mTORC1/2 Signaling in the Heart in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

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Cardiac disease, is a common cause of death in PKD patients. Study of the mechanisms of cardiac hypertrophy, beyond hypertension, is an unmet need. Furthermore, testing of novel agents that block mTORC1/2 outputs e.g. 2nd, 3rd and 4th generation mTORC1/2 inhibitors and palmitate conjugated ASOs that vigorously penetrate heart muscle, is an unmet need in cardiac hypertrophy in general as well as PKD specifically. The most exciting development in the field of mTOR inhibitors has been the development of compounds that are highly mTORC1 specific and have less side effects than first generation mTOR inhibitors. DL001 was found to be 40 times more selective for mTORC1 than rapamycin in cells and in vivo and unlike rapamycin, had no effect on glucose tolerance test, did not affect plasma lipids, had a significantly smaller effect on total T cell numbers and no effect on CD3+CD8+ (suppressor/cytotoxic) T cells. We will test DL-001 in our PKD models. The experiments challenge the pre-existing paradigm that hypertension is the main initiator of cardiac hypertrophy and diastolic dysfunction in PKD. We propose that there is increased mTORC1/2 signaling in the heart, cardiac hypertrophy and diastolic dysfunction before hypertension in Pkd1RC/RC mice. Based on the known effects of mTORC1/2 on mechanisms that are deleterious or protective in cardiac hypertrophy, the overall hypothesis is that mTORC1 causes cardiac hypertrophy in PKD while mTORC2 is protective. We propose that genetic or pharmacological inhibition of phosphorylation of mTORC1 (4E-BP1, eIF4E, pS6) will improve cardiac hypertrophy while pharmacological or genetic inhibition of mTORC2 (Rictor, Akt, PKCα) will be harmful in cardiac hypertrophy. In the short term, the genetic studies will offer mechanistic insights into novel mTORC1 and 2 signaling pathways in the heart. It is crucial to understand the pathophysiology of cardiac hypertrophy as it relates to mTORC1/2 to provide insights into the development of new therapies to treat the cardiac hypertrophy. In the long term, the potential future use of novel pharmacological mTOR inhibitors/activators in PKD will be tested in mouse models, orthologous of the human disease. The development of novel mTORC1 and 2 inhibitors, that may have a better therapeutic profile and fewer side effects than existing mTOR inhibitors, may change future clinical practice regarding the use of mTOR inhibitors in cardiac hypertrophy. The proposal is significant as it explores unanswered questions of mTORC1/2 signaling in cardiac hypertrophy: 1) The effect of genetic knockout, ASO therapies and pharmacological inhibition of different components of the 4E-BP1/eIF4E pathway, 2) The effect of new 2nd, 3rd and 4th generation mTOR inhibitors, 3) The effect of pharmacological inhibition/activation of mTORC2. 4) The effect of inhibition of mTORC2 outputs, Akt or PKCα. 5) The effect of mTORC1/2 inhibition on autophagic flux in the heart, 6) The effect of AMPK activators to restrain mTORC1 under conditions of already increased p- AMPK activation. Successful completion of the Aims of the study will lead to more attention being paid to the heart in pre-clinical/clinical studies in PKD, earlier testing of cardiac function in PKD patients and clinical studies of novel agents that target mTORC1/2 in cardiac hypertrophy in general as well as PKD specifically.