Brainstem GABAergic Neuron Development and Function

描述（由申请人提供）：本项目旨在根据脑干GABA能（产生γ-氨基丁酸（GABA））呼吸神经元的发育基因表达及其在呼吸控制中的最终功能来定义脑干GABA能呼吸神经元。在小鼠模型系统中可用的强大的遗传工具将用于从分子上描绘GABA能亚型，然后在该图上描绘和绘制功能特性。我们假设下脑干中的GABA能呼吸神经元亚型由菱形起源组织，导致能够调节不同呼吸参数（如呼吸量，频率和形状）的回路模块，并且当被破坏时，可能在先天性呼吸异常（如SIDS）中发挥作用-SIDS是美国新生儿后期婴儿死亡的主要原因，和雷特综合征-少女发育障碍的主要原因。该研究计划建议使用Dymecki实验室开发的工具来1）定义呼吸GABA能神经元的命运作为发育基因表达的函数，2）确定这些遗传定义的GABA能神经元亚型在调节呼吸稳态中所起的作用。通过将早期基因表达与具有不同命运和功能的GABA能神经元组联系起来，我们将发现可用于模拟人类呼吸缺陷的候选发育途径。 公共卫生相关性：与公共卫生的相关性：拟议的研究将有助于建立和应用遗传系统，以定义和描述对呼吸控制重要的神经机制。由此产生的研究结果将导致对呼吸功能和功能障碍的更深入了解，包括与许多常见和衰弱，甚至危及生命的疾病相关的呼吸功能和功能障碍，例如与婴儿早产相关的呼吸异常，Retts综合征，Joubert综合征和婴儿猝死综合征，

DESCRIPTION (provided by applicant): This project aims to define brainstem GABAergic (Gamma-aminobutryc acid (GABA) - producing) respiratory neurons in terms of their developmental gene expression and ultimately their function in respiratory control. Powerful genetic tools available in the mouse model system will be used to delineate GABAergic subtypes molecularly and upon this map, functional properties will then be delineated and plotted. We hypothesize that GABAergic respiratory neuron subtypes in the lower brainstem are organized by rhombomeric origin, resulting in circuit modules capable of regulating distinct respiratory parameters such as respiratory volume, frequency and shape, and that when disrupted, may play a role in congenital respiratory abnormalities such as SIDS - the leading cause of post-neonatal infant mortality in the United States, and Rett syndrome - the leading cause of developmental disabilities in young girls. This research program proposes to use tools developed in the Dymecki lab to 1) define the fates of respiratory GABAergic neurons as a function of developmental gene expression, and 2) determine the role played by these genetically-defined GABAergic neuron subtypes in regulating respiratory homeostasis. By linking early gene expression to groups of GABAergic neurons with distinct fates and functions, we will uncover candidate developmental pathways that can be used to model respiratory defects seen in humans. PUBLIC HEALTH RELEVANCE: Relevance to public health: The proposed studies will contribute to building and applying a genetic system for defining and delineating neural mechanisms important to the control of breathing. The resulting findings will lead to a deeper understanding of respiratory function and dysfunction, including that associated with many common and debilitating, even life-threatening disorders, such as the respiratory abnormalities associated with infant prematurity, with Retts syndrome, Joubert syndrome, and sudden infant death syndrome,