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Role of mRNA-binding protein tristetraprolin in cardiac mRNA regulation and the development of heart failure

Award Number: R01HL155953
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Role of mRNA-binding protein tristetraprolin in cardiac mRNA regulation and the development of heart failure - Heart failure (HF) is a major health epidemic in developed countries, however, its underlying pathology is not well characterized. Tristetraprolin (TTP) is a tandem zinc finger protein that binds to AU-rich elements (ARE) in the 3’-untranslated region (UTR) of target mRNA molecules, and induces their degradation. Global TTP knockout (KO) mice display systemic inflammation, since TNFα mRNA is normally degraded by TTP, and deletion of TTP leads to elevated TNFα levels. Thus, very few studies have assessed the role of TTP in metabolism despite its original discovery as an insulin-inducible gene, and genetic studies linking TTP to metabolic syndrome. We are addressing this fundamental gap in knowledge, and our strong preliminary data suggest critical activities by TTP in cardiac metabolism and the development of HF. Specifically, we have shown that TTP inhibits fatty acid (FA) and branched-chain amino acid (BCAA) metabolism (independent of its effects on inflammation), and reduces the mRNA levels of key proteins in these processes, i.e., peroxisome proliferator-activated receptor (PPAR)-α and branched-chain α–ketoacid acid dehydrogenase complex (BCKDC)-E2 subunits. The central hypothesis of this proposal is that TTP inhibits cardiac FA and BCAA metabolism by binding to and degrading PPARα and BCKDC-E2 mRNAs, and that TTP exacerbates the development of HF by impairing FA and BCAA metabolism. In Aim 1, we will assess whether TTP inhibits cardiac FA metabolism by binding to PPARα mRNA and promoting its degradation. We will assess whether TTP binds to PPARα mRNA by performing RNA co-immunopreciptation (co-IP) and deletion studies of PPARα 3’-UTR AREs. We will also measure FA uptake and metabolism in the hearts from cardiac-specific TTP KO (csTTP-KO) mice, and will determine whether these changes are through PPARα using TTP/PPARα double KO mice. In Aim 2, we will determine whether TTP decreases BCAA catabolism through binding and degradation of BCKDC-E2 mRNA. We will first determine whether TTP binds BCKDC-E2 mRNA by performing RNA co-IP and deletion studies on BCKDC-E2 3’-UTR AREs. We will also measure BCAA levels and BCKDC activity in heart tissue from csTTP-KO mice. To demonstrate whether the reduction in BCAA catabolism with TTP KO is through BCKDC-E2, we will perform similar studies with knockdown of TTP and BCKDC-E2. In Aim 3, we will determine whether TTP has detrimental effects on the heart under stress conditions, and whether this depends upon impaired FA and BCAA metabolism. We will subject csTTP-KO mice to pressure overload and ischemia, then assess their cardiac function and metabolism. To determine the role of PPARα and BCKDC in this process, we will use csTTP/PPARα double KO mice and will cross csTTP-KO with protein phosphatase 2Cm KO mice (which have reduced BCKDC activity), and assess cardiac response to stress. We will also show our studies to develop novel drugs that target TTP without inducing inflammation, providing potential clinical implications for Aim 3. These studies will improve our understanding of cardiac metabolism, and may lead to new avenues for treatment of HF.


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: 2026 ( Subtotal = $0 )
2026	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	4	10/20/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $576,042 )
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	4	11/23/2024	NON-COMPETING CONTINUATION	$518,437
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	001	4	9/24/2025	NON-COMPETING CONTINUATION	$57,605
														Subtotal = $576,042

Issue Date FY: 2024 ( Subtotal = $566,077 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	002	3	6/24/2024	NON-COMPETING CONTINUATION	$46,210
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	001	3	12/15/2023	NON-COMPETING CONTINUATION	$519,867
2024	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	2	10/31/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $566,077

Issue Date FY: 2023 ( Subtotal = $577,630 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	001	2	3/10/2023	NON-COMPETING CONTINUATION	$57,763
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	2	11/21/2022	NON-COMPETING CONTINUATION	$519,867
														Subtotal = $577,630

Issue Date FY: 2022 ( Subtotal = $572,830 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	1	12/27/2021	NEW	$572,830
														Subtotal = $572,830

Grand Total All Awards = $2,292,579

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Role of mRNA-binding protein tristetraprolin in cardiac mRNA regulation and the development of heart failure

Award Number: R01HL155953

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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