The goal of this Career Development Award is to develop the skills to address the cellular mechanisms controlling hypertrophy in renal disease. The kidney responds to loss of nephrons or metabolic derangements by increasing the size of existing glomeruli and tubules rather than by duplicating nephrons. While this hypertrophy of the kidney helps the body adapt to conditions which require increased filtration and reabsorption, hypertrophy is not always beneficial. Diabetes mellitus and loss of renal mass cause renal hypertrophy that has been associated with the development of sclerosis and progressive loss of renal function. While the cellular mechanisms causing hypertrophy are unclear, recent advances in the control of cell growth provide an opportunity to address the mechanisms causing protein accumulation in hypertrophy. The candidate is an academic nephrologist with a longstanding interest in the cellular mechanisms of renal hypertrophy who is trying to develop an independent laboratory. The research development plan is aimed both to teach the candidate new techniques in control of cellular protein metabolism, and also broaden his back ground in mitogenic cell signaling, an area where he already has limited expertise. Experience with studying cellular mechanisms in vivo models of hypertrophy will be especially useful. The advisors and consultants have expertise in specific areas vital to both current and future research (Protein metabolism, mitogenic signaling, and hypertrophic renal diseases). The research plan addresses mechanisms of protein accumulation by renal epithelial cells. In tissue culture models of hypertrophy, it will investigate how EGF plus TGF beta decreases protein degradation Experiments examine the role that the metabolism of proteins that are targeted for lysosomal breakdown play in the increase in protein half- life. Results from this aim will define if a specific lysosomal import pathway acts to regulate protein accumulation in EGF+TGF beta and ammonium chloride mediated hypertrophy, and if specific candidate proteins are regulated. Using the mechanisms found in these in vitro experiments, studies will be performed in well defined rat models of renal hypertrophy. Results from this aim will determine if specific pathways of protein degradation play a role in the tissue specific protein accumulation seen in diabetic and acidotic models of renal hypertrophy, and test if our cell culture model accurately depicts the mechanisms associated with hypertrophy in vivo. It should also lay the ground work for further investigations into the mechanisms behind renal hypertrophy.
