Functional Roles of Integrins in Modulating Neural Responses of Mechanically Sens

描述（由申请人提供）：研究者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触觉如何改变，并利用这些知识改善触觉退化患者的治疗。触觉的显著丧失导致生活质量的深刻变化，并且可导致外周组织的严重变性的发展（例如，糖尿病神经病变中的手或脚）。目前的建议，旨在调查的功能作用，跨膜蛋白，整合素，发挥调节神经反应的皮肤机械感受器。理论上，整联蛋白将机械感受器的感受性末梢偶联至细胞外基质（ECM），并且特别是胶原。软组织的机械强度和顺应性主要是由于胶原蛋白，其承载在压缩和/或拉伸期间产生的机械应力场。因此，通过将机械感受器偶联至ECM，整联蛋白可以起到调节机械感受器对机械刺激的转导的作用。据推测，皮肤机械感受器中整合素的破坏将增加阈值并降低神经响应对受控机械负荷的敏感性。本研究以大鼠为模型，主要目的如下：1）确定特定类型的皮肤机械感受器和机械伤害感受器的感受性末梢中表达的不同类型的整合素; 2）测量从细胞外基质中解耦的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;和3）测量将细胞骨架与整联蛋白的胞质结构域解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对侧后肢采集的皮肤。功能研究将使用一个发育良好的，孤立的大鼠皮肤神经模型，允许记录从单个神经元，同时施加受控的机械压缩，张力，或组合负载到他们的感受野。所获得的结果将进一步我们的理解的分子和细胞的事件参与机械转导皮肤mechanoreceptors。

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.