Wednesday, February 18, 2026 2/18/2026

Role of Toll-Like Receptor Signaling in Cardiac Ischemia

Award Number: R01HL071837
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2003
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Role of Toll-Like Receptor Signaling in Cardiac Ischemia - Cardiovascular disease (CVD) is the number one killer in the United States. Every year about 735,000 Americans have a heart attack (myocardial ischemic injury). Of these, 525,000 are a first heart attack and 210,000 happen in people who have already had a heart attack. Cardiovascular endothelial dysfunction contributes to myocardial ischemic injury. Endothelial cells express pattern recognition receptors (PRRs), including Toll-like receptors (TLRs). PPRs recognize pathogen associated molecular patterns (PAMPs) and endogenous (danger associated molecular patterns) ligands and initiate innate immune and inflammatory responses which promote immune cell infiltration into the myocardium. Recent evidence suggests that infiltrating macrophages and resident macrophages may have differential functions in mediating cardiac injury or cardiac repair following myocardial infarction (MI). Therefore, cardiac macrophage function may be critical for preservation of endothelial cell function, reducing myocardial ischemic injury and promoting repair of damaged heart tissue. During the last grant period, we have made a novel and exciting observation that endothelial cell specific heat shock protein A12B (HSPA12B) is an important mediator of crosstalk between endothelial cells and macrophages during MI. HSPA12B is a newly discovered member of the HSP70 family. It is predominantly expressed in endothelial cells, and plays an important role in the induction of angiogenesis by activation of phosphoinositide-3 kinase (PI3K)/Akt signaling. In our preliminary studies, we have discovered a novel role for HSPA12B in the regulation of macrophage function and angiogenesis during MI. Specifically, we found that endothelial cell specific HSPA12B deficiency (HSPA12B-/-) results in cardiac rupture which is associated with increased infiltrating macrophages and reduced resident macrophages in the myocardium during early phase of MI. In the late phase of MI, HSPA12B-/- mice exhibit worsened cardiac dysfunction and impaired cardiac angiogenesis. In contrast, transgenic mice which overexpress endothelial HSPA12B show significantly improved cardiac function and angiogenesis following MI. Thus, our findings indicate that endogenous endothelial cell HSPA12B exerts protection against myocardial ischemic injury. Importantly, we have discovered that HSPA12B is released from endothelial cells in exosomes that are uptaken by macrophages where it regulates macrophage phenotypes, thus reducing inflammatory responses. In addition, HSPA12B translocates into the nucleus accompanied by YAP/TAZ in endothelial cells and promotes angiogenesis. YAP/TAZ are two important co-effectors in Hippo signaling and they play an important role in the regulation of cell proliferation and angiogenesis. When taken together, our findings indicate that endothelial HSPA12B plays an important role not only in endothelial cell proliferation and angiogenesis but also in macrophage phenotypes during MI. Our preliminary data also suggests that endothelial HSPA12B may mediate crosstalk between endothelial cells and macrophages for repairing damaged heart tissue following MI. This application is focused on deciphering the cellular and molecular mechanisms by which endothelial HSPA12B differentially regulates macrophage phenotype and endothelial cell function during myocardial ischemic injury. Based on the preliminary data, we hypothesize that “endothelial HSPA12B is a novel effector for the protection against myocardial ischemic injury by differentially regulating macrophage phenotype and endothelial cell function”. To critically evaluate this hypothesis, we propose the following specific aims. Specific aim 1. Define the mechanisms by which endothelial HSPA12B regulates the function of infiltrating and resident macrophages during MI. Specific aim 2. Investigate the novel mechanisms by which HSPA12B regulates cardiac repair and angiogenesis following MI. Specific aim 3. Evaluate the therapeutic potential


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 = -$3,249 )
2025	2022	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	000	16	5/2/2025	NON-COMPETING CONTINUATION	-$3,249
														Subtotal = -$3,249

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	000	16	2/9/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $532,226 )
2022	2022	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	001	16	5/31/2022	NON-COMPETING CONTINUATION	$53,224
2022	2022	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	000	16	2/20/2022	NON-COMPETING CONTINUATION	$479,002
														Subtotal = $532,226

