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ACE and myeloid cell metabolism

Award Number: R01AI164519
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/11/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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ACE and myeloid cell metabolism - A long sought goal of medical research is to identify ways to increase the effectiveness of the immune response. Here, we present a means of increasing myeloid cell function by increasing cell expression of angiotensin converting enzyme (ACE). We show that 1) under natural circumstances in both humans and mice, myeloid cells increase their production of ACE in response to immune challenge. This is an adaptive response that allows the cells to better respond to the challenge. 2) When this process is exaggerated by using genetic means to augment ACE expression in either macrophages or neutrophils, the result is a marked increase in the ability of mice to mount both an innate and adaptive immune response against a variety of immune challenges. This increase in response is directly due to the catalytic activity of the over-expressed ACE protein. 3) The enhanced immune response is the result of ACE-induced metabolic changes that increase oxidative phosphorylation and increase myeloid cell ATP. This is quite different from the well described myeloid metabolic effects of LPS. That ACE affects cell levels of ATP is a very new finding based on mass spectrometry and chemical analysis of ATP levels in two lines of mice. In contrast, myeloid cells genetically lacking ACE have reduced ATP and reduced immune function. 4) Similar to the genetic ACE KO, ACE inhibitors (ACEi) reduce neutrophil superoxide and anti-bacterial response in both humans and mice. Thus, there is a direct relationship between the level of ACE expression by myeloid cells, myeloid cell ATP content, and effectiveness of the immune response. Understanding how ACE affects myeloid cell immunometabolism will reveal a totally new biochemical means of enhancing myeloid function that might ultimately be manipulated to enhance human response. In Aim 1, we examine the detailed metabolism of myeloid cells with increased ACE expression to identify changes affecting immune function. In Aim 2, we will study the role of the transcription factor PPARα in inducing the immune phenotype of myeloid cells expressing increased ACE. We also ask how ACE activity induces increased cell PPARα. In Aim 3, we study whether ACE acts as an autocrine or paracrine factor and whether we can characterize the peptide product of ACE responsible for affecting cell metabolism and increasing the immune response of myeloid cells.


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 = $560,426 )
2026	2026	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	5	1/31/2026	NON-COMPETING CONTINUATION	$560,426
														Subtotal = $560,426

Issue Date FY: 2025 ( Subtotal = $543,615 )
2025	2025	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	4	3/6/2025	NON-COMPETING CONTINUATION	$543,615
														Subtotal = $543,615

Issue Date FY: 2024 ( Subtotal = $899,227 )
2024	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	002	3	7/25/2024	SUPPLEMENT FOR EXPANSION	$338,801
2024	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	3	1/17/2024	NON-COMPETING CONTINUATION	$504,383
2024	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	3	5/24/2024	NON-COMPETING CONTINUATION	$56,043
														Subtotal = $899,227

Issue Date FY: 2023 ( Subtotal = $566,378 )
2023	2023	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	1/25/2023	NON-COMPETING CONTINUATION	$566,378
														Subtotal = $566,378

Issue Date FY: 2022 ( Subtotal = $555,387 )
2022	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	2/11/2022	NEW	$555,387
														Subtotal = $555,387

Grand Total All Awards = $3,125,033

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ACE and myeloid cell metabolism

Award Number: R01AI164519

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/11/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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