Defining Astrocyte Heterogeneity in the Retrotrapezoid Nucleus

 描述(申请人提供)：中枢化学接收是大脑调节呼吸的机制，以响应位于脑干感觉的组织pH-CO2/H+传感器的变化。pH变化调节呼吸深度和频率。药物敏感性在睡眠中尤其重要，它的中断与几种病理状态有关，包括睡眠呼吸暂停、Rett综合征、癫痫原因不明的猝死和中风引起的呼吸功能障碍。尽管有一致的研究，但化学感受的细胞和分子基础还没有完全阐明。特别是，脑干星形胶质细胞的一部分已被证明具有中枢化学感受器的功能，但关于这些细胞的分子识别尚不清楚。这项研究的长期目标是了解星形胶质细胞化学感受器的独特功能，以及这些细胞是如何专门支持呼吸过程的。这一应用的中心假设是星形胶质细胞化学感受器是一个功能离散的群体，它表达一个独特的分子信号，然后可以用来将这些细胞与更大的星形胶质细胞群体区分开来。我还提出，星形胶质细胞化学感受器是专门调节呼吸控制的，因此对于对化学药物敏感的呼吸中心是独一无二的。这项拟议的研究将使用电生理和单细胞转录组分析相结合的方法来确定RTN中对化疗敏感的星形胶质细胞的独特分子特征。该项目的两个目标是：1)确定功能不同的RTN星形胶质细胞群体的转录组；2)研究在其他延髓脑干呼吸中心是否发现了对化疗敏感的星形胶质细胞。这项工作的结果将识别对化疗敏感的RTN星形胶质细胞的分子特征，并通过这样做使分子工具的开发成为可能，该工具将允许选择性地标记和操纵这一特定的星形胶质细胞亚群。这项工作还可能通过确定新的潜在治疗靶点来治疗呼吸控制问题，从而具有直接的临床意义。此外，作为这一计划的一部分 研究培训计划我将学习各种新的分子、细胞和遗传学方法，我可以将这些方法应用于了解神经胶质生理学的重要问题上，从而使我处于竞争地位，获得独立的学术研究职位。

 DESCRIPTION (provided by applicant): Central chemoreception is the mechanism by which the brain regulates breathing in response to changes in tissue pH -CO2/H+ sensors located in the brainstem sense pH changes to regulate depth and frequency of breathing. Chemosensitivity is especially important during sleep and its disruption has been associated with several pathological states including sleep apnea, Rett syndrome, sudden unexplained death in epilepsy and stroke-induced respiratory dysfunction. Despite concerted investigation, the cellular and molecular basis for chemoreception has not been fully elucidated. In particular, a subset of brainstem astrocytes have been shown to function as central chemoreceptors, yet nothing is known regarding the molecular identify of these cells. The long term objective of this research is to understand the unique function of astrocyte chemoreceptors, and how these cells are specialized to support the process of breathing. The central hypothesis of this application is that astrocyte chemoreceptors are a functionally discrete population that expresses a unique molecular signature that can then be used to distinguish these cells from the larger astroglial population. I also propose that astrocyte chemoreceptors are specialized to regulate respiratory control and as such are unique to chemosensitive respiratory centres. The proposed research will use a combination of electrophysiological and single-cell transcriptome analysis to determine the unique molecular signature of chemosensitive astrocytes in the RTN. The two aims of this project are: 1) determine the transcriptome of functionally distinct populations of RTN astrocytes, and 2) investigate whether chemosensitive astrocytes are found in other medullary brainstem respiratory centers. Results of this work will identify the molecular signature of chemosensitive RTN astrocytes, and in doing so make possible the development of molecular tools that will allow selective labeling and manipulation of this specific astrocyte subset. This work may also have immediate clinical relevance by identifying new potential therapeutic targets for the treatment of respiratory control problems. Furthermore, as part of this research training plan I will learn a variety of new molecular, cellular and genetic approaches that I can bring to bear on issues important for understanding glial physiology and thus place me in a competitive position to obtain an independent academic research position.