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microRNA regulation of osteocyte metabolism in bone remodeling

Award Number: F30DE029986
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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microRNA regulation of osteocyte metabolism in bone remodeling - Matrix turnover in bone occurs through bone remodeling and is essential to maintaining bone homeostasis and health. Osteocytes, which are cells embedded in the bone matrix, regulate bone remodeling both directly by controlling the activity of osteoblasts and osteoclasts and indirectly through perilacunar/canalicular remodeling (PLR). The ability of osteocytes to regulate osteoblast and osteoclast activity in bone remodeling and homeostasis is well known, but many questions remain about the direct role of osteocyte in remodeling via PLR in bone homeostasis or disease states. In PLR, osteocytes directly resorb and deposit bone matrix surrounding their lacuno-canalicular network (LCN). Indeed, osteocyte-intrinsic deletion of TGFβ signaling in TβRIIocy−/− mice causes defective PLR and bone quality. Furthermore, preliminary data from RNAseq of TβRIIocy−/− bone shows significant mitochondrial dysfunction. However, the underlying molecular mechanism of how TGFβ regulates mitochondrial function and PLR in osteocytes is currently poorly understood. One of the most well-known molecular regulators of mitochondrial function and metabolism in other cell/tissue types is microRNAs (miRs). miRs are endogenous, small non-coding RNAs that facilitate sequence-dependent post-transcriptional gene regulation and coordinately target gene networks of complex biological processes, such as cellular metabolism. However, the role of miRs in mediating osteocyte mitochondrial function has not been explored. This project will test the hypothesis that osteocytic TGFβ signaling regulates mitochondrial function via a miRNA-dependent mechanism to control osteocyte function by focusing on a microRNA cluster, miR-181a/b. Aim 1 will determine the requirement of miR-181a/b for osteocyte function. Aim 2 will determine the extent to which miR-181a/b regulate mitochondrial function in osteocytes. Aim 3 will determine whether the regulation of mitochondrial function by TGFβ is miR-181a/b-dependent. This study will aid our understanding of mechanisms responsible for maintaining homeostatic PLR and potentially aid in the development of new, innovative approaches to treat or prevent bone diseases, including in the craniofacial skeleton, due to bone remodeling defects.


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 = $55,338 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	5	6/24/2025	NON-COMPETING CONTINUATION	$55,338
														Subtotal = $55,338

Issue Date FY: 2024 ( Subtotal = $54,774 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	4	6/28/2024	NON-COMPETING CONTINUATION	$54,774
														Subtotal = $54,774

Issue Date FY: 2023 ( Subtotal = $53,494 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	3	5/22/2023	NON-COMPETING CONTINUATION	$53,494
														Subtotal = $53,494

Issue Date FY: 2022 ( Subtotal = $52,552 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	2	6/16/2022	NON-COMPETING CONTINUATION	$52,552
														Subtotal = $52,552

Issue Date FY: 2021 ( Subtotal = $42,844 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	1	2/5/2021	NEW	$0
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	1	2/5/2021	NEW	$42,844
														Subtotal = $42,844

Grand Total All Awards = $259,002

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microRNA regulation of osteocyte metabolism in bone remodeling

Award Number: F30DE029986

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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