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Oral Epithelial Cells, Candida and PMN Activation

Award Number: R01DE013986
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: 09/29/2000
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Oral Epithelial Cells, Candida and PMN Activation - PROJECT SUMMARY The oral mucosal microbiota is a complex ecosystem primarily represented by bacteria and fungi. Most oropharyngeal fungal infections are caused by the genus Candida and are assumed to result from an overgrowth of indigenous species, primarily C. albicans. C. albicans is a commensal colonizer of the oral mucosa in humans, but is also responsible for infections afflicting immunocompromised hosts. Persistent oropharyngeal thrush is refractory to most antifungals and a significant clinical problem in pharmacologically immunosuppressed patients. Corticosteroid-induced and chemotherapy-induced immunosuppression, are two main risk factors for oropharyngeal candidiasis in humans. C. albicans also causes fungemia, a serious consequence of cancer cytotoxic chemotherapy, which is thought to develop from fungal translocation through compromised mucosal barriers. Changes in endogenous bacterial population size or composition and in the host environment can transform fungal commensals into pathobionts. Work in our previous funding cycle established a synergistic relationship of mitis group streptococci with C. albicans in the pathogenesis of oral candidiasis. We identified mechanisms of synergy which involved both a direct effect on fungal virulence gene expression and a modification of host responses. In this project we will build on our ongoing studies examining the interplay of the resident oral mucosal bacterial microbiota and C. albicans. We will use mouse models of commensal colonization or mucosal infection to interrogate oral bacterial microbiome parameters that promote C. albicans virulence. In aim 1 we will characterize dysbiotic changes in mucosa-associated bacterial communities in oropharyngeal candidiasis, using our established mouse models of cortisone- and chemotherapy-induced immunosuppression. We will then test the hypothesis that certain endogenous bacterial species isolated from dysbiotic states can exhibit pathogenic synergy with C. albicans. In aim 2 we will define the regulatory mechanisms of fungal-bacterial mucosal biofilm growth in each immunosuppression state. Finally, in aim 3 we will examine the role of the dysbiotic communities and host response in mucosal barrier breach and bloodstream dissemination by C. albicans. The proposed studies have the potential to lead to a paradigm shift in how clinicians and scientists view the microbiome changes characterizing mucosal Candida infections. This project will identify certain oral bacteria as new, clinically relevant mediators of invasive fungal infections thus providing justification for the combined use of antifungal and anti-bacterial treatments in at risk patients. A better understanding of the relationship between fungi and the oral microbiome could also result in new biomarkers of infection risk or identification of probiotic commensals that could lower the likelihood of invasive mucosal candidiasis in high-risk populations such as patients undergoing intensive cancer chemotherapy.


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: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Oral Diseases and Disorders Research	000	20	5/7/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $507,193 )
2024	2024	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Oral Diseases and Disorders Research	000	20	7/23/2024	NON-COMPETING CONTINUATION	$507,193
														Subtotal = $507,193

Issue Date FY: 2023 ( Subtotal = $585,220 )
2023	2023	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Oral Diseases and Disorders Research	000	19	7/17/2023	NON-COMPETING CONTINUATION	$585,220
														Subtotal = $585,220

Issue Date FY: 2022 ( Subtotal = $564,656 )
2022	2022	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Oral Diseases and Disorders Research	000	18	7/18/2022	NON-COMPETING CONTINUATION	$564,656
														Subtotal = $564,656

Issue Date FY: 2021 ( Subtotal = $576,344 )
2021	2021	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Oral Diseases and Disorders Research	002	17	7/14/2021	NON-COMPETING CONTINUATION	$576,344
2021	2020	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Oral Diseases and Disorders Research	001	16	2/2/2021	COMPETING CONTINUATION	$53
2021	2018	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Oral Diseases and Disorders Research	000	15	2/2/2021	NON-COMPETING CONTINUATION	-$53
														Subtotal = $576,344

Issue Date FY: 2020 ( Subtotal = $576,344 )
2020	2020	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Oral Diseases and Disorders Research	000	16	7/31/2020	COMPETING CONTINUATION	$576,344
														Subtotal = $576,344

Issue Date FY: 2018 ( Subtotal = $398,750 )
2018	2018	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Oral Diseases and Disorders Research	000	15	4/24/2018	NON-COMPETING CONTINUATION	$398,750
														Subtotal = $398,750

Issue Date FY: 2017 ( Subtotal = $398,750 )
2017	2017	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Oral Diseases and Disorders Research	000	14	5/19/2017	NON-COMPETING CONTINUATION	$398,750
														Subtotal = $398,750

Issue Date FY: 2016 ( Subtotal = $398,750 )
2016	2016	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON CENTER	FARMINGTON	CT	06030	CAPITOL	USA	Oral Diseases and Disorders Research	000	13	4/6/2016	NON-COMPETING CONTINUATION	$398,750
														Subtotal = $398,750

