Functional Roles of Integrins in Modulating Neural Responses of Mechanically Sens

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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.