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Principal Investigator: CHARLES Louis EDELSTEIN
Organization: VA EASTERN COLORADO HEALTH CARE SYSTEM
Fiscal Year: 2024
Funding agency: Veterans Affairs
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.
Terms: <3'5'-cyclic ester of AMP><4E-BP1><ADPKD><AKT><ASO therapeutics><ASO therapy><ASO treatment><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Adult Polycystic Kidney Disease><Akt protein><Antisense Oligonucleotide Therapy><Apoptosis><Apoptosis Pathway><Attention><Autophagocytosis><Autosomal Dominant Polycystic Kidney><Autosomal Dominant Polycystic Kidney Disease><Binding><Blood Plasma><Blood Pressure><CD3><CD3 Antigens><CD3 Complex><CD3 molecule><CD8><CD8B><CD8B1><CD8B1 gene><Cardiac><Cardiac Diseases><Cardiac Disorders><Cardiac Function Tests><Cause of Death><Cell Body><Cell Communication and Signaling><Cell Count><Cell Number><Cell Signaling><Cells><Clinical Research><Clinical Study><Complex><Cyclic AMP><Cyst><D-Glucose><Data><Development><Dextrose><Dominant Polycystic Kidney Disease><Dysfunction><EIF4EBP1><EIF4EBP1 gene><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Functional disorder><Future><Generalized Growth><Generations><Genetic><Genetic study><Glucose><Glucose tolerance test><Goals><Growth><Heart><Heart Diseases><Heart Function Tests><Heart Hypertrophy><Hexadecanoates><Hypertension><IPGTT><Immune><Immunes><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Knock-out><Knockout><LYT3><Link><Lipids><Mechanistic Target of Rapamycin><Mediating><Mice><Mice Mammals><Modeling><Molecular Interaction><Murine><Mus><Muscle Cells><Myocardium><Myocytes><OKT3 antigen><Output><PKC(alpha)><PKCA><PKCα><PRKCA><PRKCA gene><Palmitates><Pathway interactions><Patients><Penetration><Phosphorylation><Phosphorylation Inhibition><Physiopathology><Plasma><Plasma Serum><Programmed Cell Death><Protein Kinase B><Protein Kinase C Alpha><Protein Kinase C α><Protein Kinase Calpha><Protein Phosphorylation><Proteins><Proto-Oncogene Proteins c-akt><Protocol><Protocols documentation><Publishing><RAC-PK protein><RAFT1><Rapamune><Rapamycin><Reticuloendothelial System, Serum, Plasma><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Sirolimus><Structure><T-Cells><T-Lymphocyte><T3 Antigens><T3 Complex><T3 molecule><Testing><Therapeutic><Therapeutic Effect><Tissue Growth><Translations><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Weight><adenosine 3'5' monophosphate><anti-sense oligonucleotide drug><anti-sense oligonucleotide therapy><anti-sense oligonucleotide treatment><anti-sense therapy><antisense drug><antisense oligonucleotide therapeutic><antisense therapeutics><antisense therapy><autophagy><biological signal transduction><c-akt protein><cAMP><cardiac hypertrophy><cardiac muscle><clinical practice><cytotoxic><developmental><experiment><experimental research><experimental study><experiments><heart disorder><heart muscle><high blood pressure><human disease><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><improved><in vivo><inhibition of autophagy><inhibitor><insight><interventional strategy><intraperitoneal glucose tolerance test><kinase inhibitor><mTOR><mTOR Inhibitor><mammalian target of rapamycin><mouse model><murine model><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><ontogeny><overexpress><overexpression><pathophysiology><pathway><pharmacologic><pre-clinical><preclinical><protein kinase Cα><proto-oncogene protein RAC><proto-oncogene protein akt><rac protein kinase><related to A and C-protein><restraint><side effect><social role><targeted agent><thymus derived lymphocyte><translation><weights>