Pathobiology of Renal Epithelial Injury
This aspect of our investigation has been directed towards a detailed analysis and understanding of the complex morphologic features, physiologic mechanisms and metabolic processes which are involved in the recovery from acute renal failure. The present investigations are designed to determine the cellular and molecular basis of the morphologic and physiologic preservation that accompanies recovery from renal epithelial injury and specifically to investigate the role of adenine nucleotide metabolism in the initiation of renal cellular injury, activation of the stress response and recovery. Studies to investigate the integrity of cell plasma membrane structure and function and how it is affected by ATP depletion are being conducted to determine the signaling mechanisms that provide a cross link between the cytoskeletal alterations, cellular nucleotides, induction of the stress response and the loss of membrane integrity. The contribution of the stress response via the induction of heat shock proteins is being studied to determine how these proteins may be involved in cytoprotection by recycling of proteins displaced from their correct membrane domains and how polymorphisms of the gene affect their expression.
Function and Structure of Transporting Epithelia
The structural and functional characteristics of various transporting epithelia are being studied in a variety of normal, adaptive, and pathologic states and it is intended to correlate structure and function at the cellular level. Ultrastructural and confocal microscopy techniques are being used to study adaptive changes in the transporting epithelium. A second area of investigation concentrates on the use of monoclonal antibodies and molecular probes to membrane associated transport proteins. These techniques have been used to assess some aspects of the functional characteristics of NaK-ATPase as well as studying cellular biosynthesis, assembly, and polar insertion into the plasma membrane. In addition, tissues such as colon, liver, heart and brain are also being studied relative to the distribution of isoforms of this enzyme and its relationship to specific transport functions. Additional studies are being directed at the isolation of other transport proteins to study their distribution and function. These include the potassium-proton pump of the colon, CFTR, the polycystins and vacuolar H-ATPase. In addition, studies are underway to investigatethe interactions of transport proteins with adaptor molecules and cytoskeletal elements and the role of these interactions in the development and maintenance of cell polarity as well as in cyst formation.
Pathology of Progressive Glomerular Sclerosis
This area of investigation is designed to examine the factors which are involved in the initiation and progression of renal scarring. Mesangial cells are grown on different defined matrices and are examined for the effect of growth factors on the expression of the phenotypic features, such as their biosynthetic profiles of matrix and cytoskeletal proteins including laminin, fibronectin and collagen types I, III, IV and V, myosin as well as neutral proteases, and cytokines under diabetic conditions. The intracellular signaling mechanisms which are disturbed under these conditions are also being investigated.