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.
