Defining Astrocyte Heterogeneity in the Retrotrapezoid Nucleus

定义梯形后核中星形胶质细胞的异质性

• 批准号: 8910089
• 负责人: Virginia Hawkins
• 金额: $ 6万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8910089
• 关键词: Astrocytes; Biological Markers; Brain; Brain Stem; Breathing; Carbon Dioxide; Cell Nucleus; Cell physiology; Cells; Cessation of life; Characteristics; Chemoreceptors; Complement; Development; Epilepsy; Foundations; Frequencies; Functional disorder; Gene Expression Profile; Gene Expression Profiling; Goals; Heterogeneity; Individual; Investigation; Knowledge; Label; Learning; Modeling; Molecular; Molecular Profiling; Neurons; Neurotransmitters; Output; Pathology; Physiology; Population; Population Heterogeneity; Positioning Attribute; Process; Property; Regulation; Research; Research Training; Respiratory Center; Rett Syndrome; Role; Site; Sleep; Sleep Apnea Syndromes; Stroke; Techniques; Testing; Tissues; Ursidae Family; Work; base; cell type; clinically relevant; extracellular; genetic approach; genetic profiling; mind control; new therapeutic target; next generation sequencing; public health relevance; respiratory; response; sensor; therapeutic target; tool

 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.

 描述（由申请人提供）：中枢化学感受是大脑调节呼吸的机制，以响应位于脑干中的组织pH -CO2/H+传感器的变化，感知pH变化以调节呼吸的深度和频率。化学敏感性在睡眠期间尤其重要，并且其破坏与几种病理状态相关，包括睡眠呼吸暂停、Rett综合征、癫痫中的不明原因猝死和中风引起的呼吸功能障碍。尽管协调一致的调查，细胞和分子的化学感受的基础尚未完全阐明。特别是，脑干星形胶质细胞的一个子集已被证明作为中央化学感受器，但没有什么是已知的关于这些细胞的分子鉴定。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，以及这些细胞如何专门支持呼吸过程。本申请的中心假设是星形胶质细胞化学感受器是功能离散的群体，其表达独特的分子特征，然后可用于将这些细胞与较大的星形胶质细胞群体区分开。我还提出，星形胶质细胞化学感受器专门调节呼吸控制，因此是独特的化学敏感的呼吸中心。拟议的研究将使用电生理学和单细胞转录组分析的组合来确定RTN中化学敏感性星形胶质细胞的独特分子特征。该项目的两个目的是：1）确定RTN星形胶质细胞功能不同群体的转录组，2）研究是否在其他延髓脑干呼吸中心发现化学敏感性星形胶质细胞。这项工作的结果将确定化学敏感的RTN星形胶质细胞的分子特征，并在这样做使得可能的分子工具，将允许选择性标记和操纵这个特定的星形胶质细胞子集的发展。这项工作也可能有直接的临床意义，通过确定新的潜在的治疗目标，治疗呼吸控制问题。此外，作为这一 研究培训计划我将学习各种新的分子，细胞和遗传学方法，我可以把对理解神经胶质生理学的重要问题承担，从而使我处于竞争地位，以获得一个独立的学术研究职位。