。通过使用已建立的转基因小鼠和化学遗传学技术，拟议的研究将确定星形胶质细胞GS偶联受体信号传导是否影响神经元立即早期基因表达（Aim 1），神经网络振荡（Aim 2）和神经元可塑性（Aim 3），所有这些都与记忆的机制有关。这些研究还将确定星形胶质细胞GS偶联受体（Aim 3）下游的信号传导机制。这些研究有望揭示新的记忆相关的神经生物学过程，推进我们对星形胶质细胞功能的理解，并揭示衰老和疾病中记忆丧失的新治疗策略。指导研究将使候选人能够将星形胶质细胞信号与复杂的神经过程联系起来，并确定星形胶质细胞信号在突触，细胞和网络水平上的影响。候选人的短期目标是1）获得与记忆机制相关的额外培训，2）获得职业培训并获得独立的终身教职，3）获得资金支持她对星形胶质细胞受体信号在记忆中的作用的独立研究。候选人的长期目标是推进研究工作，阐明星形胶质细胞信号传导在认知，脑老化和神经缺陷中的性质和功能，并开发针对星形胶质细胞的新的治疗策略。 受体信号传导机制来调节疾病过程。拟议的研究和职业培训将使候选人能够制定一个强大的独立研究计划，重点是星形胶质细胞-神经元相互作用在健康和疾病中的作用。格拉德斯通研究所和加州大学旧金山分校将为开展拟议的培训提供理想的学术环境。一个主要的导师和一个咨询委员会将为候选人提供相关的专业知识，资源和指导，以进行拟议的研究，并成为一名独立的调查员。

DESCRIPTION (provided by applicant): Memory loss is prevalent in the aging population and is a key feature of Alzheimer's disease (AD), the most common age-related neurodegenerative disorder. As the global population ages, we must define the mechanisms underlying memory and find effective strategies to prevent memory loss. The roles of astrocytes in memory are poorly understood. The candidate's preliminary findings suggest that G protein-coupled signaling in astrocytes affects long-term memory. In mice, the activation of astrocytic Gs-coupled receptors interfered with long-term memory, while reduction in the expression of an astrocytic Gs-coupled adenosine receptor enhanced long-term memory. The levels of this receptor were found to be increased in postmortem human brain tissue from AD patients. These findings raise the intriguing possibilities that astrocytic Gs-coupled receptors regulate long-term memory and contribute to memory loss. However, it is not known how these astrocytic receptors regulate memory. The main objective of the proposed research is to determine how astrocytic Gs-coupled signaling affects the neural processes underlying memory. By using established transgenic mice and chemogenetic techniques, the proposed studies will determine if astrocytic Gs-coupled receptor signaling influences neuronal immediate early gene expression (Aim 1), neural network oscillations (Aim 2) and neuronal plasticity (Aim 3), all of which have been implicated in the mechanisms that underlie memory. The studies will also define the signaling mechanisms downstream of astrocytic Gs-coupled receptors (Aim 3). These studies promise to reveal novel memory-linked neurobiological processes, advance our understanding of astrocytic functions and uncover new therapeutic strategies for memory loss in aging and disease. Mentored research will enable the candidate to link astrocytic signaling with complex neural processes and determine the effects of astrocytic signaling at the synaptic, cellular and network levels. The short-term goals of the candidate are to 1) obtain additional training related to the mechanisms of memory, 2) obtain career training and secure an independent tenure-track faculty position, and 3) receive funding to support her independent research on the roles of astrocytic receptor signaling in memory. The long-term goals of the candidate are to advance research efforts that elucidate the nature and functions of astrocytic signaling in cognition, brai aging and neurological deficits, and to develop novel therapeutic strategies that target astrocytic receptor signaling mechanisms to modulate disease processes. The proposed research and career training will enable the candidate to develop a strong independent research program focusing on the roles of astrocytic-neuronal interactions in health and disease. The Gladstone Institutes and UCSF will provide an ideal academic environment for carrying out the proposed training. A primary mentor and an advisory committee will provide the candidate with the pertinent expertise, resources and guidance for carrying out the proposed research and becoming an independent investigator.