![]() Many projects in the lab involve unbiased expression profiling of endothelial cells. Current work in the lab is determining the gene-specific and common functions of CLIC1 and CLIC4 that allow these proteins to link GPCRs, like the S1P receptor and other endothelial receptors, to downstream GTPase and vascular function. Recent work in our lab has demonstrated that these proteins play critical roles in endothelial response to S1P, a central signaling factor in the control of endothelial barrier formation and vascular leakiness. CLIC1 and CLIC4 are expressed in endothelial cells and are vital for angiogenesis in vitro and in vivo. Chloride intracellular channels (CLICs) are a poorly understood family of six metamorphic proteins with potential functions either as ion channels or glutathione-S-transferases, however, these activities have not been linked to specific intracellular processes or physiological functions. Current work in the lab is also exploring critical roles of other Notch receptors and ligands in TNBC and other cancer types.īlood vessels must maintain a delicate balance between sufficient permeability to pass necessary proteins, nutrients, signaling factors, and cells, while maintaining sufficient barrier function to prevent edema, dysregulated immune response, and thrombosis. Most studies on Notch-mediated tumor angiogenesis focus on Notch1 and the ligand Dll4. Current work in the lab is aimed at elucidating how Jag1 affects the interactions between tumor cells and adjacent blood vessels to control tumor growth and the ability of tumor cells to enter the bloodstream and metastasize. Jag1-specific Notch decoys reduce tumor growth, tumor blood vessels, and perfusion. The lab has previously developed a class of proteins, called Notch decoys which only block specific elements of the Notch signaling pathway and which show little or no toxicity. Researchers have previously attempted to stop tumor growth by blocking all of Notch signaling, but currently available inhibitors of Notch signaling have failed due to severe gastrointestinal toxicity or vascular malformations. TNBC tumors frequently overexpress Notch ligand Jag1, which is thought to promote tumor growth by increasing the tumor’s ability to recruit blood vessels from neighboring tissue so that the tumor receives oxygen and nutrients. Targeted therapies for TNBC are badly needed to improve the quality of life for patients. Unlike other forms of breast cancer, TNBC generally requires treatment with chemotherapy, radiation, or surgery. Triple-negative breast cancer (TNBC) is diagnosed in approximately 40,000 women each year in the United States. In particular, several projects focus on specific Notch effectors and how they regulate specific aspects of Notch-mediated endothelial phenotypes. Current work in the lab explores the roles of Notch-driven angiogenesis in tumor formation and metastasis (described below), cardiovascular disease, and aging-related cognitive decline. Defining such targets is a significant step forward in obtaining a deeper knowledge of the role of Notch in healthy vessels and human disease. We have recently identified several novel classes of rapid-response Notch targets and are starting to explore the role(s) of these genes in angiogenesis. We use unbiased screening of Dll4- or Jag1-Notch induced endothelial transcription to identify putative direct Notch targets, validate those targets in loss- and gain-of function angiogenic assays, and determine their in vivo relevance. Our knowledge of Notch-regulated angiogeneic mediators outside of the VEGF family is limited. In endothelial cells, the Notch ligand Dll4 signals in normal and pathological angiogenesis to restrict sprout formation and promote perfusion, whereas the Notch ligand Jag1 may have both Notch activating and inhibitory roles. Notch acts to regulate expression of downstream targets that carry out Notch functions (Notch effectors). Abnormal Notch signaling is a significant contributor to cardiovascular diseases including blindness, stroke, ischemia, arteriovenous malformations (AVM) and tumor angiogenesis. Notch signaling has essential and diverse functions in angiogenesis. Our overall goal is to define the mechanisms by which Notch signaling controls normal and pathological angiogenesis and identify therapeutic targets to treat human disease.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |