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Long noncoding RNA MALAT1 ablation reverses sepsis in mouse: epitranscriptomic mechanisms and therapeutic application

Award Number: R21AI152050
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Sepsis is a disease with high incidence and lethality and is accompanied by profound metabolic disturbances of the methionine metabolism cycle. In mammalian methionine metabolism, S-adenosylmethionine (SAM) is produced, which occupies a central position in the metabolism of all cells as an essential methyl donor to maintain normal methylation of DNA, RNA, histones as well glutathione which is important for cellular redox system. Methionine adenosyltransferase (MAT2A) is essential for the biosynthesis of SAM and the gene expression of MAT2A is regulated at transcriptional and post-transcriptional levels through m6A RNA methylation of the 3’UTR of MAT2A mRNA. Post-transcriptionally, the mRNA of MAT2A stability is regulated by the m6A methylation mediated by RNA methylation writer METTL16 which regulates MAT2A mRNA by methylating 3’UTR of the MAT2A mRNA. METTL16 forms a complex with a lncRNA MALAT1. The role of MALAT1 in regulating MAT2A however, is not clear. In genetically ablated MALAT1 mice, MAT2A gene expression is up-regulated and LPS-induce ROS was significantly suppressed with increases in the levels of glutathione. MALAT1 null mice are highly resistant to the septic shock induced by endotoxemia with increased global m6A methylation. Our central hypothesis is MALAT1 regulates SAM biosynthesis by controlling MAT2A gene expression and MALAT1-regulated methionine metabolism pathway is a therapeutic target for sepsis. The specific aims are: Aim 1. Epitranscriptomic mechanisms of endotoxemia-induced inflammation through regulating m6A RNA methylation METTL16 which is the key enzyme for methylating 3’UTR of MAT2A, resulting in either intron retention or decay of the mRNA. The potential regulatory effects of lncRNA MALAT1 on MATTL16 will be analyzed using macrophage from MALAT1 null mice in comparison with the wild type control. The m6A-seq analysis will be performed to analyze the effects of endotoxemia-induced alteration of global m6A methylation and identify the critical methylation sites. The regulatory effect of MALAT1 on the gene expression of MAT2A will be analyzed. The effects of supplementation of methyl donor (SAM, Methionine) counteracting LPS-induced inflammatory cytokines secretion in peritoneal macrophage, while the inhibition of SAM synthesis by competitive inhibitor of MAT2A cLEU exacerbates the inflammatory responses. The experimental results in this aim will provide basis for therapeutic strategy development . Aim 2. Therapeutic targeting MALAT1 for improving methionine metabolic functions and anti- inflammatory function in mouse models. Motivated by the strong evidence of MALAT1 in regulating methionine cycle, concurrently with Aim 1, the antisense RNA approach with a highly effective antisense oligonucleotide, LNA GapmeR against MALAT1 will be tested for treatment of sepsis in mouse model in combination with methionine/SAM.


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 = -$7,108 )
2024	2021	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	2	3/14/2024	NON-COMPETING CONTINUATION	-$7,108
														Subtotal = -$7,108

Issue Date FY: 2021 ( Subtotal = $187,772 )
2021	2021	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	2	5/7/2021	NON-COMPETING CONTINUATION	$187,772
														Subtotal = $187,772

Issue Date FY: 2020 ( Subtotal = $233,016 )
2020	2020	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	1	6/2/2020	NEW	$233,016
														Subtotal = $233,016

Grand Total All Awards = $413,680

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Long noncoding RNA MALAT1 ablation reverses sepsis in mouse: epitranscriptomic mechanisms and therapeutic application

Award Number: R21AI152050

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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