The Division of Vascular Surgery has active research programs in both clinical and basic science. The Division has developed a clinical focus on surgical outcomes and the functional health of patients with vascular disease. The central objective of the basic science program is to develop an improved understanding of the important cell-cell and cell-biomaterial interactions within the vasculature.
Basic Science Research
Dr. Shaohua Li leads the basic science effort for the Division. We are interested in understanding the mechanisms that control the formation of organized tissue structures from embryonic stem (ES) cells and induced pluripotent stem (iPS) cells. We are particularly interested in the extracellular cues, their cell surface receptors and downstream signaling pathways in epithelial morphogenesis, vasculogenesis and cardiogenesis. We use a combination of genetic, biochemical and molecular cell biology approaches to dissect the complex interactions between these molecules in the model system of ES/iPS-derived embryoid bodies.
Epithelial morphogenesis. Formation of polarized epithelium is fundamental to embryonic development. During the peri-implantation stage, the undifferentiated inner cell mass of the blastocyst is converted from a non-polar cell aggregate to a highly organized epithelial cyst. This morphogenetic transformation involves the polarization and basement membrane-dependent survival of the epiblast epithelium. Despite the fundamental importance of these processes, both to development and to epithelial biology, there is limited understanding of the molecular mechanisms underlying these events. Thus, the goal of this project is to identify the extracellular cues and transmembrane cascades that regulate epiblast polarization and survival. Using the embryoid body model system, we show that basement membrane formation directs the assembly of an adhesion complex, which serves as a signaling platform to regulate epiblast polarization and survival. We are currently analyzing the functions of the Rho family of small GTPases in epithelial morphogenesis.
Vasculogenesis. Vascular morphogenesis takes place via one of two processes: vasculogenesis, in which progenitor cells differentiate into endothelial cells that construct a nascent vascular network; and angiogenesis, the formation of new blood vessels from existing vessels via sprouting and remodeling. Vasculogenesis mainly occurs during embryonic development but also in response to ischemic insults in adult. ES cell differentiation has been used as a model to investigate the mechanisms of vasculogenesis and as a source of endothelial precursors for potential therapeutic vasculogenesis. A large body of evidence exists that demonstrates a role for growth factors and their receptors in endothelial cell specification, proliferation and migration during vascular morphogenesis. However, relatively little is known about the extracellular matrix associated with early endothelial precursors, and the receptors and intracellular signaling pathways that coordinate with growth factor-mediated signaling to control the vasculogenic process. The goal of this project is to elucidate the extracellular matrix-mediated signaling events that regulate the vasculogenic process during ES cell differentiation. Recently, we have found that cohesive cell aggregates expressing endothelial lineage markers can arise in differentiated embryoid bodies that form yolk sac-like structures. These endothelial precursors are associated with a nascent basement membrane, which coordinates with vascular endothelial growth factor to activate Rho GTPases. Genetic analysis reveals Rho GTPases are required for vascular network assembly. Currently we are investigating the upstream activators and downstream effectors of the small GTPases during vasculogenesis.
Cardiogenesis. Heart failure due to myocardial infarction is the leading cause of mortality in the developed nations. Given that adult cardiomyocytes have very limited ability to regenerate, the use of ES/iPS cell-derived cardiomyocytes to repair damaged heart becomes a new therapeutic paradigm. In order to generate a large number of cardiomyocytes at their appropriate differentiation stage for transplantation and to ensure their integration and maturation in the diseased heart, it is necessary to understand the mechanisms of cardiogenesis during embryonic development and ES/iPS cell differentiation. We have developed a model system in which ES cells are first differentiated into cystic embryoid bodies that contain both visceral and parietal endoderm as well as epiblast. The inhibitory parietal endoderm is selectively removed and the remaining EBs are allowed to attach on a fibronectin substrate for further differentiation. We found that the formation of visceral endoderm significantly enhances cardiac differentiation. This effect is mediated by soluble factors secreted by visceral endoderm. We are currently examining the visceral endoderm-derived factor capable of promoting cardiogenesis from ES/iPS cells.
Our efforts have focused on two areas of vascular surgery which the Division has extensive expertise: aortic aneurysmal disease and carotid disease.Our vast experience in treating aneurysmal disease allows us to collect large volumes of data and compare our results with national trends. Over the past several years we have participated in several industry-sponsored clinical trials evaluating new endovascular devices for treatment of aneurysms.
Our large clinical experience has allowed us to evaluate the patient’s quality of life after surgery using the SF-36 questionnaire. This information has allowed us to provide both state of the art and minimally invasive patient-directed quality care.
Our Division's ability to compare our large series with state and national database will further assist in developing a greater understanding of the importance aneurysmal disease, as well as potentially influence health care policies.
