Molecular control of spinal relay sensory neuron phenoypes and pain behaviors

描述(申请人提供)：这次竞争性更新之前的R01的长期目标是研究控制脊髓背部疼痛中继感觉神经元表型的遗传程序。在之前的资助期间，我和我的同事们编制了小鼠神经系统转录因子的基因组规模表达图。后来的遗传学研究表明，Tlx3是一种同源盒类转录因子，是脊髓中继性感觉神经元的关键调节因子，包括谷氨酸和多肽类神经递质的指定。此外，Tlx3在成年动物中的持续表达仅限于可能的痛觉传递神经元所在的浅层。这里描述的研究建立在这项前期工作的基础上。我们未来五年的研究目标是阐明Tlx3在调节脊髓中继性伤害性感受器表型和疼痛行为中的作用，并深入了解疼痛感知的分子和细胞基础。我们有四个具体目标。目的1是确定Tlx3在控制对痛觉至关重要的上行投射神经元发育中的作用。目的2是确定Tlx3的动态表达如何控制背侧脊髓的板层组织。目的3确定Tlx3在维持背角兴奋性神经元表型中的作用，从而确定Tlx3介导的核心转录程序是否为治疗疼痛的潜在靶点。目的4确定依赖于Tlx3的分化程序在控制疼痛行为中的作用。这些目标中的每一个都建立在一组初步数据的基础上，这些数据导致了一个可检验的假设。我们已经开发的一组遗传工具将检验这些假说的预测。

DESCRIPTION (provided by applicant): The long-range goal of this competitive renewal of a previous R01 is to investigate genetic programs that control pain relay sensory neuron phenotypes in the dorsal spinal cord. During the previous funding interval, my colleagues and I have compiled a genome-scale expression map of transcription factors in the mouse nervous system. Subsequent genetic studies demonstrate that Tlx3, a homeobox class transcription factor, is a pivotal regulator of spinal relay sensory neurons, including specification of both glutamate and peptide neurotransmitters. Furthermore, persistent Tlx3 expression in adult animals is confined to superficial laminae, where putative pain relay neurons are located. The research described here builds upon this preliminary work. The goal of our research over the next five years is to illustrate the roles of Tlx3 in regulating spinal relay nociceptor phenotypes and pain behaviors and to gain insights into the molecular and cellular basis underlying pain perception. We have four specific Aims. Aim 1 is to determine the roles of Tlx3 in controlling the development of ascending projection neurons that are critical for pain perception. Aim 2 is to determine how dynamic Tlx3 expression controls lamina organization of the dorsal spinal cord. Aim 3 is determine the roles of Tlx3 in maintaining dorsal horn excitatory neuron phenotypes, thereby determining if Tlx3-mediated core transcription program is a potential target for pain treatment. Aim 4 is to determine the roles of Tlx3-dependent differentiation programs in controlling pain behaviors. Each of these aims is built upon a set of preliminary data that lead to a testable hypothesis. A panel of genetic tools that we have already developed will test the predictions of these hypotheses.