Liu Vascular Research Laboratory
A major focus of the Liu lab is understanding the regulatory mechanisms underlying normal functions of vascular smooth muscle cells (SMCs) and how these regulatory mechanisms malfunction in vascular disease, particularly in restenosis (intimal hyperplasia) and abdominal aortic aneurysms. Using a combination of molecular, biochemical and genetic approaches, Dr. Liu and colleagues identified several signaling proteins that are critical for modulating cell death. Protein kinase C-delta (PKCδ) is a member of the protein kinase C family. Activation of PKCδ is necessary for multiple cellular functions ranging from cell apoptosis to intracelullar protein trafficking, and chemokine expression. Receptor interacting protein kinase 1 and 3 (RIP1 and RIP3) regulate a form of necrosis called necroptosis. Dr. Liu’s group is the first to report necroptosis in pathogenesis of aneurysm.
Both restenosis and aneurysm are complex disease processes, involving abnormal behavior of multiple cell types. Restenosis, or intimal hyperplasia, is a progressive thickening of the arterial wall in part due to proliferation of residential SMCs and the recruitment of circulating and/or tissue progenitors. In contrast, abdominal aortic aneurysm involves weakening and expansion of the aortic wall which is associated with extensive inflammation. By studying communications between residential SMCs and circulating cells, Dr. Liu and her co-investigators aim to reveal new molecular insights of vascular disease and use such knowledge to develop novel therapeutic strategies.
In order to better study complex human disease, Dr. Liu emphasizes multidisciplinary and collaborative approaches. Her investigative team includes basic scientists and clinicians from a wide range of scientific and medical disciplines. Every team member is encouraged to learn and use various experimental techniques ranging from molecular biology to cell biology and animal science. This multidisciplinary and collaborative approach has proven to be productive for elucidating novel mechanistic insights and, more importantly, for translating basic findings to clinical applications.
Extracellular Matrix and Inflammation
Naomi Chesler, PhD, Biomedical Engineering
Nader Sheibani, PhD, Department of Ophthalmology & Visual Sciences
Deane Mosher, MD, Department of Medicine
Clinical data shows that aging is an independent risk factor for cardiovascular disease including abdominal aortic aneurysm. Why aged arteries are prone to aneurysm remains elusive. Through an interdisciplinary collaboration, the Liu and Chesler labs study how age-associated changes in extracellular matrix proteins affect aneurysm progression by skewing infiltrating macrophages toward pro-inflammatory phenotypes.
Thrombospondins (TSPs) represent a class of non-structural extracellular matrix proteins called matricellular proteins. The collaborative effort among Liu, Mosher and Sheibani led to the identification of a novel function of TSP1 in regulation of tissue invasion by macrophages. The team is currently testing whether conditional knockout of the gene encoding TSP1 is sufficient to confer the aneurysm resistant phenotype.
Progenitor biology and vascular disease
K. Craig Kent, MD, Department of Surgery
William Murphy PhD, Department of Biomedical Engineering
Igor Slukvin, MD, PhD, Department of Pathology and Cell and Regenerative Biology
Endothelial cell injury underlies several major vascular diseases including atherosclerosis and restenosis. The goal of this collaborative project is to define the role of endothelial progenitor cells in endothelium regeneration and arterial injury repair. Dr. Liu and her colleagues recently showed that PKCδ-mediated release of chemokines influences the recruitment of endothelial progenitor cells or EPCs residing in the outmost layer of the arterial wall. Detailed understanding on how progenitor cells are activated and mobilized is necessary for the development of novel strategies designed to boost the regenerative capacity of human body and promote endothelial regeneration.
David Lynn, PhD, Department of Chemical Engineering
Gene therapy has a tremendous potential to provide highly specific and effective treatments for many different diseases. Cardiovascular disease is an attractive candidate for gene therapy. A major road blocker of gene therapy is the safety concern associated with the currently used viral vectors (immune response, toxicity and chromosomal integrations). The overall goal of Liu-Lynn collaboration is to translate the nanoparticle film technology developed by Dr. Lynn to localized, catheter-mediated DNA, siRNA or protein delivery systems. Specifically, this collaborative team will develop and test a group of novel polymers with various DNA/RNA binding/releasing capacities for therapeutic potentials in cell cultures and in animal models.