Integrins and mechanoreception in the inflames TMJ.

描述(申请人提供)：患有颞下颌关节紊乱病的患者经常抱怨与下颌运动相关的衰弱疼痛。颞下颌关节中的伤害性感受器通过一种称为机械接受或机械传导的过程对机械刺激作出反应。然而，感觉神经元机械接受的机制尚不清楚。最近的证据表明，细胞骨架和细胞外基质分子之间的功能联系对机械接受至关重要。此外，有证据表明，这些重要的联系是通过跨膜受体建立的，称为整合素。整合素是一种异源二聚体(即α-β异源二聚体)跨膜蛋白，它与特定的细胞外基质分子或其他细胞表面受体结合，并与细胞质蛋白连接，包括f-肌动蛋白和信号转导分子。因此，整合素在细胞外基质和细胞骨架之间建立联系，这对机械接受至关重要。这个项目将检验一个中心假设，即整合素是支配颞颌关节的感觉神经元机械接收的关键调节因素。在特定的目标#1中，我们将确定支配颞下颌关节的感觉神经元表达的特定整合素，并确定那些介导机械接受的整合素。在特定的目标#2中，我们将研究三叉神经节神经元中可能涉及整合素依赖的机械接受的潜在机制。缓激肽是一种产生于有症状的人类颞下颌关节的痛性生化物质，它通过整合素增强三叉神经节神经元的机械接受能力。在具体目标#3中，我们将确定缓激肽引起这种效应的机制。最后，在特定的目标#4中，我们将使用动物模型来确定RGD结合整合素在炎症的TMJ中作为机械接受的介体的作用。这些研究应该对TMJ疼痛和神经源性炎症所涉及的机械感受机制有一个基本的理解，有可能导致新的治疗方法。

DESCRIPTION (provided by applicant): Patients who suffer from temporomandibular joint disorders often complain of debilitating pain that is associated with jaw movement. Nociceptors in the temporomandibular joint respond to mechanical stimulation by a process referred to as mechanoreception or mechanotranduction. However, the mechanisms that underlie mechanoreception by sensory neurons are unknown. Recent evidence indicates that functional linkages between the cytoskeleton and molecules of the extracellular matrix are vital to mechanoreception. Furthermore, evidence indicates that these important linkages are established via transmembrane receptors, termed integrins. Integrins are heterodimeric (i.e., alphabeta heterodimers) transmembrane proteins that bind specific extracellular matrix molecules or other cell surface receptors and connect with cytoplasmic proteins, including f-actin and signal transduction molecules. Thus, integrins establish linkages between the extracellular matrix and the cytoskeleton that are vital to mechanoreception. This project will test the central hypothesis that integrins are key regulators of mechanoreception by sensory neurons innervating the temporomandibularjoint. In specific aim #1. we will determine the specific integrins that are expressed by sensory neurons innervating the temporomandibular joint and identify those integrins that mediate mechanoreception. In specific aim #2, we will investigate potential mechanisms that may be involved in integrin-dependent mechanoreception in trigeminal ganglion neurons. Bradykinin, a algesic biochemical produced in symptomatic human temporomandibular joints, enhances mechanoreception through integrins in trigeminal ganglion neurons. In specific aim #3, we will determine the mechanism by which bradykinin elicits this effect. Finally, in specific aim #4, we will determine the role of RGD-binding integrins as mediators of mechanoreception in the inflamed TMJ using an animal model. These studies should generate a fundamental understanding of mechanoreceptive mechanisms involved in TMJ pain and neurogenic inflammation, potentially leading to novel therapeutics.