Fouad T. Chebib, M.D., studies autosomal dominant polycystic kidney disease (ADPKD) from multiple points of view: the molecular, translational and epidemiologic levels.
In Dr. Chebib's laboratory, researchers focus on understanding the mechanisms that cause the kidneys to form fluid-filled cysts that lead eventually to kidney failure. Dr. Chebib is interested in restoring the disrupted balance within kidney cells by targeting several ion channels. His approach includes combining the use of state-of-the-art technologies such as genetically encoded biosensors, perfusion systems and high-throughput platforms.
Tolvaptan, a recently approved treatment for rapidly progressive ADPKD, slows but does not stop its progression. Therefore, development of complementary or more-effective therapies is an urgent and unmet need. Dr. Chebib aims to find novel targets and therapies to maximize the effectiveness in stopping the progression of ADPKD, the most common inherited kidney disease.
- Role of calcium and cAMP signaling in ADPKD. Disruption of intracellular calcium likely underlies the upregulation of cyclic AMP (cAMP) signaling and the proliferative and secretory phenotype of the cystic epithelium in ADPKD. However, the mechanisms by which polycystins reduce cytoplasmic calcium remain elusive. Understanding the pathogenesis of ADPKD will allow a targeted and effective therapy. Calcium disruption is central to the pathogenesis of ADPKD and upstream of all pathways. Dr. Chebib's group focuses on understanding the calcium and cAMP homeostasis in ADPKD.
- Role of mechanotransduction in cystogenesis. Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations to PKD1 or PKD2 encoding polycystin-1 (PC1) and polycystin-2 (PC2), is characterized by focal invaginations of the tubular epithelium that become disconnected blind sacs. Polycystins have been suggested to play a role in mechanotransduction, the process of sensing mechanical stimuli and converting them to biochemical signals such as calcium. Dr. Chebib aims to understand the role of polycystins in mechanotransduction and how their interaction with other mechanosensitive ion channels such as Piezo1 play a role in cystogenesis.
- Translational research in ADPKD. As a physician-scientist, Dr. Chebib's primary goal is to find therapy options that are effective in slowing or preventing the kidney cyst formation. Dr. Chebib explores several treatment options through targeted approaches as well as broad approaches to find novel small molecules by using high-throughput screening platforms. Dr. Chebib tests these novel targets on several cystic disease models starting from cells to animals with cystic disease. His hope is to find the most effective and tolerated drug possible that could be offered to patients with ADPKD.
- Genotype to phenotype characterization in ADPKD. ADPKD surprisingly has a variable phenotype among family members with the disease. Using the large database of ADPKD patients at Mayo Clinic, Dr. Chebib studies the effect of PKD mutations on multiple extrarenal manifestations.
- Implementation of novel therapies into practice. The U.S. Food and Drug Administration approved tolvaptan as the first drug treatment to slow kidney function decline in adults at risk of rapidly progressing ADPKD. Dr. Chebib has been involved in developing treatment protocols and structuring the tolvaptan clinic to ensure that this treatment is implemented safely and effectively.
Significance to patient care
Dr. Chebib is dedicated to the discovery of novel therapies with the ultimate goal of preventing patients with ADPKD from reaching end-stage kidney failure.
- Recipient, Team Science Award, Mayo Clinic, 2020