Liu Vascular Research Laboratory

Primary Research

Regulatory Mechanism underlying Cell Death

Abnormal cell death contributes to the pathophysiology of multiple human diseases. Owing to recent scientific advances, we now know that cell necrosis, previously thought to be incidental, can be regulated by intracellular signaling mechanisms. Necroptosis is a form of regulated cell necrosis that requires activation of receptor interacting protein kinase 1 and 3 (RIPK1 and RIPK3). Dr. Liu and her trainees are the first to demonstrate that necroptosis is an important pathological event contributing to the development of aortic aneurysms – common yet potentially lethal vascular disorders characterized by progressive weakening and dilatation of the aorta. The group has discovered a novel class of inhibitors to RIPK1 and RIPK3 that show high therapeutic potentials.

Currently, the Vascular Research Lab investigates two fundamental questions in the context of aortic aneurysm:  how RIPK3 is regulated and how it signals. The group has shown that diseased blood vessels contain higher levels of RIPK3 than normal vessels. Subsequent studies using mouse models suggest that a transcription enhancer may be responsible for the epigenetic regulation of the Ripk3 gene.

Compared to apoptosis, the signaling mechanism required for necroptosis is less understood. Prior studies identified that phosphorylation of MLKL by RIPK3 is a critical event. Recent results from the lab suggest that RIPK3 play have necroptosis-indenpenent functions in vascular cells.

Cell-cell Communications and Extracellular Vesicles (EVs)

The arterial wall contains three cellular layers: the intima, media and adventitia. In order for blood vessels to maintain proper vascular tone, all layers must work in synergy. In disease states, cells from different layers communicate injury as well as repair signals. Our single cell RNAsequencing analysis suggests that the sganling flow from macrophages to vascular smooth muscle cells is prominent in the vessel wall affected by aneurysm. EVs are cell-derived membranous structures that have a variety of important biologic functions, including cell-cell communication. Using multiple rodent models of arterial injury and bioinformatics, the Liu lab demonstrated that medial smooth muscle cells promote endothelial regeneration by secreting soluble factors. Recently, the group collaborated with Dr. Ying Ge of Cell and Regenerative Biology to perform highly sensitive mass spectrometry-based proteomics on EVs released by healthy or necroptotic cells. Dr. Liu’s trainees identified multiple protein cargos that are unique to EVs released by cells undergoing necroptosis. Currently, the lab focuses on investigating the role of EVs in the pathogenesis of aneurysms and thrombosis, and delineating the intracellular mechanisms that govern EV functions and biogenesis during cell death.

Matrix Biology

Increasing evidence indicates the role of extracellular matrix proteins is far beyond providing supporting matrix to cells. Recently, the Liu lab discovered the matrix protein thrombospondin-1 (TSP1) is necessary for monocytes/macrophages to efficiently infiltrate tissues. Currently, the group combines single-cell RNA sequencing with a conditional knockout approach to address the molecular mechanisms whereby macrophage TSP1 promotes the inflammatory response in vascular diseases including aortic aneurysm and venous thrombosis. The lab also investigates how TSP1 contributes to homestasis of endothelial cells.

Translational Studies

Recently, the Liu lab identified a novel class of small molecule inhibitors to RIPK3 and RIPK1 through screening chemical libraries. The therapeutic potential of these new inhibitors was demonstrated in mouse models of aortic aneurysm as well as venous thrombosis. Through collaboration with chemists in the School of Pharmacy, the Liu lab is working on translating their inhibitors into therapies. In addition, the group is working with material engineers to develop novel implantable vascular devices with built-in anti-inflammatory and stenosis-resistant properties.

Collaborators

University of Wisconsin School of Medicine and Public Health:

Ying Ge, PhD, Department of Cellular and Regenerative Biology

Timothy Hacker, PhD, Department of Medicine (Cardiology)

Paul DiMusto, MD, Department of Surgery (Vascular Surgery)

Courtney Morgan, MD, Department of Surgery (Vascular Surgery)

Suzanne Ponik, PhD, Department of Cellular and Regenerative Biology

John Sheehan, MD, Department of Medicine (Hematology)

Nader Sheibani, PhD, Department of Ophthalmology & Visual Sciences

Weiping Tang, PhD, School of Pharmacy

Xudong Wang, PhD, School of Engineering

Baylor College of Medicine:

Ying Shen, MD, PhD

Scott LeMaire, MD

University of Kentucky:

Hong Lu, MD, PhD

Alan Daugherty, PhD

University of Michigan School of Medicine:

Peter Henke, MD

Active Funding/Grants

NIH/NHLBI R01HL149404-01 (Liu, PI)

7/1/2020-6/30/2024

Role of RIP3-laden extracellular vesicles in thrombosis and aortic aneurysms.