Issue Date FY: 2015 ( Subtotal = $398,583 )
2015	2015	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON CENTER	FARMINGTON	CT	06030	CAPITOL	USA	Oral Diseases and Disorders Research	000	12	4/2/2015	NON-COMPETING CONTINUATION	$398,583
														Subtotal = $398,583

Issue Date FY: 2014 ( Subtotal = $412,250 )
2014	2014	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON CENTER	FARMINGTON	CT	06030	CAPITOL	USA	Oral Diseases and Disorders Research	001	11	7/3/2014	COMPETING CONTINUATION	-$32,155
2014	2014	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON CENTER	FARMINGTON	CT	06030	CAPITOL	USA	Oral Diseases and Disorders Research	000	11	6/27/2014	COMPETING CONTINUATION	$444,405
														Subtotal = $412,250

Issue Date FY: 2013 ( Subtotal = $0 )
2013	2011	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON CENTER	FARMINGTON	CT	06032	CAPITOL	USA	Oral Diseases and Disorders Research	000	10	5/24/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2011 ( Subtotal = $503,652 )
2011	2011	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON CENTER	FARMINGTON	CT	06030	CAPITOL	USA	Oral Diseases and Disorders Research	000	10	6/13/2011	NON-COMPETING CONTINUATION	$503,652
														Subtotal = $503,652

Issue Date FY: 2010 ( Subtotal = $623,078 )
2010	2010	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON CENTER	FARMINGTON	CT	06030	CAPITOL	USA	Oral Diseases and Disorders Research	001	9	6/9/2010	NON-COMPETING CONTINUATION	$514,782
2010	2009	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON CENTER	FARMINGTON	CT	06030	CAPITOL	USA	Trans-NIH Recovery Act Research Support	000	8	2/3/2010	SUPPLEMENT FOR EXPANSION	$108,296
														Subtotal = $623,078

Issue Date FY: 2009 ( Subtotal = $611,990 )
2009	2009	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON CENTER	FARMINGTON	CT	06030	CAPITOL	USA	Trans-NIH Recovery Act Research Support	001	8	9/18/2009	SUPPLEMENT FOR EXPANSION	$105,142
2009	2009	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON CENTER	FARMINGTON	CT	06030	CAPITOL	USA	Oral Diseases and Disorders Research	000	8	5/29/2009	NON-COMPETING CONTINUATION	$506,848
														Subtotal = $611,990

Issue Date FY: 2008 ( Subtotal = $401,595 )
2008	2008	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON CENTER	FARMINGTON	CT	06032	CAPITOL	USA	Oral Diseases and Disorders Research	000	7	4/25/2008	COMPETING CONTINUATION	$401,595
														Subtotal = $401,595

Issue Date FY: 2006 ( Subtotal = $318,584 )
2006	2006	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON CENTER	FARMINGTON	CT	06032	CAPITOL	USA	Oral Diseases and Disorders Research	000	6	6/30/2006	NON-COMPETING CONTINUATION	$318,584
														Subtotal = $318,584

Issue Date FY: 2005 ( Subtotal = $290,000 )
2005	2005	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON CENTER	FARMINGTON	CT	06032	CAPITOL	USA	Oral Diseases and Disorders Research	000	5	6/17/2005	NON-COMPETING CONTINUATION	$290,000
														Subtotal = $290,000

Issue Date FY: 2004 ( Subtotal = $290,000 )
2004	2004	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON CENTER	FARMINGTON	CT	06032	CAPITOL	USA	Oral Diseases and Disorders Research	000	4	9/28/2004	COMPETING CONTINUATION	$290,000
														Subtotal = $290,000

Issue Date FY: 2002 ( Subtotal = $184,875 )
2002	2002	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON CENTER	FARMINGTON	CT	06032	CAPITOL	USA	Oral Diseases and Disorders Research	000	3	8/8/2002	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$184,875
														Subtotal = $184,875

Issue Date FY: 2001 ( Subtotal = $217,388 )
2001	2001	COLUMBIA UNIVERSITY, SCHOOL OF ARTS & SCIENCES	106 LOW LIBRARY	NEW YORK-NEW YORK	NY	10027		USA	Oral Diseases and Disorders Research	000	2	7/30/2001	NON-COMPETING CONTINUATION	$217,388
														Subtotal = $217,388

Issue Date FY: 2000 ( Subtotal = $217,388 )
2000	2000	COLUMBIA UNIVERSITY, SCHOOL OF ARTS & SCIENCES	106 LOW LIBRARY	NEW YORK-NEW YORK	NY	10027		USA	Oral Diseases and Disorders Research	000	1	9/15/2000	NEW	$217,388
														Subtotal = $217,388

Grand Total All Awards = $8,475,390

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Oral Epithelial Cells, Candida and PMN Activation

Award Number: R01DE013986

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: 09/29/2000

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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