Genetic Control of Nociceptive Sensory Neuron Development and Pain Behavior

描述（由申请人提供）：长期目标是确定控制特定感觉通路形成的遗传程序，并深入了解疼痛感知的分子和细胞基础。在这个更新应用程序中，我们试图解决两个主要的知识缺口。首先，大多数临床相关的疼痛来源于深层组织，如肌肉、关节、骨骼和内脏器官。尽管有临床意义，分子

DESCRIPTION (provided by applicant): The long-range goal is to identify the genetic programs controlling the formations of specific sensory pathways and to gain insight into the molecular and cellular basis of pain perception. In this renewal application, we try to address two major knowledge gaps. First, most clinically relevant pain is derived from deep tissues, such as muscle, joint, bone, and visceral organs. Despite this clinical significance, the molecular and cellular basis of "deep" pain is still poorly understood, which is in stark contrast to the tremendous progress made in the past decades in understanding cutaneous pain. In Aim 1 studies, we will establish a molecular map for sensory neurons innervating distinct deep tissues. We will also determine if Meis1 represents the first transcription factor that controls the development of deep tissue sensory neurons. Second, the cellular basis of mechanical allodynia (pain evoked by innocuous mechanical stimuli), a hallmark for most, if not all, chronic pain disorders, needs further clarification. In case of neuropathic pain, it was proposed that central disinhibition will allow low threshold myelinated A� mechanoreceptors to directly activate the pain pathways. However, a recent study proposed that unmyelinated low threshold c- mechanoreceptors, marked by the expression of the vesticular glutamate transporter VGLUT3, may play an essential role in the readout of the mechanical allodynia. Our preliminary genetic fate-mapping studies show that VGLUT3 lineage neurons are in fact composed of both 1) unmyelinated c-mechanoreceptors that form free nerve endings in the skin epidermis and lanceolate endings around hair follicles, and 2) myelinated m-mechanoreceptors that form the Merkel-cell neurite complex. In Aim 2, we will determine if Zfp521, a transcription factor expressed exclusively in VGLUT3 lineage c-mechanoreceptor, is necessary for the development of these c-mechnaoreceptors. We will also determine if mechanical allodynia is differentially affected in mice that will have a selective developmental defect in VGLUT3 lineage c- mechanoreceptors or a defect in the VGLUT3-expressing Merkel cell-neurite complex. Together, these studies will gain insight into 1) the genetic programs that control the formation of the deep tissue pain pathways, and 2) the identities of low threshold mechanoreceptors mediating the readout of mechanical allodynia.