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Neurological control of periodontal homeostasis through microRNA, TGF-beta, and Wnt signaling

Award Number: R01DE027930
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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The periodontium is a richly innervated tissue that undergoes continuous modelling and remodeling by alveolar bone osteoblasts, osteocytes, and osteoclasts. Studies from our laboratory have demonstrated a close spatial relationship between trigeminal nerve ganglia and the Epithelial Rests of Malassez (ERM), an epithelial cell network residing within the non-mineralized periodontal ligament. Inferior alveolar nerve (IAN) transection studies resulting in dento-alveolar ankylosis and a reduction in ERM have confirmed the essential role of sensory innervation for periodontal homeostasis. For the present application, we have established the IAN transection model in our laboratory and provided radiographic evidence for enhanced mineralization and ankylosis in the periodontal region of rat molars. Gene expression profiling comparing IAN transected and control tissues demonstrated an unexpected 28-fold significant increase in galanin (GAL) and a more than two-fold decrease in the TGF-ß signaling molecules Smad2, Smad3 and Tgf-ß1, and the Wnt inhibitors Dkk1, Dkk2 and Gsk-3ß. In the same IAN transection group, microRNA miR-92b expression was more than two-fold upregulated, as verified via miRNA profiling and RT-PCR. MiR-92b upregulation after IAN transection in conjunction with bioinformatics data implicating Wnt and Tgf-ß as possible miR-92b targets prompted us to speculate that GAL affects its skeletogenic downstream effects through miR-92b. In vitro studies revealed that GAL treatment promoted osteogenic differentiation of PDL progenitors and increased mineralization, while reducing osteoclastogenesis of BMMCs. Block of RhoA or application of GAL antagonist affected PDL cytoskeletal organization and gene expression, indicating that GAL functions through G protein coupled receptors. IWhen applied to periodontal pockets of animals suffering from periodontitis, GAL tissue engineering constructs accomplished a 20% increase in alveolar bone levels compared to controls, resulting in a clinically significant increase in alveolar bone height. Based on this promising new set of data we have designed a research plan to define the role of GAL in response to IAN transection, determine the mechanism underlying its effect on skeletogenesis, and exploit its applicability for bone regeneration and the prevention of periodontal ankylosis. The overall goal of our research plan is to test the hypothesis that periodontal nerves affect alveolar bone homeostasis through a GAL–GPCR–miR-92b–TGF-ß/Wnt regulatory loop and that application of GAL neurosecretory peptides will stimulate Wnt signaling and new bone formation. We anticipate that the outcomes of our study will lead to innovative neuropeptide based/engineering hybrid approaches that will restore periodontal health in millions of patients and prevent the emotional and functional scars associated with lost teeth and incomplete dentitions.


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: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Oral Diseases and Disorders Research	001	7	12/26/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$356,214
2024	2022	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Oral Diseases and Disorders Research	000	6	12/23/2023	NON-COMPETING CONTINUATION	-$356,214
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Oral Diseases and Disorders Research	000	6	7/21/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $356,214 )
2022	2022	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Oral Diseases and Disorders Research	000	6	5/19/2022	NON-COMPETING CONTINUATION	$356,214
														Subtotal = $356,214

Issue Date FY: 2021 ( Subtotal = $359,813 )
2021	2021	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Oral Diseases and Disorders Research	000	5	5/19/2021	NON-COMPETING CONTINUATION	$359,813
														Subtotal = $359,813

Issue Date FY: 2020 ( Subtotal = $356,945 )
2020	2020	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Oral Diseases and Disorders Research	003	4	5/27/2020	NON-COMPETING CONTINUATION	$343,750
2020	2019	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Oral Diseases and Disorders Research	001	3	4/27/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$200,514
2020	2019	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Oral Diseases and Disorders Research	002	3	5/22/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2020	2019	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Oral Diseases and Disorders Research	000	2	4/24/2020	NON-COMPETING CONTINUATION	-$187,319
2020	2019	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Oral Diseases and Disorders Research	004	2	9/5/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $356,945

Issue Date FY: 2019 ( Subtotal = $341,169 )
2019	2019	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Oral Diseases and Disorders Research	000	2	5/29/2019	NON-COMPETING CONTINUATION	$341,169
														Subtotal = $341,169

Issue Date FY: 2018 ( Subtotal = $341,169 )
2018	2018	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Oral Diseases and Disorders Research	000	1	8/4/2018	NEW	$341,169
														Subtotal = $341,169

Grand Total All Awards = $1,755,310

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Neurological control of periodontal homeostasis through microRNA, TGF-beta, and Wnt signaling

Award Number: R01DE027930

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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