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Novel mechanisms for the generation of resolving monocytes

Award Number: R01HL163948
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Novel mechanisms for the generation of resolving monocytes - PROJECT SUMMARY Low-grade inflammatory monocytes are increasingly recognized as key contributors for the pathogenesis of atherosclerosis through their enhanced recruitment and retention within the atherosclerotic plaques, as well as their compromised ability of cleaning up necrotic cell debris. However, mechanisms responsible for resolving monocyte inflammation are poorly understood, thus hindering translational efforts in resolving monocyte- mediated inflammatory polarization and the treatment of atherosclerosis. The PI recently reported that the training of low-grade inflammatory monocytes requires the critical cellular TLR4 adaptor molecule TRAM. Our data show that TRAM is uniquely responsible for the inflammatory polarization of monocytes, through a novel mechanism in disrupting pexophagy-mediated peroxisome homeostasis. Tram-/- monocytes have elevated PPAR and PEX5, enhanced pexophagy, reduced ROS, and reduced inflammatory polarization. Intriguingly, Tram-/- monocytes also express increased anti-inflammatory mediators (RvD1 and CD200R) characteristic of “resolving” monocytes, and can actively propagate resolution to neighboring monocytes through CD200R in vitro and in vivo. Tram-/- mice exhibit reduced development of atherosclerosis. Transfusion of Tram-/- resolving monocytes can reduce atherosclerosis pathogenesis. Based on these novel findings, the long term goal is to define novel therapeutic targets for sustaining monocyte homeostasis and preventing/treating atherosclerosis. The current objective is to define molecular and cellular mechanisms by which TRAM may serve as a key switch controlling the generation of either inflammatory or resolving monocytes relevant to the pathogenesis or treatment of atherosclerosis. The central hypothesis is that TRAM deletion will not only block the polarization of low-grade inflammatory monocytes, but also enable the generation and propagation of resolving monocytes conducive for the treatment of atherosclerosis, through enhancing peroxisome homeostasis. To test this hypothesis, the following integrated studies will be conducted. Aim 1 will test the hypothesis that the TRAM- PSMB10 circuitry drives the inflammatory polarization of low-grade inflammatory monocytes through disrupting pexophagy. Aim 2 will test the hypothesis that TRAM deletion and reduction of immunoproteasome PSMB10 enable the generation of anti-inflammatory resolving monocytes through sustained activation of PPAR /peroxisome homeostasis. Aim 3 will test the translational hypothesis that resolving monocytes with enhanced peroxisome homeostasis can propagate resolution memory and reduce the pathogenesis of atherosclerosis. Together, the proposed studies will advance the field of innate immune memory, by delineating the novel role of TRAM-circuitry in the training of “inflammatory” vs “resolving” monocytes, bearing translational relevance to the pathogenesis and treatment of atherosclerosis.


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	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Cardiovascular Diseases Research	000	4	2/19/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $390,405 )
2025	2025	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Cardiovascular Diseases Research	000	4	3/28/2025	NON-COMPETING CONTINUATION	$390,405
														Subtotal = $390,405

Issue Date FY: 2024 ( Subtotal = $390,684 )
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Cardiovascular Diseases Research	000	3	3/5/2024	NON-COMPETING CONTINUATION	$390,684
														Subtotal = $390,684

Issue Date FY: 2023 ( Subtotal = $390,956 )
2023	2023	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Cardiovascular Diseases Research	000	2	3/28/2023	NON-COMPETING CONTINUATION	$390,956
														Subtotal = $390,956

Issue Date FY: 2022 ( Subtotal = $391,219 )
2022	2022	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Cardiovascular Diseases Research	000	1	3/7/2022	NEW	$391,219
														Subtotal = $391,219

Grand Total All Awards = $1,563,264

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Novel mechanisms for the generation of resolving monocytes

Award Number: R01HL163948

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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