Saliva performs a number of extremely important biological functions that are instrumental in maintaining oral health. It has been estimated that more than 2 million people in the U.S. is compromised by from salivary gland dysfunction. Secretion of saliva is driven by concerted activities of a number of ion channels and transporters. Although, it is well established that calcium is the primary intracellular factor which regulates fluid secretion, the molecular mechanism involved in the regulation of cytosolic calcium is not clearly understood. This is primarily due to the absence of information regarding the calcium channels present in salivary glands. Moreover, in Sjogren's syndrome patients, although the acinar tissues appear to be normal, they do not function properly and have a decreased calcium response to agonist-stimulation. This observation raises the possibility that calcium channels might be altered in this pathological condition. Members of the Transient Receptor Potential (TRP) superfamily have been identified as calcium channels, which could be important in agonist-stimulated fluid secretion. Therefore, this study is designed to thoroughly characterize the role of cytosolic calcium in salivary gland function and to determine the relationship between transient receptor potential (TRPC1) protein-1 and saliva secretion. Our preliminary data indicates that TRP proteins are expressed in salivary glands and are involved in salivary secretion. The hypothesis of this study is that since calcium plays a pivotal role in the physiological function of salivary glands, characterization of calcium channels in salivary glands will be important to understand the mechanism of saliva secretion, which could represent as drug targets in salivary gland dysfunction. We will coordinate our efforts in order to determine the functional significance of TRPC1 channel protein by examining its effect by gene disruption using TRPC1 knockout mice.
In Aim 2, we will investigate the localization and biochemical characterization of TRPC1 protein in mouse submandibular gland cells.
Aim 3 will identify the mechanism involved in the regulation of TRPC1 protein. The results of our studies are expected to provide new insights into the role of calcium channels and the molecular mechanism involved in saliva secretion. Greater understanding of these events responsible for saliva secretion will be important in elucidating new therapy for salivary gland dysfunction. ? ? ?
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