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Contributions of vascular chemokine receptors to cardiovascular function after traumatic-hemorrhagic shock

Award Number: R01GM139811
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Loss of vascular tone is characteristic for cardiovascular collapse during hemorrhagic shock and fluid resuscitation (HS/R). Dysfunction and desensitization of a1-adrenergic receptors (ARs) is considered the hallmark in the development of vasodilatory shock. The mechanisms responsible for a1-AR dysfunction are unknown. The chemokines (C-C motif) chemokine ligand 2 (CCL2), CCL3, CCL5 and CCL22 have been identified as key drivers of the initial inflammatory response to HS/R, and as early biomarkers that segregate surviving and non-surviving trauma patients. The pathophysiological and molecular mechanisms underlying these important clinical correlations, however, remain to be determined. We discovered that the chemokine receptors (CRs) (C-C motif) chemokine receptor 1 (CCR1), CCR2 and CCR4, which are receptors for CCL2, CCL3, CCL5 and CCL22, form heteromeric complexes with a1-AR in the tunica media of resistance arteries. We provide preliminary evidence that activation of CCR2 antagonizes a1-AR mediated constriction of isolated resistance arteries and cross-recruits b-arrestin to a1-AR, a molecular signaling event that initiates removal of a1-AR from the plasma membrane. This leads to our main hypothesis that chemokine release during early phases of HS/R impairs vascular tone and blood pressure regulation through activation of their CRs, which interact with and regulate a1-AR in vascular smooth muscle cells (VSMCs). This implies that pharmacological targeting of the CRs that interact with a1-AR will provide new therapeutic options to stabilize vascular tone and hemodynamics, prevent cardiovascular collapse and improve resuscitation after HS. To test this hypothesis, we propose three specific aims: 1) To determine how the CR heteromerization partners of a1-AR regulate vascular function ex vivo. We will utilize pressure myography with isolated resistance arteries as a test platform to define the roles of the identified CR heteromerization partners in the regulation of intrinsic vascular function and vasopressor responsiveness. 2) To test how pharmacological targeting of the CR heteromerization partners of a1-AR modulates cardiovascular function in vivo. We will determine how blockade and activation of CR heteromerization partners affect normal cardiovascular function, vasopressor responsiveness and cardiovascular function during HS/R. 3) To determine the molecular mechanisms by which the CR heteromerization partners of a1-AR regulate a1-AR function. We will determine the mechanisms of cross-talk between the identified CRs and a1-AR, and elucidate the pathways by which the CR heteromerization partners of a1-AR modulate a1-AR-induced signaling and VSMC contraction. New knowledge gained from this proposal will advance our understanding of the regulation of vascular function and identify new molecular targets that could be used to improve blood pressure control during HS/R, and in hemodynamically instable critically ill patients in general.


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: 2023 ( Subtotal = $373,750 )
2023	2023	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Biomedical Research and Research Training	000	4	6/21/2023	NON-COMPETING CONTINUATION	$373,750
														Subtotal = $373,750

Issue Date FY: 2022 ( Subtotal = $498,524 )
2022	2022	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Biomedical Research and Research Training	001	3	6/15/2022	SUPPLEMENT FOR EXPANSION	$124,774
2022	2022	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Biomedical Research and Research Training	000	3	6/14/2022	NON-COMPETING CONTINUATION	$373,750
														Subtotal = $498,524

Issue Date FY: 2021 ( Subtotal = $498,524 )
2021	2021	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Biomedical Research and Research Training	001	2	6/30/2021	SUPPLEMENT FOR EXPANSION	$124,774
2021	2021	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Biomedical Research and Research Training	000	2	6/28/2021	NON-COMPETING CONTINUATION	$373,750
														Subtotal = $498,524

Issue Date FY: 2020 ( Subtotal = $360,381 )
2020	2020	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Biomedical Research and Research Training	000	1	9/4/2020	NEW	$360,381
														Subtotal = $360,381

Grand Total All Awards = $1,731,179

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Contributions of vascular chemokine receptors to cardiovascular function after traumatic-hemorrhagic shock

Award Number: R01GM139811

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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