Our research interests also include Health Services Research and Outcomes Research in all areas of vascular surgery. We have performed Outcomes Analysis on a variety of research studies:
Currently, we conduct research projects in some of the above areas with large cohorts of patients using data from large computerized administrative databases. These retrospective databases provide a large population-based sample of all surgical procedures and information on patient diagnoses and comorbidities, medical care received during admission, resource utilization (length of stay, total and detailed charges/cost), medical facility characteristics (location, ownership, teaching status), payers, etc.
Nationwide Inpatient Sample (NIS) is the largest all-payer inpatient database in the US containing information on approximately 8 million hospital admissions each year at 1000 hospitals that is a 20% national sample. The State Inpatient Database (SID) and State Ambulatory Surgery Database (SASD) are the whole datasets that allow analyzing and comparison of surgical practices and outcomes in inpatient and outpatient settings in the state. We are currently working on the design of projects based on the analysis of the Medicare data. These national data contain information about health services for population at age 65 years and above, which is an important segment of surgical population. The results of our analytical studies using administrative databases are valuable for hypothesis-generating information for evaluating surgical performance and improving surgical quality.
Divisional Research Grants
Dr. Paul Haser is collaborating with Dr. Moghe and Dr. Ulrich of Rutgers University on Dr. Moghe’s recently approved Coulter grant.
This grant,NanoLipoBlockers (NLBs): Design of a New Class of Vascular Stents,gives money towards the ex-vivo model for carotid plaque investigation by allowing direct investigation of the vascular stent and the NanoLipoBlockers themselves on atherosclerotic plaque (smooth muscle cell uptake of oxidized cholesterol, monocyte uptake and metabolism effects and endothelial cell receptor modifications). The study looks specifically at the engineering of the NLB onto a stent, the interaction of the coated stent on plaque in a human, ex-vivo model, and then the NLB-stent effects in an arterial injury model in animals.
UMDNJ-Foundation Grant. Intervention for Carotid Stenosis. 2008 - 2010
UMDNJ-Foundation Grant. Arterial Access Catheter 2008- 2010. Patent Office Grant.
Nationally Funded Research Grants
National Natural Science Foundation of China Key Program grant, 81130072/H0203
CREG modulation of cardiogenesis from iPS cells and iCM reprogramming
1-1-2012~12-31-2016 (Co-PI, PI: Y. Han)
National Institutes of Health, R01GM081674
Regulation of embryonic epithelial morphogenesis
American Heart Association Grant-in-aid, 0755935T
Role of CREG in vascular smooth muscle cell phenotype modulation
New Jersey Stem Cell Research Grant, 07-2042-014-84
Regulation of vasculogenesis from embryonic stem cells
National Institutes of Health, R01GM081674-02S1 (special supplement to iPS cell research)
Using induced pluripotent stem cells to study embryonic development
National Institutes of Health, R01NS038469
Laminin-induced membrane complexes in muscle and nerve.
7-1-2004 ~ 6-30-2009, Co-investigator
National Institutes of Health, R37DK036425 (MERIT award)
Basement membrane self-assembly and structure.
1-1-2002 ~ 12-31-2012, Co-investigator
American Heart Association January 1, 2009‐December 31, 2010
Title: Lower extremity angioplasty: Impact of Obesity, Gender, and Ethnicity on Utilization and Outcomes
NCRP Clinical Research Program
AHA Identification Number: 0980011N
Division Clinical Research Trials:
Title: CANOPY: Carotid Artery Stenting Outcomes in the Standard Risk Population for Carotid Endarterectomy
Description: The purpose of the study is to assess the performance outcome (death and stroke rate) of the RX Acculink Carotid Stent System under commercial use by collecting long term post-approval data in patients at standard risk for adverse events from CAROTID ENDARTERECTOMY enrolled by a broad group of physicians.
Title: CHOICE: Carotid Stenting for High Surgical Risk Patients
Description: The purpose of this study is to provide additional information that that the commercially available Abbott Vascular Carotid Stent Systems can be used successfully by a wide range of physicians under commercial use conditions.
Vascutek Anaconda Stent Graft System Phase II IDE Study
Description: The purpose of this study is to test the safety and effectiveness of the ANACONDA Stent Graft System for infrarenal abdominal aortic aneurysms. The system is an investigational device that is being studied for its potential to repair aneurysms located in the abdominal aorta.
Trivascular Ovation Study
Description – The purpose of this study is to test the safety and efficacy of a new endovascular aortic aneurysm repair stent-graft.
Medtronic Valiant Thoracic Stent Graft with the Captiva Delivery System
Description: The purpose of this study is to test the safety and efficacy of a new thoracic endovascular stent graft for thoracicaneurysms.
INNOVATION Trial, Cordis Corporation, Inc.
Description: A multicenter, prospective, non-randomized study of the CordisINCRAFT™ AAA stent graft system in subjects with abdominal aortic aneurysm, to assess the safety of a new stent graft system.