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MACROLIDE ACCUMULATION BY HOST CELLS IN THE GINGIVA

Award Number: R21DE018804
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2009
PERIOD OF PERFORMANCE END DATE: 09/30/2013

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MACROLIDE ACCUMULATION BY HOST CELLS IN THE GINGIVA - DESCRIPTION (provided by applicant): Aggressive and recurrent forms of periodontitis are associated with infections by A. actinomycetemomitans and P. gingivalis. The ability of these pathogens to invade epithelial cells and phagocytes makes them difficult to eliminate by conventional scaling and root planing alone. However, the use of systemic antibiotics in conjunction with scaling and root planing significantly enhances clinical and microbiological treatment outcomes. While not widely prescribed by periodontists, azithromycin and clarithromycin are potentially useful because they are taken up by host cells and have favorable antimicrobial activity. Both agents can potentially attain higher levels in gingiva than in serum. Preliminary studies suggest that active transport plays an important role in this process. Cultured gingival fibroblasts, epithelial cells and PMN-like HL-60 cells appear to take up clarithromycin by a concentrative and saturable transport mechanism. Clarithromycin uptake by fibroblasts is temperature-dependent and exhibits Michaelis-Menten kinetics, suggesting the involvement of an energy-dependent transport system. We hypothesize that gingival fibroblasts, epithelial cells and PMNs possess active transporters that accumulate macrolides. These transporters play a beneficial role by enhancing macrolide levels in the soft tissue wall of the periodontal pocket, in phagocytes and in gingival crevicular fluid. Since fibroblasts are a relatively large cellular compartment of the gingiva, macrolide transporters could permit these cells to function as drug reservoirs that enhance and sustain macrolide levels in gingival connective tissue and in gingival crevicular fluid. In epithelial cells and PMNs, these transporters could facilitate elimination of invasive pathogens by enhancing intracellular macrolide accumulation. The objective of this proposal is to study mechanisms by which macrolides are transported and concentrated by host cells in the gingiva. Specific aim 1 is to characterize transport systems by which gingival fibroblasts, epithelial cells and PMNs take up these agents, using radiolabeled macrolides to assay transport activity. [Specific aim 2 is to assess the pharmacological benefits of intracellular macrolide accumulation by host cells (including effects on drug distribution). Specific Aim 3 is to assess the killing of intracellular A. actinomycetemcomitans and P. gingivalis by macrolides in cultured PMNs and gingival epithelial cells]. The broad goal of this work is to provide a rational basis for selecting the most effective agents for periodontal antimicrobial chemotherapy. Ultimately, this work could contribute to reductions in tooth loss and the cost burden of treating periodontitis. PUBLIC HEALTH RELEVANCE: This proposal will study mechanisms by which macrolide antibiotics are transported and concentrated by cells in human gingiva. Exploiting cellular accumulation of macrolides could enhance the elimination of invasive periodontal pathogens that are difficult to treat with conventional scaling and root planing. By providing a rational basis for selecting an antibiotic for periodontal antimicrobial chemotherapy, this work could ultimately contribute to reductions in tooth loss and the cost burden of treating destructive periodontitis.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2013 ( Subtotal = $0 )
2013	2010	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Oral Diseases and Disorders Research	000	2	2/20/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $0 )
2012	2010	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Oral Diseases and Disorders Research	000	2	2/27/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2010 ( Subtotal = $185,625 )
2010	2010	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Oral Diseases and Disorders Research	001	2	4/28/2010	NON-COMPETING CONTINUATION	-$185,625
2010	2010	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Oral Diseases and Disorders Research	000	2	4/6/2010	NON-COMPETING CONTINUATION	$185,625
2010	2010	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Oral Diseases and Disorders Research	004	2	5/14/2010	NON-COMPETING CONTINUATION	$185,625
2010	2010	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Oral Diseases and Disorders Research	003	2	5/6/2010	NON-COMPETING CONTINUATION	-$185,625
2010	2010	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Oral Diseases and Disorders Research	002	2	5/4/2010	NON-COMPETING CONTINUATION	$185,625
														Subtotal = $185,625

Issue Date FY: 2009 ( Subtotal = $225,000 )
2009	2009	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Oral Diseases and Disorders Research	000	1	3/6/2009	NEW	$225,000
														Subtotal = $225,000

Grand Total All Awards = $410,625

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MACROLIDE ACCUMULATION BY HOST CELLS IN THE GINGIVA

Award Number: R21DE018804

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2009

PERIOD OF PERFORMANCE END DATE: 09/30/2013

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