ABSTRACT Dry eyes and contact lens wear often cause foreign body sensation. This abnormal mechanosensation is associated with “Lid Wiper Epitheliopathy” (LWE), a condition induced by the mechanical damage to the marginal palpebral conjunctiva (also known as “lid wiper”). However, the underlying neurosensory mechanism remains elusive. We recently found that a population of primary sensory neurons defined by the expression of MrgprD selectively innervates the lid wiper and is sensitive to shear force. This proposal aims to determine whether MrgprD-expressing sensory fibers mediate ocular mechanosensation and regulate lacrimation. In Aim 1, we will characterize the innervations and mechanosensitivity of MrgprD-expressing sensory fibers in the lid wiper. Using genetic labeling and axonal tracing approaches, we will perform detailed anatomical analysis of organization and terminal ultrastructure of MrgprD-expressing sensory fibers in the lid wiper. In addition, we will test whether MrgprD-expressing sensory fibers in the lid wiper can be activated by shear force by conducting ex vivo calcium imaging. These studies will shed light on the role of MrgprD-expressing sensory fibers in ocular mechanosensation. In Aim 2, we will further determine whether MrgprD-expressing sensory fibers sense shear force during eye movements. We will determine whether genetic ablation or pharmacological silencing of MrgprD-expressing neurons alleviates the ocular mechanosensation induced by enhanced shear force. This study will provide insight on the neurosensory mechanism of the lid wiper mechanosensation. In Aim 3, we will determine whether the lid wiper mechanosensation regulates lacrimation to maintain the lubrication of the ocular surface. Specifically, we will examine whether ablation of MrgprD-expressing sensory fibers affects basal lacrimation and mechanically-induced lacrimation. Furthermore, we will test whether chemogenetic activation of MrgprD-expressing sensory fibers in the lid wiper promotes lacrimation. Finally, we will determine whether pharmacological activation of MrgprD-expressing sensory fibers is a potential therapeutic strategy for promoting lacrimation under dry eye conditions. These studies will reveal the neural basis of ocular mechanosensation associated with physiological tear evaporations and pathological dryness of the ocular surface, which will have a significant impact in our understanding of ocular mechanosensation as a protective mechanism and its clinical implication in dry eye treatments.