Issue Date FY: 2021 ( Subtotal = $532,226 )
2021	2021	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	000	15	2/15/2021	NON-COMPETING CONTINUATION	$532,226
														Subtotal = $532,226

Issue Date FY: 2020 ( Subtotal = $532,226 )
2020	2020	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	000	14	2/25/2020	NON-COMPETING CONTINUATION	$532,226
														Subtotal = $532,226

Issue Date FY: 2019 ( Subtotal = $532,226 )
2019	2019	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	003	13	6/28/2019	COMPETING CONTINUATION	$64,680
2019	2019	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	001	13	2/22/2019	COMPETING CONTINUATION	$532,226
2019	2017	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	002	12	6/28/2019	NON-COMPETING CONTINUATION	-$64,680
2019	2017	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	000	12	2/20/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $532,226

Issue Date FY: 2017 ( Subtotal = $365,000 )
2017	2017	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	000	12	6/20/2017	NON-COMPETING CONTINUATION	$365,000
														Subtotal = $365,000

Issue Date FY: 2016 ( Subtotal = $365,000 )
2016	2016	EAST TENNESSEE STATE UNIVERSITY	BOX 24460A	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	000	11	5/24/2016	NON-COMPETING CONTINUATION	$365,000
														Subtotal = $365,000

Issue Date FY: 2015 ( Subtotal = $359,525 )
2015	2015	EAST TENNESSEE STATE UNIVERSITY	BOX 24460A	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	000	10	6/29/2015	NON-COMPETING CONTINUATION	$359,525
														Subtotal = $359,525

Issue Date FY: 2014 ( Subtotal = $365,000 )
2014	2014	EAST TENNESSEE STATE UNIVERSITY	BOX 24460A	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	000	9	4/11/2014	COMPETING CONTINUATION	$365,000
														Subtotal = $365,000

Issue Date FY: 2013 ( Subtotal = $0 )
2013	2011	EAST TENNESSEE STATE UNIVERSITY	BOX 24460A	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	000	8	2/6/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2011 ( Subtotal = $357,500 )
2011	2011	EAST TENNESSEE STATE UNIVERSITY	BOX 24460A	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	000	8	2/25/2011	NON-COMPETING CONTINUATION	$357,500
														Subtotal = $357,500

Issue Date FY: 2010 ( Subtotal = $357,500 )
2010	2010	EAST TENNESSEE STATE UNIVERSITY	BOX 24460A	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	000	7	2/11/2010	NON-COMPETING CONTINUATION	$357,500
														Subtotal = $357,500

Issue Date FY: 2009 ( Subtotal = $356,667 )
2009	2009	EAST TENNESSEE STATE UNIVERSITY	BOX 24460A	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	000	6	3/2/2009	NON-COMPETING CONTINUATION	$356,667
														Subtotal = $356,667

Issue Date FY: 2008 ( Subtotal = $355,000 )
2008	2008	EAST TENNESSEE STATE UNIVERSITY	BOX 24460A	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	000	5	3/15/2008	COMPETING CONTINUATION	$355,000
														Subtotal = $355,000

Issue Date FY: 2006 ( Subtotal = $274,712 )
2006	2006	EAST TENNESSEE STATE UNIVERSITY	BOX 24460A	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	000	4	6/19/2006	NON-COMPETING CONTINUATION	$274,712
														Subtotal = $274,712

Issue Date FY: 2005 ( Subtotal = $278,544 )
2005	2005	EAST TENNESSEE STATE UNIVERSITY	BOX 24460A	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	000	3	6/17/2005	NON-COMPETING CONTINUATION	$278,544
														Subtotal = $278,544

Issue Date FY: 2004 ( Subtotal = $273,956 )
2004	2004	EAST TENNESSEE STATE UNIVERSITY	BOX 24460A	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	000	2	6/28/2004	NON-COMPETING CONTINUATION	$273,956
														Subtotal = $273,956

Issue Date FY: 2003 ( Subtotal = $271,502 )
2003	2003	EAST TENNESSEE STATE UNIVERSITY	BOX 24460A	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cardiovascular Diseases Research	000	1	6/15/2003	NEW	$271,502
														Subtotal = $271,502

Grand Total All Awards = $6,105,561

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Role of Toll-Like Receptor Signaling in Cardiac Ischemia

Award Number: R01HL071837

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2003

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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