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Clonal hematopoiesis and periodontal disease

Award Number: R01DE033643
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: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Clonal hematopoiesis and periodontal disease - Project Summary With aging, hematopoietic stem and progenitor cells (HSPC) in the bone marrow (BM) accumulate somatic mutations that may confer a proliferative advantage to the mutant cell; this enhanced clonal expansion gives rise to mutant progeny cells which (i) comprise an outsized fraction of leukocytes in the peripheral blood and tissues and (ii) typically have increased proinflammatory activity relative to normal leukocytes. In individuals with no overt hematological malignancy, this age-related acquisition of somatic mutations that confer HSPC clonal expansion advantage is designated clonal hematopoiesis of indeterminate potential (CHIP). CHIP affects >10% of individuals older than 65 and predominantly involves genes encoding epigenetic regulators, such as, DNMT3A (DNA methyltransferase 3A), which is the most commonly mutated gene in CHIP. CHIP has thus far been conclusively linked with increased risk of hematologic malignancies and atherosclerotic cardiovascular disease. We hypothesized that the generation in the BM and release in the circulation of CHIP-mutant leukocytes may contribute to increased inflammatory destruction in tissues where they are recruited, such as the inflamed periodontium. Our overall objective is to show that DNMT3A-driven CHIP increases the severity of periodontal disease and to investigate the underlying mechanisms. Our hypothesis will be addressed in preclinical models of CHIP and ligature-induced periodontitis in mice. CHIP will be modelled with Dnmt3aR878H/+ HSPC derived from mice that harbor a mutation (R878H) that is equivalent to the human hotspot heterozygous mutation (R882H), which causes a dominant negative loss of DNMT3A methylation activity. The experimental system involves competitive BM transplantation with clinically relevant 10% CHIP-mutant cells (Dnmt3aR878H/+ CD45.2+ cells) and 90% wild-type CD45.1+ cells in CD45.1 recipient mice. Control CD45.1 recipient mice will be transplanted with 10% Dnmt3a+/+ CD45.2+ cells and 90% wild-type CD45.1+ cells, i.e., exclusively normal BM cells. In Specific Aim 1, we will investigate whether the expansion of Dnmt3a mutant clones is associated with exacerbation of periodontal disease (‘to establish PHENOTYPE’). In Specific Aim 2, our objective is to establish a mechanistic basis that can link DNMT3A-driven CHIP and periodontal disease (‘to establish MECHANISM’). In Specific Aim 3, we explore intervention approaches to block the expansion of Dnmt3a mutant clones and their impact on periodontal disease (‘to develop THERAPY’). Our project can potentially implicate CHIP as a causal link between aging and periodontal disease. If the hypothesis is confirmed and the proposed treatment is successful, screening of the elderly for CHIP may identify individuals with increased risk for periodontal disease. Such patients may benefit from preventive treatments aiming to block the aberrant expansion of CHIP mutant clones and their harmful impact on periodontal disease (as well as on comorbidities that are also exacerbated by CHIP, such as cardiovascular disease).


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 = $345,313 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Oral Diseases and Disorders Research	001	2	5/8/2025	NON-COMPETING CONTINUATION	$34,532
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Oral Diseases and Disorders Research	000	2	3/7/2025	NON-COMPETING CONTINUATION	$310,781
														Subtotal = $345,313

Issue Date FY: 2024 ( Subtotal = $345,313 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Oral Diseases and Disorders Research	000	1	2/29/2024	NEW	$345,313
														Subtotal = $345,313

Grand Total All Awards = $690,626

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Clonal hematopoiesis and periodontal disease

Award Number: R01DE033643

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: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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