The long term goal of this research is to determine the mechanisms for sorting and storage of regulated secretory proteins in salivary glands. Aggregation is thought to play a role in this process in endocrine and exocrine cells, but aggregation has not been demonstrated specifically for salivary proteins. Aggregation may involve low pH, calcium or sulfated proteoglycans. We have tested these possibilities and found that in rat parotid secretory granules, parotid secretory protein (PSP) and a 32 kD protein (p32) aggregate at low pH, while other granule proteins do not aggregate. This result suggests that parotid granule proteins exhibit selective aggregation. Unlike non-aggregating exocrine proteins, PSP is sorted to the regulated secretory pathway in endocrine and neuroendocrine cells. Thus, it appears that aggregation is correlated with sorting to the regulated secretory pathway in these cell types. As a complement to this aggregation, it has long been assumed that sulfated proteoglycans play a role in the storage of secretory proteins in secretory granules. We have, for the first time, found that inhibition of proteoglycan synthesis in parotid tissue slices leads to increased basal secretion of PSP and, to a smaller extent amylase. This result suggests that these proteins are diverted from the regulated secretory pathway in the absence of proteoglycans. Since it is known that PSP and p32 are selectively retained in maturing secretory granules, we propose that parotid secretory proteins are sorted and retained in secretory granules by selective aggregation while non-aggregated proteins are secreted by the constitutive-like secretory pathway. To test this hypothesis, we will characterize the sorting and aggregation properties of rat PSP.
Specific aim 1 will determine the aggregation properties of parotid secretory proteins. The aggregation of secretory proteins from isolated parotid granules will be tested and correlated with their secretion by the regulated or constitutive-like secretory pathways.
In specific aim 2, the role of proteoglycans in sorting and aggregation of granule proteins will be tested.
Specific aim 3 will test the sorting of PSP in endocrine and neuroendocrine cells. We have recently found that aggregation is necessary for sorting of an endocrine protein in endocrine cells, but not in neuroendocrine cells.
In specific aim 4, we will determine if aggregation is necessary for sorting of PSP in endocrine and neuroendocrine cells. This research will for the first time show the aggregation properties of salivary proteins and determine the role of aggregation and proteoglycans in sorting of parotid secretory proteins. Elucidating the mechanisms for sorting and storage of secretory proteins in salivary glands will aid in the selection or design of therapeutic peptides to be expressed in the regulated secretory pathway and saliva.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Oral Biology and Medicine Subcommittee 1 (OBM)
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Kousvelari, Eleni
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University of Louisville
Schools of Dentistry
United States
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Gorr, Sven-Ulrik (2012) Antimicrobial peptides in periodontal innate defense. Front Oral Biol 15:84-98
Gorr, Sven-Ulrik; Abdolhosseini, Mahsa (2011) Antimicrobial peptides and periodontal disease. J Clin Periodontol 38 Suppl 11:126-41
Venkatesh, S G; Goyal, D; Carenbauer, A L et al. (2011) Parotid secretory protein binds phosphatidylinositol (3,4) bisphosphate. J Dent Res 90:1085-90
Gorr, Sven-Ulrik; Abdolhosseini, Mahsa; Shelar, Anuradha et al. (2011) Dual host-defence functions of SPLUNC2/PSP and synthetic peptides derived from the protein. Biochem Soc Trans 39:1028-32
Gorr, Sven-Ulrik (2009) Antimicrobial peptides of the oral cavity. Periodontol 2000 51:152-80
Fasciotto, Brigitte H; Kuhn, Ulrike; Cohn, David V et al. (2008) Secretory cargo composition affects polarized secretion in MDCK epithelial cells. Mol Cell Biochem 310:67-75
Venkatesh, Srirangapatnam G; Tan, Jinlian; Gorr, Sven-Ulrik et al. (2007) Isoproterenol increases sorting of parotid gland cargo proteins to the basolateral pathway. Am J Physiol Cell Physiol 293:C558-65
Shiba, Hideki; Venkatesh, S G; Gorr, Sven-Ulrik et al. (2005) Parotid secretory protein is expressed and inducible in human gingival keratinocytes. J Periodontal Res 40:153-7
Geetha, C; Venkatesh, S G; Bingle, L et al. (2005) Design and validation of anti-inflammatory peptides from human parotid secretory protein. J Dent Res 84:149-53
Gorr, S-U; Venkatesh, S G; Darling, D S (2005) Parotid secretory granules: crossroads of secretory pathways and protein storage. J Dent Res 84:500-9

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