Molecular Biology of Oral Alkali Production

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DESCRIPTION (provided by applicant): In this competing renewal we focus our efforts on 3 fundamental areas directly related to the molecular biology, physiology and role in oral diseases of alkali production by oral bacteria. We continue the work we pioneered on the molecular genetics of arginine catabolism in Streptococcus gordonii, focusing primarily on the complexities of regulation by environmental pH and growth domain. The second focus area builds on work we initiated during the previous grant period on the arginine deiminase system (ADS) of Streptococcus rattus, which has lead to new discoveries of ADS-associated regulatory proteins present in both ADS and non-ADS oral streptococci. The final focus area builds on discoveries and progress made over the last 3 years on a novel ammonia-producing pathway in Streptococcus mutans--the agmatine deiminase system (AgDS). The AgDS is part of the acid-adaptive regimen of S. mutans, but we also revealed that the system is a critical ecological determinant that is disseminated in streptococci. The goal of the proposed experimentation on the AgDS of S. mutans is to understand the molecular basis for the complex regulation by factors that profoundly influence oral ecology and oral disease progression. Collectively, these studies will provide new fundamental knowledge of the genetics and physiology of oral ammonia production and will be invaluable in developing therapeutic strategies that exploit alkali generation to modulate oral biofilm composition and activity in a way that promotes healthy plaque ecology and inhibits development of oral diseases. To accomplish our goals, we have organized, our studies into the following Specific Aims: 1. Analysis of the molecular basis for pH and post-exponential phase induction of the arginine deiminase system of Streptococcus gordonii. 2. Dissection of the role of arginine deiminase regulatory proteins in mutans streptococci. 3. Structure:function relationships in AguR, the transcriptional activator of the S. mutans agmatine deiminase system.