# A role of DPP4 in T cell trafficking and vascular inflammation

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $20,550

## Abstract

ABSTRACT
Atherosclerosis is the main cause of death and disability in industrialized nations, including the United States.
Despite of significant advances in recent years, the treatment of cardiovascular disease is unsatisfied partly
due to the limitations in our understanding of the atherosclerosis pathophysiology. Growing evidence indicates
that atherosclerosis is a chronic inflammatory process that accelerates in the context of dyslipidemia. Gaining
new knowledge on inflammatory mechanisms in this disorder is a very important endeavor as this could lead to
new therapies for the treatment of this condition. Both our previous work and preliminary study indicate that
dipeptidyl peptidase-4 (DPP4) plays a critical role in regulating T cell-mediated inflammation in cardiometabolic
disease such as atherosclerosis and diabetes. Single cell transcriptomic analysis indicates that DPP4 was
significantly upregulated in major T cell subsets from patients with atherosclerosis. Ldlr-/- chimeric mice with
Dpp4-/- bone marrow showed reduced atherosclerotic plaque burden and less T cell infiltration in the plaque.
Subsequent gene array and T cell functional studies suggest microtubule-associated E3 ubiquitin ligase
midline-1 (Mid1) mediates DPP4-induced T cell activation and migration. Both Dpp4-/- T cells and Mid1-/- T cells
showed reduced migratory activity, while lentivirus-mediated over-expression of Mid1 restored the migratory
ability of Dpp4-/- T cells. Our overall hypothesis is that DPP4 activation by ligand binding regulates
microtubule-mediated cytoskeleton rearrangement and endocytosis via Mid1-dependent mechanisms, resulting
in enhanced T cell migration to aortic plaque, a key event in the pathogenesis of atherosclerosis. In this
application, we will test the involvement of DPP4 in T cell inflammation and human atherosclerosis (aim 1). We
will also use several unique animal models (including hDpp4KI, Mid1-/-, Dpp4-/-, Dpp4-/-/Mid1-/- double knockout,
and multiple reporter mice) and state-of-the-art technologies (such as imaging flow cytometry and intravital 2-
photon microscopy) to dissect the role of DPP4-Mid1 axis in regulating T cell activation and migration to
atherosclerotic plaque (aim 2). The in vivo effects of DPP4 and Mid1 on atherosclerosis progression will be
investigated in aim 3. This proposal not only addresses important knowledge gaps in DPP4 biology, but would
also identify novel contributors to human atherosclerosis and other disease states where inflammation plays a
critical role.

## Key facts

- **NIH application ID:** 9883574
- **Project number:** 1R01HL142643-01A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Jixin Zhong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $20,550
- **Award type:** 1
- **Project period:** 2020-02-05 → 2020-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9883574

## Citation

> US National Institutes of Health, RePORTER application 9883574, A role of DPP4 in T cell trafficking and vascular inflammation (1R01HL142643-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9883574. Licensed CC0.

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