Dr. Mark Segal’s Lab
Dr. Segal received a B.S. degree in Biology from MIT in 1984. As an undergraduate he did research in the laboratory of Dr. Monty Krieger studying the alteration in the glycosylation pattern of a cell line defective in LDL receptor endocytosis. After graduating from MIT, Dr. Segal was accepted into the MSTP M.D./Ph.D. training program at the University of Texas Southwestern Medical School. He did his Ph.D. dissertation work in the laboratories of Dr. Mary-Jane Gething and Dr. Joseph Sambrook. He studied the folding pattern of the influenza hemagglutinin protein and its interaction with the heat shock protein BiP. After graduating from the M.D./Ph.D. program in 1992, he completed both his internship and residency in Internal Medicine at Parkland Memorial Hospital at Dallas. In 1995, he started his nephrology fellowship at Beth Israel Hospital under the direction of Dr. Vikas Sukhatme. During his fellowship, he worked on a developing a gene therapy vector consisting of a newly created lentiviral vector combined with an adenoviral vector to yield a novel method for gene transduction into the kidney. For this work he was awarded an NIH KO8. In addition, Dr. Segal worked on investigating the mechanism by which endostatin, an anti-angiogenic compound, is completely selective for endothelial cells in tumor vascular beds. After one year as an Instructor at Harvard Medical School, he joined the Department of Medicine at the University of Florida as an Assistant Professor. In 2008, he was promoted to Associate Professor with tenure. In 2010 he was appointed Chief of the Division of Nephrology, Hypertension, and Renal Transplantation.
The Segal Lab is interested in understanding the mechanism of increased cardiovascular risk in special populations. These populations include patients with chronic kidney disease, patients with lupus nephritis, patients receiving high doses of erythropoietin, and women who have complicated pregnancies. Our hypothesis is that the mechanism of the increased risk in these populations can be determined by analysis of components of the peripheral blood. Our lab has focused on utilizing circulating endothelial cells as a marker of increased endothelial injury and bone marrow progenitor cells as a mechanism of endothelial repair.
Circulating endothelial cells are mature endothelial cells and express phenotypic endothelial cell markers such as von Willebrand factor, VE-cadherin, CD146, and TE-7. These mature endothelial cells may detach due to mechanical disruption or as a result of apoptosis, although TUNEL assays for apoptosis performed on CEC were negative. In normal individuals, there are approximately 0-20 CEC per milliliter of blood. However in a number of difference conditions that have endothelial injury the number is significantly higher. The numberof circulating endothelial cells provides insights as to the endothelial health of patients.
Bone marrow derived endothelial cells are cells that are derived from the bone marrow that can facilitate or take part in angiogenesis. Bone marrow derived endothelial cells are found in the circulation are identified by stem cell markers CD133 or CD34. CD34+ mononuclear cells, after seven days of culture on fibronectin display an endothelial cell phenotype, are able to incorporate acetylated LDL, produce nitric oxide when stimulated with VEGF, and express PECAM and Tie-2 receptor. Bone marrow derived endothelial cells populate areas of neoangiogenesis.
We have previously shown that the number of CEC in HD patients, similar to patients with active sickle-cell disease and recent acute myocardial infarction (AMI), is increased. While normal controls have 19 ± 7.1 CEC/ml (n=25), hemodialysis patients have 29.7 ± 18.6 CEC/ml (n=29) (p<0.05). A sub-group analysis of hemodialysis patients with confirmed coronary artery or peripheral vascular disease (n=11) demonstrated that patients without ongoing symptoms suggestive of atherosclerotic disease in the past three months (n=6) had significantly fewer CEC as compared to patients (n=5) who had ongoing symptoms of atherosclerotic disease in the past three months (12.3 ± 6.7 vs. 48.7 ± 10.6, p < 0.001).
While CD34+ cells isolated from healthy individuals migrate well in response to pM and nM concentrations of SDF-1, CD34+ cells isolated from diabetic patients with retinopathy and stage V or stage I or II CKD all had defective migration. In addition, the result was the same whether the patients had Type I or Type II diabetes. We have demonstrated that CD34+ cells isolated from diabetic patients could be corrected by treatment with nitric oxide.
Our current research is focused on two different areas:
1) We are studying the levels and function of circulating endothelial cells and bone marrow derived endothelial cells in women during spontaneous pregnancies and pregnancies in women who conceived through artificial reproductive technology. We are investigating the question as to whether the health of the blood vessels during pregnancy affects future risk of heart disease?
2) Our previous work has demonstrated a novel interaction between the beta common receptor and vascular endothelial growth factor receptor-2. We are investigating the clinical consequences of this interaction.