Biochemical "Mapping" of kidney cell and tissue phenotype
This is a proposal to utilize recent and anticipated gains in genomics, proteomics and metabolomics to precisely define the biochemistry of cells or tissues that have received stimuli that are associated with chronic kidney disease. A major controversy in the pathogenesis of CKD is the role of epithelial-to-mesenchymal transition (EMT). The argument centers upon the origin of cells producing ECM, and particularly intensely ...more »
This is a proposal to utilize recent and anticipated gains in genomics, proteomics and metabolomics to precisely define the biochemistry of cells or tissues that have received stimuli that are associated with chronic kidney disease.
A major controversy in the pathogenesis of CKD is the role of epithelial-to-mesenchymal transition (EMT). The argument centers upon the origin of cells producing ECM, and particularly intensely upon whether renal tubular epithelial cell EMT contributes to the population of fibroblasts. I believe that our inability to address this problem is partly definitional, and would propose that we re-frame the argument. The problem has been stated anatomically. While the anatomy is important, we do not yet have sufficient perspective to address it. We should first consider it as a problem of pathophysiology.
Many investigators describe cells as undergoing EMT, yet they refer to almost as many different phenomena. We lack precise definitions of the events under study. Each cell might be characterized as existing on a continuum between what has been regarded as purely “epithelial” or purely “mesenchymal.” Perhaps more accurately, each cell has a molecular “signature” that determines how it responds to a given stimulus. As this signature varies over different conditions, its response to the same stimulus also will differ. Thus, whether or not the tubular epithelial cell dedifferentiates to becomes a fibroblast is only a part of the question; it also may dedifferentiate to present antigens, produce potentially fibrogenic cytokines, etc. We urgently need to develop a “map” of molecule expression and cell function that could be used to precisely characterize the nature of changers that occur during fibrogenesis. Such a map would not in itself solve the problem, but it would provide a new paradigm that could enhance our ability in:
• Basic science – Define what molecular signatures are associated with various cell activities (including the productive fibroblast), and permit lineage tracing studies to define the origin of cells with different fibrogenic functions (not only ECM production).
• Translational science – Define how specific molecular signatures are associated with different stages of disease pathogenesis and progression.
• Clinical science – Understand how molecular signatures obtained from biopsies correlate with response to specific treatment.
• Clinical medicine – Guide the clinician in applying a therapy appropriate to disease stage.
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