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Investigating Mixed Lineage Kinase 3 as a blood pressure-independent protein kinase G1 effector in heart failure

Award Number: R01HL162919
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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The cGMP-dependent protein kinase 1 alpha (PKG1a) opposes pathological left ventricular (LV) hypertrophy and remodeling via roles in the cardiac myocyte (CM) and regulates blood pressure by promoting vascular smooth muscle cell (VSMC) relaxation and vasodilation. Drugs which activate PKG1, including nitrates, sacubitril/valsartan, vericiguat, and others have improved mortality in heart failure with reduced LV ejection fraction (HFrEF) and thus represent a central advance in HFrEF treatment. However, these therapies remain limited by incomplete efficacy in HFrEF. Furthermore, hypotension from PKG1-induced vasodilation has severely limited the practical use of these agents. The overarching hypothesis of this program is that identifying downstream PKG1a anti-remodeling substrates in the LV can reveal novel therapeutic candidates to overcome these critical limitations of current PKG1-activating drugs. We have identified Mixed Lineage Kinase 3 (MLK3) as a novel PKG1a-interacting protein and anti-remodeling molecule. We propose to explore the following exciting findings which identify MLK3 as a translationally relevant molecule in HFrEF. 1) PKG1a-MLK3 interaction declines in the failing LV, and MLK3 is required for PKG1a-mediated therapeutic effects of sildenafil on LV function after pressure overload, thus identifying disruption of myocardial MLK3 regulation by PKG as promoting LV remodeling and decreasing the efficacy of PKG1-activating drugs in HF. 2) MLK3 kinase function opposes pathological CM and LV dysfunction and remodeling but does not affect blood pressure in vivo. 3) MLK3 deletion promotes hypertension in vivo, but MLK3 regulation of blood pressure occurs through MLK3 kinase independent mechanisms and independently of signaling by PKG1a. We propose to test a two-part novel model in which 1) PKG1a activation of MLK3 promotes LV compensation to pressure overload through MLK3 kinase-dependent mechanisms in the CM; and 2) MLK3 opposes hypertension through kinase-independent effects on vascular stiffness through a role in the VSMC. SA1 will use novel MLK3 cell-specific deletion models developed in our lab to determine the CM and SMC-specific roles of MLK3 in basal regulation of LV function and blood pressure and in the chronic LV response to pressure overload or myocardial infarction. SA2 will determine the kinase dependent versus kinase independent effects of MLK3 on LV function and blood pressure. SA3 will determine the translational relevance of MLK3 to HF treatment by testing the requirement of MLK3 for LV therapeutic effects versus blood pressure effects of currently available PKG1-activating drugs. These studies will define novel mechanisms through which MLK3 regulates blood pressure and through which MLK3 blood pressure- independent functions mediate the therapeutic effect of current PKG1-activating drugs. These studies have the potential to identify MLK3 kinase activation as a novel therapeutic strategy to promote PKG1 therapeutic effects on LV function and remodeling but avoid undesired hypotension which has limited PKG1 activating drugs.


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 = $759,586 )
2024	2024	TUFTS MEDICAL CENTER PARENT, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	000	3	4/11/2024	NON-COMPETING CONTINUATION	$759,586
														Subtotal = $759,586

Issue Date FY: 2023 ( Subtotal = $763,205 )
2023	2023	TUFTS MEDICAL CENTER, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	000	2	4/7/2023	NON-COMPETING CONTINUATION	$763,205
														Subtotal = $763,205

Issue Date FY: 2022 ( Subtotal = $718,807 )
2022	2022	TUFTS MEDICAL CENTER, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	5/12/2022	NEW	$718,807
														Subtotal = $718,807

Grand Total All Awards = $2,241,598

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Investigating Mixed Lineage Kinase 3 as a blood pressure-independent protein kinase G1 effector in heart failure

Award Number: R01HL162919

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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