We recently established the first-in-kind fly model of polycystic kidney disease (PKD), an incurable genetic disease affecting 12.5 million people world-wide. Because of the experimental intractability of the vertebrate kidney, we have limited knowledge of the precise mechanisms of PKD, which hinders the design of effective therapeutics. Mutations in the Bicaudal C (BicC) gene in flies and the vertebrate orthologous BicC genes cause renal cyst formation. Moreover, we have shown that BicCmay contribute to PKD-type cystogenesis in the 85% of the PKD patients carrying a PKD1 mutation. Our cystic fly model is thus a precious tool for the molecular and cellular characterization of the core mechanisms of renal cyst formation. We leverage on four key advantages of the cystic fly:
1. the Malpighian tubules are equivalent to the human nephron and, unlike the latter, can be cleanly dissected in adequate amounts to enable biochemical, cellular, and pharmacological assays for thespecific study of the tubular tissue; note: this is crucial in the specific case of PKD, because cysts form in the renal tubule;
2. vast genetic collections of mutants are available to study the highly conserved renal function genetics;
3. the fly’s short generation time and inexpensive culturing enables the multiple experimental iterations necessary to refine molecular models;
4. the fly’s minuscule size permits pioneering whole-animal drug screens with analytical amounts of compounds and the analyses of statistically significant populations. Moreover, chemical probing of cellular pathways is complementary to the molecular and genetic studies and may function as efficient whole-animal drug discovery model. We are testing various classes of compounds and have identified three molecules with anti-cystic properties. We collaborate with Chemistry Professor W. D. Lubell at the Université de Montréal to develop chemical probes and novel therapeutic candidates.