The Center focuses on six key thematic areas of emphasis that encompasses many mechanisms involved in cystic kidney disorders. These themes are:
- Cilia-related biology – The primary cilium extends into the lumen of the nephrons influencing renal function and defects in primary cilia contribute to cystic disease pathogenesis. Although the extent of activities in which the cilium is involved remains uncertain, it can mediate mechanosensory signals that regulate Ca2+. Cilia also influence many cystic kidney disease related pathways (mTor, Hh, Purinergic, STAT, Raf-1, kinase inhibitory protein, etc.) and secondary signaling factors (e.g. cAMP). Thus, dissecting cilia function is critical to the understanding HRFDs.
- Epithelial transport pathways – Cyst formation is associated with changes in cell polarity and altered ion (Na+, Cl-, and Ca2+) and fluid transport across the epithelium. Changes in these transport processes contribute to cyst expansion.
- Signal transduction pathways critical for epithelial cell proliferation and differentiation - The pathogenesis of cystic diseases is associated with changes in numerous signaling pathways and changes in the regulation of these pathways result in altered states of differentiation, apoptosis, and proliferation promoting cystogenesis or influencing the rates of cyst progression.
- Epithelial injury, repair, and differentiation -The rate of cyst formation can be exacerbated by injury or hypertrophic signaling in several mouse models. This led to an hypothesis that a third hit, such as injury, is important for rapid rates of cyst development. Injury causes inflammation, epithelial dedifferentiation, cell proliferation, and apoptosis, all of which are involved in cystic kidney diseases.
- Drug discovery and treatment strategies – Following the advances made in our understanding of the cellular changes and signaling pathways involved in HRFDs, a major goal of the Center will be to see the translation of this knowledge into pharmacological approaches to alter HRFD pathway perturbation to slow disease progression. Similar level of disease knowledge has triggered identification of effective FDA-approved treatments for other inherited disorders (e.g., cystic fibrosis or Fabry disease), and we believe that comparable success can be achieved with cyst kidney disorders. To help facilitate this goal, the Center has established the Therapeutics Development and Screening Resource to provide essential tools, models and technologies, along with an integrated experimental plan for their use in lead compound optimization and preclinical development.
- Improved diagnostics and screening – With each new mutation or cystic kidney/liver gene identified in human patients or model systems we expand our capabilities for diagnosis and future genetic counseling. Importantly, each of these new players will serve as potential sites for drug discovery and disease intervention.