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The Role of CCR10 and CCR10+ Tregs in Hypertension

Award Number: F31HL176154
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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The Role of CCR10 and CCR10+ Tregs in Hypertension - PROJECT SUMMARY Hypertension (HTN) is the leading risk factor for morbidity and mortality worldwide, accounting for nearly half of all heart disease and stroke-related deaths. Emerging evidence implicates immune cells as key mediators of HTN and its associated end-organ damage. Recently, our lab used mass cytometry to deeply phenotype the circulating immune cells of hypertensive and healthy control individuals. Notably, a key difference identified in the circulation of hypertensive patients was a selective decrease in a subset of regulatory T cells (Tregs) expressing the skin-homing receptor CCR10. Tregs are immune cells that primarily limit inflammation and are thought to be protective in HTN. Yet, Treg manipulation in rodent models has yielded inconsistent effects on blood pressure (BP), suggesting Treg subset- and/or context-specific functions in hypertension. In addition, the role of CCR10 and CCR10+ Tregs in hypertension is unknown. My preliminary studies demonstrate that in murine models of Angiotensin II (Ang II)-induced HTN, CCR10+ Tregs are decreased in the blood and selectively infiltrate the skin. In addition, CCR10-deficient (CCR10-/-) mice displayed blunted elevations in BP in response to Ang II. It is unclear how a receptor involved in immune cell recruitment to the skin elevates BP. In murine asthma and heart failure models, Tregs have been reported to promote loss of microvessels (microvascular rarefaction) through endothelial cell (EC) apoptosis. In hypertension, microvascular rarefaction occurs in the skin and contributes to BP elevations through increased vascular resistance. As a result, we hypothesize that CCR10 promotes hypertension and associated end-organ damage via cutaneous Treg recruitment leading to skin microvascular rarefaction. The goal of this proposal is to evaluate the role of CCR10 and CCR10+ Tregs in HTN using two complimentary approaches. First, I will use CCR10-/- mice and adoptive transfer studies to evaluate the role of CCR10 and CCR10+ Tregs specifically in altering skin microvessel density and hypertension development. Second, using EC tube formation co-culture assays, I will determine the impact of CCR10+ Tregs on EC apoptosis and microvessel loss in vitro. I will also test DLL4 signaling as a putative mechanism for this process. Proposed studies will provide key insight into the pathogenesis of hypertension and have significant therapeutic implications. Notably, studies will test the novel hypothesis that certain Treg subsets can play pathogenic roles in HTN, challenging the paradigm that all Tregs are beneficial. In addition, studies will test a novel role for the skin in HTN and offer the potential for future therapies targeting cutaneous immune cells. Proposed studies will also provide a foundation for development of potential new HTN therapies that will help patients live longer, healthier lives.


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 = $34,934 )
2026	2026	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cardiovascular Diseases Research	000	2	2/12/2026	NON-COMPETING CONTINUATION	$34,934
														Subtotal = $34,934

Issue Date FY: 2024 ( Subtotal = $34,370 )
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cardiovascular Diseases Research	000	1	8/15/2024	NEW	$34,370
														Subtotal = $34,370

Grand Total All Awards = $69,304

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The Role of CCR10 and CCR10+ Tregs in Hypertension

Award Number: F31HL176154

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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