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The uncharacterized nuclear protein HMGXB4 in occlusive vascular diseases

Award Number: K99HL171834
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 02/16/2026

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The uncharacterized nuclear protein HMGXB4 in occlusive vascular diseases - PROJECT SUMMARY Vascular smooth muscle cell (VSMC) phenotypic modulation, from contractile to proliferative phenotypes, is central to the etiologies of human occlusive vascular diseases, such as restenosis and atherosclerosis. Identification of the key players that regulate VSMC phenotypic switching is critical for further understanding of the underlying mechanisms of VSMC-driven occlusive vascular diseases and also for developing novel therapeutic approaches. We have previously demonstrated that HMGXB4, a novel high mobility group (HMG) box domain containing 4, attenuates smooth muscle differentiation and aggravating endotoxin-induced systemic inflammation in mice. Yet, the role and underlying mechanisms of HMGXB4 in occlusive vascular diseases in vivo remain unclear. Furthermore, a recent genome-wide association studies (GWAS) identified genetic variants in the HMGXB4 gene locus associated with increased risk of coronary artery disease (CAD), suggesting a potential role of HMGXB4 in CAD. The overarching goal of this proposal is to determine the functional role and elucidate the underlying mechanism of the uncharacterized nuclear protein HMGXB4 in occlusive vascular diseases. Novel preliminary data in this proposal include 1) HMGXB4 expression is upregulated in both human and mouse occlusive vascular samples, and correlates with VSMC inflammation and phenotypic switching in vivo. 2) The increased expression of HMGXB4 in occlusive vascular diseases is mainly located in VSMCs. 3) TNFa, a pro-inflammatory cytokine, induces HMGXB4 expression in a time- and dose-dependent manner in VSMCs in vitro. 4) Knockdown of HMGXB4 in VSMCs attenuates while over-expression of HMGXB4 promotes VSMC phenotypic switching in vitro. 5) HMGXB4 interacts with p65 and enhance p65 mediated NF-kB activation. 6) Global deletion of Hmgxb4 ameliorates wire injury-induced neointima and hyperlipidemia-induced atherosclerosis lesion formation. Three specific aims are proposed to test the central hypothesis that the pro- inflammatory cytokine TNFa upregulates HMGXB4 in VSMCs to promote VSMC inflammation and proliferation, thereby driving occlusive vascular diseases. K99 Aim 1: Test the hypothesis that specific deletion of Hmgxb4 in VSMCs attenuates occlusive vascular diseases. K99/R00 Aim 2: Test the hypothesis that TNFa upregulates HMGXB4 via an NF-kB/p65 dependent mechanism in VSMCs. R00 Aim 3: Test the hypothesis that HMGXB4/NF-kB mediates expression of PIM1 to enhance VSMC inflammation and proliferation under pathological conditions. Completion of the proposed studies will provide novel insights into the mechanisms regulating VSMC inflammation and phenotypic switching, and will determine if inhibiting HMGXB4 is an attractive novel therapeutic strategy for ameliorating occlusive vascular diseases. Additional conceptual and experimental training in vascular inflammation-related research during the K99 phase will help the applicant pursue an independent career and transform this proposal into an R01 application during the R00 phase.


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	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	2	2/13/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $132,612 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	2	7/10/2025	NON-COMPETING CONTINUATION	$132,612
														Subtotal = $132,612

Issue Date FY: 2024 ( Subtotal = $135,000 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	1	6/25/2024	NEW	$135,000
														Subtotal = $135,000

Grand Total All Awards = $267,612

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The uncharacterized nuclear protein HMGXB4 in occlusive vascular diseases

Award Number: K99HL171834

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 02/16/2026

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