Molecular control of spinal relay sensory neuron phenoypes and pain behaviors

描述（由申请人提供）：先前R01的这种竞争性更新的长期目标是研究控制脊髓背侧疼痛中继感觉神经元表型的遗传程序。在上一个资助期间，我和我的同事已经编制了小鼠神经系统中转录因子的基因组规模表达图谱。随后的遗传学研究表明，Tlx3，同源异型盒类转录因子，是脊髓中继感觉神经元的关键调节因子，包括谷氨酸和肽类神经递质的指定。此外，在成年动物中持续Tlx3表达仅限于浅层，其中假定的疼痛中继神经元位于。这里所描述的研究建立在这一初步工作的基础上。我们未来五年研究的目标是阐明Tlx3在调节脊髓中继伤害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在控制对疼痛感知至关重要的上行投射神经元发育中的作用。目的2是确定动态Tlx3表达如何控制脊髓背侧的椎板组织。目的三是确定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是疼痛治疗的潜在靶点。目的4是确定Tlx3依赖的分化程序在控制疼痛行为中的作用。每一个目标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测试这些假设的预测。 公共卫生相关性：疼痛管理仍然是各种人类疾病的主要医学问题。此外，慢性疼痛与更糟糕的疾病结果和抑郁症有关。随着时间的推移，这项工作可能使我们能够确定Tlx3介导的核心转录程序是否是疼痛管理的有效和新颖的治疗靶点。

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. PUBLIC HEALTH RELEVANCE: Pain management remains a major medical problem in a variety of human diseases. Chronic pain, moreover, is associated with worse disease outcome and depression. In the fullness of time, the work may allow us to determine whether the Tlx3-mediated core transcriptional program is a valid and novel therapeutic target for pain management.