NIH/NHLBI R01 HL158073-01 (Liu, PI)

05/01/21-04/30/25

Novel Role of Thrombospondin-1 in Protection against Rupture of Abdominal Aortic Aneurysm

AHA Transformation Award 20TPA35490307 (Liu, PI)

1/1/2021-12/31/2023

Novel extracellular function of receptor interacting protein kinase in coagulation and deep vein thrombosis.

Univ Wisconsin -Research Forward   (Liu and Wang, MPI)

7/1/2022-6/30/2024

Development of 3D-printed piezoelectric stents with self-powered anti-restenosis properties

AHA Career Development Award 20CDA35350009 (Zhou, PI)

1/1/2021-12/31/2023

American Heart Associate/ Career Development Award

Novel functions of endothelial Thrombospondin-1 in abdominal aortic aneurysm

Selected Publications (past 5 years)

1. Zhou T, Wang Q, Phan N, Ren J, Yang H, Feldman CC, Feltenberger JB, Ye Z, Wildman SA, Tang W, and Liu B. Identification of a novel class of RIP1/RIP3 dual inhibitors that impede cell death and inflammation in mouse abdominal aortic aneurysm models. Cell Death and Disease 2019 10:226 (PMC6403222)
2. Ren J, Zhou T, Pilli VS, Phan NM, Wang Q, Gupta K, Liu Z, Sheibani N, Liu B. Novel paracrine functions of smooth muscle cells in supporting endothelial regeneration following arterial injury. Circ Res 2019 124:1253-1265 (PMC6459708)
3. Khoury MK, Zhou T, Yang H, Prince SR, Gupta K, Stranz AR, Wang Q, and Liu B. GSK2593074A Blocks Progression of Existing Abdominal Aortic Dilation. JVS- Vascular Science. 2020 1:123-135 (PMC7872141)
4. Yang H, Zhou T, Sorenson CM, Sheibani N, and Liu B. Myeloid-derived TSP1 (thrombosospondin-1) contributes to abdominal aortic aneurysm through suppressing tissue inhibitor of metalloproteinases-1. Arterioscler Thromb Vasc Biol 2020 40:e350-e366 (PMC7686278)
5. Yang H, Zhou T, DeRoo, E, and Liu B. Single-cell RNA sequencing reveals heterogeneity of vascular cells in early stage murine abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol 2021 41:1158-1166 (PMC7904588)
6. Gupta K and Liu B. PLK1-mediated S369 phosphorylation of RIPK3 during G2 and M phases enables its Ripoptosome incorporation and activity. iScience 2021 24:102320 (PMC8040267)
7. Zhou T, DeRoo E, Yang H, Stranz A, Wang Q, Ginnan R, Singer HA, and Liu B. MLKL and CaMKII are involved in RIPK3-mediated smooth muscle cell necroptosis. Cells 2021 10:2397 (PMC8471540)
8. Yang H, DeRoo E, Zhou, Ting and Liu B. Deciphering cell-cell communication in abdominal aortic aneurysm from single-cell RNA transcriptomic data. Front Cardiovasc Med 2022 9:831798 (PMC8854649)
9. Gupta K, Brown KA, Hsieh ML, Hoover BM, Wang J, Khour MK, Pilli, VSS, Beyer RSH, Voruganti NR, Chaudhary S, Roberts DS, Murphy EM, Hong S, Ge, Y and Liu B. Necroptosis is associated with Rab27-independent expulsion of extracellular vesicles containing RIPK3 and MLKL. J of Extracellular Vesicles 2022 Sep;11(9):e12261. (PMC9443950)
10. DeRoo E, Khoury M, Zhou T, Yang H, Stranz A, Luke C, Henke P, Liu B. Investigating the Role of Receptor Interacting Protein Kinase 3 in Venous Thrombosis. JVS-Vascular Science. 2022 Oct 10;3:365-378. (PMC9772854)
11. DeRoo E, Zhou T, Yang H, Stranz A, Henke P, Liu B. A vein wall cell atlas of murine venous thrombosis determined by single-cell RNA sequencing. Communications Biology. 2023 Jan 31;6(1):130. (PMC9889765)

An expanded list of publications can be found at:

http://www.ncbi.nlm.nih.gov/sites/myncbi/bo.liu.2/bibliograpahy/42730945/public/?sort=date&direction=ascending