Project: Research project

Project Details


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.
StatusNot started


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