Our Research
Recovery of filtered proteins by the proximal tubule in normal and nephrotic states.
A major function of the kidney proximal tubule is the retrieval of proteins that escape the glomerular filtration barrier to maintain a protein-free urine. Megalin and cubilin receptors at the apical surface of proximal tubule cells bind and internalize the wide variety of proteins that normally enter the tubule lumen, such as albumin. Albumin uptake normally occurs via saturable uptake with a capacity tuned to the normally filtered concentration of albumin in the tubule lumen. However, the PT is able to recover much higher levels of albumin when the glomerular filtration barrier is damaged. We seek to discover how cubilin and megalin receptors synergize to maximize recovery over the broad concentration range of albumin entering the tubule lumen in normal vs nephrotic conditions. Additionally, we seek to understand why and how excessive protein leakage into the tubule is damaging to PT function.
Development, organization, and function of the proximal tubule apical endocytic pathway.
Endocytic membrane traffic plays a critical role in all aspects of proximal tubule function, including the regulation of ion transport and protein retrieval. We are developing a physiologically accurate model that describes the compartments and kinetics of apical endocytic traffic in the proximal tubule. We are also working to understand the roles of megalin and cubilin receptors and their binding partners in elaboration of this pathway.
Mechanistic basis of proteinuric disease.
Impaired proximal tubule function can trigger glomerular damage to cause chronic kidney disease. Low molecular weight (aka tubular) proteinuria, a sign of early tubule dysfunction, is observed in a variety of disease states, including early-stage diabetes, heavy metal poisoning, and sickle cell disease. Tubular proteinuria is also hallmark of the genetic disorders Dent disease and Lowe syndrome. We are unraveling the molecular and cellular mechanisms by which proteins mutated in these diseases cause tubular proteinuria. Additionally, we seek to understand why tubular proteinuria frequently progresses to more severe kidney disease.