Endothelial cells proliferate, migrate and ultimately differentiate to form tubular blood vessels. This process, known as angiogenesis, is critical for providing oxygen and nutrients to developing tissues in the embryo, and for growth and repair processes in the adult. In addition, the endothelium is a critical regulator of the tissue microenvironment; regulating many aspects such a interstitial protein composition, coagulation, and inflammation. The growth of new blood vessels, and their proper functioning, are both critical determinants in numerous pathologies where extensive tissue remodeling takes place. Our lab is interested in the cellular signaling that regulates growth control and differentiation decisions in the vascular endothelium, and how they might contribute to human diseases including:
Vascular malformations: Several genes in the Ras signaling pathway have been clinically linked with the development of vascular malformations, including RASA1, NF1, and PTEN. These can have devastating consequences when they obstruct or rupture in critical organs. A principal focus in the lab is dissecting out the molecular mechanisms involved with these cellular fate decisions in order to uncover opportunities for intervention.
Retinopathy: two of the leading causes of blindness in the US are proliferative retinopathies, whereby excessive vascular remodeling in the retina damages the surrounding tissue architecture and integrity required for sight. To provide better insights into best possible treatment modalities, we are elucidating and modeling the underlying molecular aspects that drive this dysfunctional vasculature.
Tumor Angiogenesis: The growth and metastasis of tumors is largely dependent upon the tumor's ability to stimulate angiogenesis. In addition the abnormal vasculature that tumors promote often contributes to a tumor microenvironment than can negatively contribute to effective therapy. We are interested in molecular mechanisms to dampen and normalize tumor vasculature, in order to enhance response to conventional therapy and potentially promote novel chemotherapeutic and tumor targeted interventions.
Wound Healing: Efficient wound repair and resolution requires a coordinated response from the vascular endothelial cells, epithelial cells, and tissue fibroblasts as well as immune cells to create the appropriate wound microenvironment for the stage of repair being advance. We are working closely with colleagues to better understand how alterations in these cellular dialogues contributes to pathogenic wound healing such as that seen in chronic wounds, as well as in hypertrophic scarring and keloid formation.
Our approach is to use “hierarchical” and interdisciplinary approach to investigate cellular signaling systems. We start in primary human cell culture systems using a combination of cellular biology, molecular biology, and biochemical approaches. We then expand these studies into more complex co-culture and/or three-dimensional culture systems. Finally when required, we use genetic modeling in adult animals, typically using inducible and tissue specific gene activation or deletion, in order to test the modeling of human disease.
Vascular and Tumor Biology, Tumor Microenvironment, Angiogenesis, Endothelial Cells, Neurofibromatosis, Retinopathy, Vascular Malformations, Wound Healing, Cell Signaling