The central focus of our laboratory is the study of cellular microenvironment as determined by extra cellular matrix (ECM) and basement membranes (BM) in the regulation of the cellular behavior during health and disease. This fundamental interest in matrix biology has been translated into four major focus areas in the laboratory.
Relative levels of pro- and anti-angiogenic factors likely govern tumor progression: the "angiogenic balance". Conversion of dormant in situ carcinomas into an invasive malignant phenotype is considered to involve a shift in favor of enhanced angiogenesis potential. Influenced by oncogenes and tumor suppressor genes, disruption of the "angiogenic check point" via increase in angiogenic factors such as VEGF or decrease in the physiological levels of endogenous inhibitors of angiogenesis like thrombospondin-1 and tumstatin could represent an important lethal step in the progression of cancer. Thus, genetic control of the physiological levels of endogenous inhibitors of angiogenesis might constitute a critical last line of defense against conversion of neoplastic events into a malignant phenotype of cancer. We are currently testing this hypothesis. This approach to understanding the process of angiogenesis in the laboratory has led to the discovery of seven new basement membranes, derived from anti-angiogenic protein fragments. Discoveries of such matrix derived endogenous inhibitors of angiogenesis are providing new insights into the progression of cancer.
Genetic and Acquired Kidney Diseases: Human kidneys filter 70 liters of plasma every day through the glomerular filtration apparatus consisting of a central glomerular basement membrane (GBM). Most kidney diseases are associated with proteinuria and thus an alteration within glomerular filtration apparatus. We are employing and genetic, biochemical and cell biological approaches to study the glomerular filtration apparatus in the health and disease.
Organ Fibrosis: In many organs, including the kidney and liver, fibrosis (excessive deposition of matrix molecules in association with activated fibroblasts) is the hallmark feature associated with the failure of organ function, irrespective of the etiological onset of disease. Thus, organ fibrosis represents a common final pathway leading to destruction of tissue architecture and function. Our laboratory examines the contribution of epithelial to mesenchymal transition (EMT) involving resident epithelial cells in the accumulation of scar-forming activated fibroblasts during organ fibrosis.
Basement Membrane Assembly, Tissue Engineering and Stem Cells: Basement membranes are composed of large glyco-proteins such as type IV collagen, laminin, heparin sulfate proteoglycan and nidogen/entactin. In the recent years, tissue specific variants/isoforms of type IV collagen, laminin, etc have been identified, leading to the proposal of a new concept that 'not all basement membranes are created equal'. This immediately raises the question as to the function of these specific basement membranes in the regulation of cellular behavior tailored to the need to a given tissue. In the laboratory we have now isolated several tissue specific basement membranes and performed in vitro self-assembly studies. Immediate research goals for these tissue specific basement membranes include studies related to tissue engineering and propagation of stem cell cultures. Recent studies in the laboratory suggest that stem-cell therapy can be successfully used to repair matrix defects in the kidney and elsewhere.