Molecular basis of cystic kidney disorders
The unit is interested in understanding the morphogenetic mechanisms driving establishment and maintenance of renal tubular diameter in physiological conditions and that are deranged in pathologies such as cystic kidney disorders. This group uses as a prototype disease Polycystic Kidney Disease (PKD), a genetic disorder, due to mutations in two genes: PKD1 and PKD2, encoding for two membrane proteins Polycystin-1 and 2, respectively. The two proteins localize in cilia, their precise function is unclear.
Over the years this unit found that Polycystin-1 and 2 regulate the cellular cytoskeleton and cell migration as well as tissue morphogenesis in the developing kidney. Furthermore, they discovered that metabolic reprogramming is a key feature of PKD which includes the use of aerobic glycolysis, glutaminolysis and mitochondrial impairment. Several of these derangements depend on the mTOR pathway.
- What is the normal function of the Polycystins? And their role in epithelial morphogenesis during renal development?
- Is the function of the polycystins exclusively due to their activity in cilia, or there are additional functional roles for these proteins?
- What is the origin of the metabolic derangement and mitochondrial alterations observed in PKD animal models?
- Why despite the numerous similarities with cancer, PKD cysts do not transform into carcinomas?
Chiaravalli M, Rowe I, Mannella V, Quilici G, Canu T, Bianchi V, Gurgone A, Antunes S, D’Adamo P, Esposito A, Musco G and Boletta A. 2-Deoxy-D- Glucose Effectively Ameliorates Polycystic Kidney Disease Progression, J. Am Soc. Neph. 2016 Jul;27(7):1958-69.
Pema M, Drusian L, Chiaravalli M, Castelli M, Yao Q, Ricciardi S, Somlo S, Qian F, Biffo S, Boletta A. mTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex. Nat Commun. 2016 Mar 2;7:10786
Castelli M, De Pascalis C, Distefano G, Ducano N, Oldani A, Lanzetti L, Boletta A. Regulation of the microtubular cytoskeleton by Polycystin-1 favors focal adhesions turnover to modulate cell adhesion and migration. BMC Cell Biol. 2015 May 7;16:15.
Nigro EA, Castelli M, Boletta A. Role of the Polycystins in Cell Migration, Polarity, and Tissue Morphogenesis. Cells. 2015 Oct 30;4(4):687-705.
Rowe I, Boletta A. Defective metabolism in polycystic kidney disease: potential for therapy and open questions. Nephrol Dial Transplant. 2014 Aug;29(8):1480-6.
Castelli M, Boca M, Chiaravalli M, Ramalingam H, Rowe I, Distefano G, Carroll T, Boletta A. Polycystin-1 Binds Par3/aPKC and Controls Polarized Cell Migration and Renal Tubular Morphogenesis. Nature Communications, 2013 Oct 24;4:2658.
Rowe I, Chiaravalli M, Mannella V, Ulisse V, Mari S, Pema M, Song X, Quilici G, Xueng H, Qian F, Pei Y, Musco G, Boletta A. Defective Glucose Metabolism in Polycystic Kidney Disease Identifies a Novel. Nat Med 2013 Apr;19(4):488-93.