The Biology of Microglia: Adenosine A3 Receptor Suppression

小胶质细胞是存在于大脑和脊髓范围内的免疫细胞。以前认为小胶质细胞只是神经元的支持细胞，现在很清楚，小胶质细胞有许多重要的作用：它们是塑造发育和成熟神经系统细胞结构的雕塑家，修改神经元电路的电工，以及保护大脑和脊髓的监护人。小胶质细胞如何承担这些不同的任务还不清楚。我的研究和培训计划侧重于了解小胶质细胞的基本生物学和控制这些细胞活动的核心过程。我们最近取得了令人兴奋的发现，即小胶质细胞受腺苷A3受体（A3 R）的调节-这些受体保持小胶质细胞的活性。拟议的研究剖析了A3 R信号传导的基本步骤（“坚果和螺栓”）以及对小胶质细胞如何与其他细胞沟通的影响。实验还将研究A3 R控制转录因子Runx 1活性的机制，以及驱动A3 R介导的白细胞介素-10释放的过程，白细胞介素-10是一种关键的小胶质细胞信号分子。我们将使用先进的生物化学，分子和成像方法来解构A3 R如何控制小胶质细胞功能。这一新知识将对理解小胶质细胞通信产生直接影响，并为更广泛地理解整个中枢神经系统的小胶质细胞生物学形成一个概念框架。这项研究的核心是培养高素质的个人，他们将成为学术界、政府和工业界未来的领导者。

Microglia are immune cells that reside within the confines of the brain and spinal cord. Previously assumed to be merely support cells for neurons, it is now clear that microglia have many important roles: they are sculptors that shape the cellular architecture of the developing and mature nervous system, electricians that modify neuronal circuitry, and guardians that protect the brain and spinal cord. How microglia undertake these different tasks is not well understood. My research and training program focuses on understanding the fundamental biology of microglia and the core processes that control activity of these cells. We recently made the exciting discovery that microglia are regulated by adenosine A3 receptors (A3R) - these receptors keep microglia activity in check. The proposed research dissects the essential steps in A3R signaling (`the nuts and bolts') and the impact on how microglia communicate with other cells. Experiments will also examine the machinery by which A3R controls activity of the transcription factor Runx1 and the process that drives A3R-mediated release of interleukin-10, a key microglia signaling molecule. We will use advanced biochemical, molecular, and imaging approaches to deconstruct how A3R controls microglia function. This new knowledge will have direct implications for understanding microglia communication, and form a conceptual framework for broader understanding of microglia biology throughout the central nervous system. At the core of this proposed research is the training of highly qualified individuals who will become future leaders in academia, government, and industry.