Liu Vascular Research Laboratory

Primary Research

A major focus of the Liu lab is to understand the regulatory mechanisms underlying normal functions of vascular smooth muscle cells (SMCs) and how these regulatory mechanisms become malfunction in vascular disease, in particular restenosis (intimal hyperplasia) and abdominal aortic aneurysms. Using a combination of molecular, biochemical and genetic approaches, Dr. Liu and colleagues identified a signaling protein called protein kinase C-delta (PKCδ) as a central mediator of stress response in SMCs. Activation of PKCδ is necessary for multiple cellular functions ranging from cell apoptosis to intracelullar protein trafficking. Recently, they showed that a caspase-mediated cleavage of PKCδ is a critical step in the execution of apoptosis. While gene deletion of PKCδ affects multiple cellular functions, inhibition of PKCδ cleavage may specifically target apoptosis of SMCs.

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. Histological and biochemical analyses revealed a profound upregulation of PKCδ in human restenotic lesions and aneurismal aortas. By studying the interplay between PKCδ and other stress mediators in animal models of restenosis and aneurysm, Dr. Liu and her coinvestigators aim to learn 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 in unveiling novel mechanistic insights and more importantly to translate basic findings to clinical applications.

Collaborative Research

TGF-beta signaling
Collaborators:
Michael Hoffman, PhD, Department of Oncology
K. Craig Kent, MD, Department of Surgery

Transforming growth factor-beta (TGFβ) is an important regulator of multiple cellular functions and has been implicated in vascular disease and fibrosis. We focus on a family of signaling proteins called SMADs. Collaborative studies with Dr. Kent show that expression of Smad3 is upregulated in human and experimental restenosis. Both in vivo and in vitro data indicate that the upregulated Smad3 is responsible at least in part for the abnormal phenotype of smooth muscle cells associated with vascular injury. This is a novel finding because the TGFβ signaling is generally thought to inhibit cell proliferation. Through collaborations with Dr. Michael Hoffman, the group is investigating the molecular mechanism through which Smad3 may interact with other cell cycle regulators. Additionally, a panel of Smad3 mutants is being evaluated for their potential use in treating restenosis.

Gene therapy and tissue-specific drug targeting
Collaborators:
David Lynn, PhD, Department of Chemical Engineering
Shaoqin “Sarah” Gong, PhD, Department of Bioengineering

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.

Also using the nanoparticle technology, the collaborative studies with Dr. Gong’s group aim to develop multifuncitonal nanocarriers (e.g., unimolecular micelles, polymer vesicles, functionalized inorganic nanoparticles) for tissue-specific delivery of therapeutic or diagnostic agents for vascular disease.

Progenitor biology and vascular disease
Collaborators:
Shahin Rafii, MD, Weill Cornell Medical College
Nader Sheibani, PhD, Department of Ophthalmology and Visual Science

Endothelial cell injury underlies several major vascular diseases including atherosclerosis and restenosis. The goal of this collaborative project with Drs. Rafii and Sheibani 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 including MCP-1 activates endothelial progenitor cells or EPCs residing in the outmost layer of the arterial wall. Given their proximity to the site of injury, arterial EPCs are likely to play prominent role in repairing damaged endothelium. Therefore, studying how these progenitor cells are activated and mobilized is likely to produce new information that will facilitate the development of novel strategies designed to boost the regenerative capacity of human body and promote healing of endothelium. Such strategies could be utilized in therapeutic approaches to treat atherosclerosis/restenosis as well as in tissue engineering of synthetic vascular grafts.