The candidate's long-term goal is to identify cellular and molecular mechanisms that mediate the early events in nephrolithiasis. The candidate and his sponsor, Dr. F. Gary Toback, have developed an educational plan which foster acquisition of the investigative skills and techniques necessary to conduct state-of-the-art research in renal cell physiology, and provides the opportunity to apply these studies directly to patients with nephrolithiasis. Development of the candidate into an independent investigator will be facilitated b receipt of a Clinical Investigator Award. During the course of the proposed award, he will expand previous collaborative efforts with established investigators in the basic sciences at the University of Chicago, as well as initiate new collaborations which extend his studies into new fields. The candidate will have the unique advantage of close contact with the University of Chicago Kidney Stone Program and a recognized expert in nephrolithiasis. During the past 2 1/2 years the candidate has developed a tissue culture model of nephrolithiasis and used it to characterize how renal epithelial cells respond to an interaction with the most common crystal in urine and stones, calcium oxalate monohydrate (COM). He found that COM crystals adhere to the renal cell surface, undergo endocytosis, and initiate subsequent cellular response such as early gene expression, cytoskeletal reorganization, and DNA synthesis. A novel observation, that Tamm-Horsfall glycoprotein (THP), the most abundant protein in human urine, inhibits endocytosis of COM crystals will be studied in depth because recent work reveals that this protein appears to have lost its inhibitory function in specific patients with recurrent nephrolithiasis.
Specific aims of the project are to: 1) Define a specific surface receptor (s) for COM crystal on renal epithelial cells. 2) Characterize the interaction of THP with renal epithelial cells. 3) Investigate THP structure and function in patients with nephrolithiasis. 4) Define factors that regulate adhesin and subsequent endocytosis of COM crystals. 5) Identify structural and functional alteration in the plasma membrane, cytoskeleton, and nucleus of renal epithelial cells following attachment and endocytosis of COM crystals. 6) Determine if adhesion and/or endocytosis of COM crystals induces release of autocrine/paracrine factors from renal cells. 7)Identify potential therapeutic agents that block individual steps in the cascade of cellular and molecular events set in motion when a COM crystal interacts with a renal epithelial cell. Achieving these specific aims will increase understanding of how kidney epithelial cell respond to urinary crystals. Elucidation of these processes at the cellular and molecular level could help attain the long-term goal of formulating rational new therapeutic strategies to prevent renal crystal retention and the formation of calculi.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08DK002272-01
Application #
2134127
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1994-01-01
Project End
1998-12-31
Budget Start
1994-01-01
Budget End
1994-12-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Lieske, J C; Toback, F G; Deganello, S (2001) Sialic acid-containing glycoproteins on renal cells determine nucleation of calcium oxalate dihydrate crystals. Kidney Int 60:1784-91
Lieske, J C; Toback, F G (2000) Renal cell-urinary crystal interactions. Curr Opin Nephrol Hypertens 9:349-55
Koka, R M; Huang, E; Lieske, J C (2000) Adhesion of uric acid crystals to the surface of renal epithelial cells. Am J Physiol Renal Physiol 278:F989-98
Lieske, J C; Huang, E; Toback, F G (2000) Regulation of renal epithelial cell affinity for calcium oxalate monohydrate crystals. Am J Physiol Renal Physiol 278:F130-7
Lieske, J C; Deganello, S; Toback, F G (1999) Cell-crystal interactions and kidney stone formation. Nephron 81 Suppl 1:8-17
Asplin, J R; Parks, J H; Chen, M S et al. (1999) Reduced crystallization inhibition by urine from men with nephrolithiasis. Kidney Int 56:1505-16
Lieske, J C; Deganello, S (1999) Nucleation, adhesion, and internalization of calcium-containing urinary crystals by renal cells. J Am Soc Nephrol 10 Suppl 14:S422-9
Lieske, J C; Toback, F G; Deganello, S (1998) Direct nucleation of calcium oxalate dihydrate crystals onto the surface of living renal epithelial cells in culture. Kidney Int 54:796-803
Lieske, J C; Norris, R; Swift, H et al. (1997) Adhesion, internalization and metabolism of calcium oxalate monohydrate crystals by renal epithelial cells. Kidney Int 52:1291-301
Lieske, J C; Hammes, M S; Hoyer, J R et al. (1997) Renal cell osteopontin production is stimulated by calcium oxalate monohydrate crystals. Kidney Int 51:679-86

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