Functional Roles of Integrins in Modulating Neural Responses of Mechanically Sens

描述(申请人提供)：研究人员的长期目标是阐明触觉形成的基本机制，以及在疾病和损伤过程中它是如何改变的，并利用这些知识来改进对触觉退化患者的治疗。严重的触摸丧失会导致生活质量的深刻变化，并可能导致周围组织的严重退化(例如，糖尿病神经病变中的手或脚)。目前的建议试图调查跨膜蛋白，整合素，在调节皮肤机械感受器的神经反应中所起的功能作用。理论上，整合素将机械感受器的感受端与细胞外基质(ECM)，特别是与胶原蛋白偶联。软组织的机械强度和顺应性主要是由于胶原蛋白，它承载了在压缩和/或拉伸过程中形成的机械应力场。因此，通过将机械感受器偶联到细胞外基质，整合素可能发挥功能来调节机械感受器对机械刺激的转导。有人假设，破坏皮肤机械感受器中的整合素将提高阈值，降低神经对受控机械负荷的反应的敏感性。利用大鼠模型，该项目包括以下具体目标：1)确定在特定类型的皮肤机械感受器和机械伤害性感受器的感受器末端表达的不同类型的整合素；2)测量从细胞外基质解偶联整合素对皮肤机械感受器对受控机械负荷的神经元反应的影响；以及3)测量将整合素的细胞骨架与整合素的细胞质结构域去偶联对皮肤机械感受器对受控机械负荷的神经元反应的影响。免疫组织化学研究将使用从麻醉大鼠大腿内侧采集的皮肤，以及在功能研究期间从另一只后肢采集的皮肤。功能研究将使用一个发展良好的、孤立的大鼠皮肤神经模型，该模型允许从单个神经元进行记录，同时对其感受场施加受控的机械压缩、拉伸或组合载荷。所获得的结果将进一步加深我们对皮肤机械感受器参与机械转导的分子和细胞事件的理解。

DESCRIPTION (provided by applicant): The long-term objectives of the investigators are to elucidate fundamental mechanisms whereby touch sensation is developed, how it is altered in the course of disease and injury, and to use that knowledge to improve treatments of patients who have suffered degradation of touch sensation. Significant loss of touch leads to profound changes in the quality of life, and can lead to the development of severe degeneration of peripheral tissues (e.g., hands or feet in diabetic neuropathy). The current proposal seeks to investigate the functional roles that trans-membrane proteins, integrins, play in modulating neural responses of cutaneous mechanoreceptors. It is theorized that integrins couple the receptive endings of mechanoreceptors to the extracellular matrix (ECM), and especially to collagen. The mechanical strength and compliance of soft tissues is predominantly due to collagen, which carries the mechanical stress field developed during compression &/or stretch. Hence, by coupling mechanoreceptors to the ECM, integrins may function to modulate the transduction of mechanical stimuli by mechanoreceptors. It is hypothesized that disruption of integrins in cutaneous mechanoreceptors will increase thresholds and decrease sensitivity of neural responses to controlled mechanical loads. Using a rat model, the project consists of the following specific aims: 1) Determine the different types of integrins expressed in receptive endings of specific types of cutaneous mechanoreceptors and mechano-nociceptors; 2) Measure the effects of decoupling integrins from the extracellular matrix on the neuronal response of cutaneous mechanoreceptors to controlled mechanical loading; and 3) Measure the effects of decoupling the cytoskeleton from the cytoplasmic domains of integrins on the neuronal response of cutaneous mechanoreceptors to controlled mechanical loading. Immunohistochemical studies will use skin harvested from the medial thigh of anesthetized rats, as well as skin from the opposite hindlimb during functional studies. Functional studies will use a well-developed, isolated rat skin-nerve model that allows recording from single neurons while applying controlled mechanical compression, tension, or combined loadings to their receptive fields. Results obtained will further our understanding of the molecular and cellular events involved in mechanotransduction by cutaneous mechanoreceptors.