Polycystic Kidney Disease (PKD) is a common cause of kidney failure, and affects around 600,000 people in the US (1), and is characterized by progressively enlarging cysts that eventually destroys the surrounding renal parenchyma. PKD also causes disturbances in renal tubular and blood flow, potentially leading to manifestations such as nephrolithiasis, infection and hypertension. Recent evidence in several animal models and in human PKD supports the idea that the mTOR signaling pathway is hyperactivated and may be a common pathogenic element in PKD (2). MTOR functions in two known complexes, mTORC1 and mTORC2;mTORC1 functions primarily in protein synthesis and proliferation, while mTORC2 functions in the regulation of metabolism, ion transport, cytoskeletal rearrangements and apoptosis, which are all altered in PKD (4). Recent literature and our own preliminary data support the idea that both complexes are activated in PKD (5). It has been shown that progression of the disease can be slowed by use of the mTOR inhibitor rapamycin in some animal models of PKD (17-22);however, two recent human trials did not show any significant benefit to reducing kidney size or preserving renal function with either rapamycin or everolimus (a rapamycin analogue) (23,24). We postulate that there are two potential reasons for these observations: one is that the dose needed to adequately down-regulate mTOR in the kidney may be too high for other tissues, including liver and immune organs, as the dose of rapamycin used in the rodent models was much higher than those in the clinical trials (17). The other reason is that rapamycin is primarily an inhibitor of mTORC1 and has variable effects on mTORC2, and it has been suggested that the inconsistent effect on mTORC2 may play a role in its efficacy (5). Recently developed mTOR active site inhibitors, torkinibs (26), block both mTOR complexes and present an attractive alternative to rapamycin for the study and treatment of PKD. We hypothesize that both mTORC1 and mTORC2 play significant but distinct roles in cystogenesis, and that blockade of both mTORC1 and mTORC2 through torkinibs may have a significant impact on preventing cystogenesis. Inhibiting all of the targets of mTOR in combination may allow for more tolerable doses of drug or simply be a more effective method of inhibiting cyst formation and growth. We look to further characterize the distinct contributions of each mTOR complex on cystogenesis in mice with PKD1 mutation """"""""(V/V)"""""""" (31) and in the Han:SPRD rat (33). We are also currently working on assessing the torkinibs in their effectiveness in treating PKD. To that end, we will test the above animal models of PKD with torkinibs and assess for changes to renal function, kidney size, cyst volume and parenchymal volume as well as monitor for adverse biochemical effects. Finally, we will generate and characterize compound mutants which are homozygous for the PKD (V/V) allele and also homozygous null for SGK1, Akt or p4EBP1 respectively, to potentially better understand the relative contributions of the various mediators downstream of mTOR in the development of PKD.
The thrust of this grant will be to fund an opportunity to investigate a new class of drugs, the torkinibs, and their usefulness in the treatment of Polycystic Kidney Disease, which is marked by conditions of unrestrained cyst growth and eventually progress to End Stage Renal Disease (ESRD). There has been substantial evidence in specific rodent models showing that cysts can be reduced and kidney function can be improved with the drug rapamycin, most likely due to the fact that the protein mTOR, rapamycin's target, is hyperactive and its'blockade ameliorative. However, a clinical trial showed no significant benefit to using rapamycin in humans, potentially due to the fact that it does not block mTOR uniformly. The torkinibs would allow for this uniform blockade of mTOR and in studying them we hope to investigate a potential treatment option for PKD and learn more about mTOR's signaling pathways and its'relation to cyst formation and growth.