Apoptosis and cell death; Cell Cycle; Cytoskeleton and cell motility; Gene Expression; Genomics and proteomics; Molecular Basis of Disease; Molecular and Cellular Biology; Signal Transduction
One third of our tissue mass is extracellular matrix (ECM). The ECM provides structural support for cells in tissues and varies from being stiff like bone to soft like skin. Importantly, the stiffness of the ECM affects how cells proliferate and migrate and this can be changed by injury or disease. My research is in blood vessels and particularly in arterial stiffening, which is a significant risk factor for the progression of cardiovascular disease, (leading worldwide cause of death). While medications reduce hypertension and cholesterol, none specifically treat arterial stiffness. My lab will identify what happens to cells when arteries become stiffened and determine how this contributes to cardiovascular disease. To understand how arterial stiffening affects cells, we will use mouse and cellular models to mimic the stiffening process in patients. We believe that cells within a stiffer matrix overproduce certain proteins that lead to uncontrolled cell growth, which then begets even more stiffening. Identifying and understanding the proteins in these pathways will allow the development of drugs to counteract their function. Our research will bring fundamental new knowledge about arterial stiffness and lead to new medications that help reduce a key cause of cardiovascular disease.
Oncology; Cell Cycle; Cell growth, differentiation and development; Gene Expression; Molecular Basis of Disease; Molecular and Cellular Biology; Signal Transduction; Transcription and Translation
Protein phosphorylation is an essential mechanism by which intercellular signals regulate specific intracellular events. Protein kinases, the enzymes catalyzing protein phosphorylation reactions, represent a major superfamily of genes, collectively representing 2% of the protein coding potential of the human genome. Current projects in Dr. Edelman‘s lab are devoted to the role of protein kinases in neuronal development and in specific types of cancer. These projects utilize a wide range of techniques and involve, in the case of the latter focus, a collaboration with investigators at Roswell Park Cancer Institute to develop a protein kinase-targeted therapy for prostate cancer.
Cell growth, differentiation and development; Molecular Basis of Disease; Proteins and metalloenzymes; Gene Expression; Inherited Metabolic Disorders; Protein Function and Structure; Cell Cycle
Protein Methylation in Growth and Differentiation. Protein methylation was recently found by systems biology approaches to play a major role in regulating yeast cell growth. Consistent with this finding, we found that disruption of the gene encoding S-adenosylhomocysteine (SAH1) hydrolase markedly inhibited growth. S-adenosylmethionine (SAM) is the universal methyl donor,and SAH1 is the product of all methyltransferase(MTase) reactions.The SAH1 disruption leads to a 50% decrease in protein synthesis which,in turn leads to major decreases in the levels of Cln3p.Unexpectedly,when cells were transfected with a modified gene for Cln3 ,that desreased its rate of degradation,growth rates were normal.This result was unexpected because the basic defect of lacking SAH1 remained.We are currently testing the hypothesis that normal rates of growth are due to increased gene expression for multiple enzymes known to be involved in Met and SAM synthesis. We are also identifying substrates for specific MTases in yeast. Copper deficiency is known to affect brain development, and Menkes disease is fatal due to impaired brain development from low brain copper. A reduction in (SAH1) levels, as occurs in copper deficiency, may affect brain development by inhibiting protein methylation.We demonstrated that inhibiting SAH1 maredly inhibited development of two nerve cell models.
Cardiology; Cardiovascular Disease; Internal Medicine; Apoptosis and cell death; Cell Cycle; Cell growth, differentiation and development; Gene therapy; Stem Cells
I am a researcher with formal training and practice in both general and interventional cardiology. My research expertise is in coronary physiology and physiological studies in large animals with ischemic heart disease. Based on my background, my research is focused on therapeutic approaches to effect cardiac regeneration in large animals with acute and chronic ischemic heart disease. In my laboratory, I use a preclinical porcine model of hibernating myocardium with chronic left anterior descending (LAD) coronary artery occlusion and collateral-dependent myocardium or infarcted myocardium caused by coronary ischemia-reperfusion. I have addressed the problem with several different therapeutic approaches involved in gene therapy, pharmacological and stem cell therapies. We routinely perform physiological studies on these porcine models with quantitative analyses of myocardial morphometry and immune-histochemical analyses. The information we have collected in completed work demonstrates remarkable functional recovery and myocyte regeneration in the adult porcine heart. Intracoronary adenoviral gene transfer with fibroblast growth factor (FGF-5), the HMG-CoA inhibitor pravastatin and intracoronary mesenchymal stem cells (MSCs) all stimulate the proliferation of endogenous cardiac myocytes and, to some extent, generate new myocytes and vessels. Our current work is focused on understanding the regenerative capability of cardiosphere-derived cells (CDCs) originating from heart tissue in acute or chronic ischemic myocardium. The result of this work will play an important role in advancing the care of many patients with acute and chronic ischemic heart disease. In my laboratory, I mentor research fellows through their rotation. Fellows who work in my laboratory have the unique opportunity of being exposed to large animal experimentation and learning skills related to it--in physiology and coronary angiography, as well as computed tomography (CT) and magnetic resonance imaging (MRI) techniques. Under my supervision, fellows also may work on independent projects and learn about cell biology and molecular biology, with the chance to present at international meetings and to publish as an author in international journals.