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CaMK4 as a Critical Mediator of Inflammation Resolution and Trained Immunity

Award Number: F31HL172670
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/29/2024
PERIOD OF PERFORMANCE END DATE: 06/28/2027

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CaMK4 as a Critical Mediator of Inflammation Resolution and Trained Immunity - PROJECT SUMMARY Atherosclerotic cardiovascular disease (CVD) is the leading cause of death globally. Despite conventional lipid- lowering therapies to treat CVD, nearly 50% of patients suffer recurrent cardiac events that is attributed to excessive inflammation. Recent work from our group and others has demonstrated that failed resolution of a chronic inflammatory response is an important driver of inflammation seen in atherosclerotic plaques that result in clinical events. The resolution program is orchestrated by the efficient clearance of apoptotic cells (ACs) and the production of anti-inflammatory agonists known as specialized pro-resolving lipid mediators (SPMs). Notably, continual efferocytosis, which entails the successive uptake of ACs by individual macrophages in settings where cell death is rampant, is necessary to resolve inflammation. Advanced atherosclerotic plaques are characterized by large necrotic cores, caused by inefficient efferocytosis, and an imbalance of pro-inflammatory to pro- resolving mediators compared to early lesions, suggestive of failed resolution. Our primary aim for project is to uncover the endogenous cues that underlie dysregulated inflammation resolution seen in atherosclerosis. Intriguingly, recent publications suggest macrophages can have a memory-like response called “trained innate immunity”. In response to an inflammatory stimulus such as oxidized low density lipoproteins (oxLDL), innate immune cells undergo metabolic and epigenetic reprogramming that primes them to a ‘hyperactive’ state, where they can more rapidly mount an augmented secondary response. Hyper-responsiveness upon activation by a second innate stimuli ultimately boosts bacterial and viral immunity but may be detrimental for chronic diseases like atherosclerosis. Our preliminary data identified Ca2+/Calmodulin-Dependent Protein Kinase IV (CaMK4) as regulator of both resolution and innate immune memory. Our preliminary data suggests that CaMK4 supports the proinflammatory phenotypes seen in innate immune memory in part due to its negative regulation on efferocytosis. Based on these findings, we hypothesize that myeloid CaMK4 is a critical mediator of immune memory and that immune training impairs resolution through a CaMK4-dependent mechanism. Aim 1 will test the hypothesis that trained immunity impairs continual efferocytosis in myeloid cells, promoting atheroprogression. Aim 2 will explore the role of CaMK4 in the development of trained immunity through its negative regulation of important resolution genes.


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 = $34,859 )
2025	2025	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cardiovascular Diseases Research	000	2	8/14/2025	NON-COMPETING CONTINUATION	$34,859
														Subtotal = $34,859

Issue Date FY: 2024 ( Subtotal = $34,295 )
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cardiovascular Diseases Research	000	1	12/29/2023	NEW	$33,015
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cardiovascular Diseases Research	001	1	12/29/2023	NEW	$0
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cardiovascular Diseases Research	002	1	9/6/2024	NEW	$1,280
														Subtotal = $34,295

Grand Total All Awards = $69,154

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CaMK4 as a Critical Mediator of Inflammation Resolution and Trained Immunity

Award Number: F31HL172670

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/29/2024

PERIOD OF PERFORMANCE END DATE: 06/28/2027

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