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Novel Mechanism of RBFox1 Mediated RNA Metabolism in Heart Failure

Award Number: K99HL141626
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2021

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Novel Mechanism of RBFox1 Mediated RNA Metabolism in Heart Failure - PROJECT SUMMARY RNA metabolism from synthesis, processing, translation to degradation is an integrated part of gene regulation that ultimately determines the overall cardiac transcriptome complexity and reprogramming during heart failure. RNA binding proteins are central to every process of RNA metabolism and therefore establishing their roles in the onset and progression of heart failure should lead to novel disease mechanisms and potential therapeutic targets. Earlier reports by the PI (Dr. Chen Gao) have revealed that global RNA splicing changes are important part of cardiac transcriptome reprogramming in failing heart. Furthermore, this fetal-like RNA- splicing reprogramming is regulated by RBFox1, a muscle enriched RNA splicing factor. However, in new study, PI found cardiac RBFox1 gene also encoded a cytosolic isoform (RBFox1c) due to its own alternative mRNA splicing. While the nuclear RBFox1n contributes to cardiac hypertrophic response through global alternative splicing regulation as demonstrated by the PI, the functional role of the cytosolic RBFox1c in cardiac pathology is yet to be explored. In preliminary studies both in vitro and in vivo, PI found the cytosolic RBFox1c played a critical role in cardiac remodeling associated with reduced pro-inflammatory gene expression in stressed heart muscle cells. This proposal aims at characterizing the non-canonical function of RBFox1c in cardiac disease progression and exploring the RBFox1c mediated post-transcriptional regulatory mechanism in heart. It also outlines an extensive career development plan for Dr. Chen Gao to complete postdoctoral training under the supervision of Dr. Yi Xing and to transition into an independent investigator well equipped with a unique combination of research skills, scientific insights and highly promising research pipeline. During the K99 phase of this proposal, the PI will characterize the functional impact of RBFox1c in cardiac fibrotic response using both genetic mouse model and in vitro cultured cardiomyocytes. The second aim of the K99 phase is to determine the molecular mechanism of RBFox1c mediated inflammatory gene repression. During the R00 phase, the PI will characterize isoform specific impact of RBFox1 in cardiac physiology and pathological remodeling using isoform specific manipulated mouse models. The PI will also explore the post- transcriptional regulatory mechanisms mediated by RBFox1c in heart through BRIC-Seq, TRAP ribo-seq and microRNA competition analysis. The proposed experiments will create exciting new opportunities of fundamental discovery in an important yet vastly under-explored area in cardiac biology, and new insight will also fill an important gap in the current understanding to the pathogenesis of cardiac remodeling induced by pathological stress.


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: 2022 ( Subtotal = -$2,615 )
2022	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	000	3	10/14/2021	EXTENSION WITH OR WITHOUT FUNDS	$0
2022	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	001	3	2/7/2022	EXTENSION WITH OR WITHOUT FUNDS	-$2,615
														Subtotal = -$2,615

Issue Date FY: 2021 ( Subtotal = $39,690 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	002	3	8/12/2021	EXTENSION WITH OR WITHOUT FUNDS	$39,678
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	3	3/13/2021	EXTENSION WITH OR WITHOUT FUNDS	$39,690
2021	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	001	2	8/12/2021	NON-COMPETING CONTINUATION	-$39,678
														Subtotal = $39,690

Issue Date FY: 2020 ( Subtotal = $144,543 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	2	4/2/2020	NON-COMPETING CONTINUATION	$144,543
														Subtotal = $144,543

Issue Date FY: 2019 ( Subtotal = $144,543 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	1	3/21/2019	NEW	$144,543
														Subtotal = $144,543

Grand Total All Awards = $326,161

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Novel Mechanism of RBFox1 Mediated RNA Metabolism in Heart Failure

Award Number: K99HL141626

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2021

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