The kidney is composed of several cell types, which are organized into a complex network of tissues for processing the blood and regulating the final composition of urine. Many processes involved in kidney development are also required for proper kidney maintenance and function.
Dr. Sussman's laboratory focuses on pathogenic alterations in kidney development and maintenance leading to cyst formation and polycystic kidney disease (PKD). PKD is primarily characterized by progressive renal cyst formation, ultimately leading to renal failure. It occurs in two major forms: autosomal dominant (ADPKD) and autosomal recessive (ARPKD).
ADPKD is the most common genetic cause of renal failure and often presents in the prime of life (third to fourth decades). It causes approximately 10 percent of end-stage renal disease cases; nearly 10 percent of people undergoing kidney dialysis are doing so because of ADPKD. ARPKD is less common but more severe, as it causes approximately 30 percent mortality within the first year of life.
Mutations in polycystin-1, polycystin-2 and fibrocystin/polyductin proteins account for most, but not all, cases of PKD. Additionally, variability in the onset and severity of PKD indicates the importance of additional modifier proteins in the etiology of PKD. This is especially true for the more prevalent autosomal dominant form. Identification of modifier and novel causal proteins is critical for their diagnostic and prognostic value — and for the development of new therapeutics.
Dr. Sussman's lab is using zebrafish to characterize putative novel modifier and causal proteins in PKD. The zebrafish model system has several advantages for these studies. Zebrafish have external fertilization, so kidney development is readily visible throughout embryogenesis. In addition, the relevance of several zebrafish models of PKD has been demonstrated; similar morphological and physiological changes occur in zebrafish in response to the alteration of proteins involved in PKD in humans.
Most notably, zebrafish develop dilation of renal tubules, renal cysts, and impaired fluid balance and renal function. These validated zebrafish models of PKD are useful for assessing contributions of additional candidate proteins to PKD. The genetic tractability of zebrafish facilitates in vivo studies targeting specific proteins, and there are several lines of renal fluorescent reporter fish to facilitate detection of renal effects.
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