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

心脏病，是PKD患者的常见死因。心脏疾病发病机制的研究进展 除高血压外，肥大是一种未得到满足的需求。此外，对阻止新药的测试 MTORC1/2输出例如第二代、第三代和第四代mTORC1/2抑制剂和棕榈酸酯偶联ASO 强有力地穿透心肌是心肌肥厚和PKD的一种未得到满足的需求 具体地说。MTOR抑制剂领域最令人兴奋的进展是 与第一代mTOR抑制剂相比，具有高度mTORC1特异性且副作用较少的化合物。 DL001被发现在细胞和体内对mTORC1的选择性是雷帕霉素的40倍，不同于 雷帕霉素对糖耐量试验无影响，对血脂无影响，有明显减小 对T细胞总数有影响，对CD3+CD8+(抑制性/细胞毒性)T细胞无影响。我们将测试DL-001 在我们的PKD模型中。这些实验挑战了高血压是主要诱因的先前存在的范式 PKD患者的心肌肥厚和舒张期功能障碍。我们认为mTORC_1/2增加了 Pkd1RC/RC小鼠高血压前的心脏信号、心肌肥厚和舒张期功能障碍。 基于已知的mTORC1/2对心脏有害或保护机制的影响 肥厚，总体假设是mTORC1导致PKD心肌肥厚，而mTORC2是 防护性的。我们认为，遗传或药物抑制mTORC1(4E-BP1， EIF4E，pS6)将改善心肌肥厚，而药物或遗传抑制mTORC2(Rictor， AKT、PKC、α)在心肌肥大中具有一定的危害性。在短期内，基因研究将提供机械性的 对心脏中新的mTORC1和2信号通路的洞察。重要的是要理解 心肌肥厚的病理生理学，因为它与mTORC1/2有关，以提供对心肌肥厚发展的洞察 治疗心肌肥厚的新疗法。从长远来看，小说未来的潜在用途 PKD中的药理mTOR抑制剂/激活剂将在与人类同源的小鼠模型中进行测试 疾病。新型mTORC1和2抑制剂的开发，可能具有更好的治疗方案和 副作用比现有的mTOR抑制剂更少，可能会改变未来关于使用 心肌肥厚中的mTOR抑制剂。该提案具有重要意义，因为它探索了以下悬而未决的问题 心肌肥厚中的mTORC1/2信号转导：1)基因敲除、ASO治疗和 4E-BP1/eIF4E途径不同成分的药理抑制作用，2)新的2、3号的作用 和第四代mTOR抑制剂，3)药物对mTORC2的抑制/激活作用。4) 抑制mTORC2输出、Akt或PKCα的效果。5)mTORC1/2抑制对自噬通量的影响 在心脏，6)AMPK激动剂在已经增加p-1的条件下抑制mTORC-1的作用。 AMPK激活。研究目标的圆满完成将使人们更加关注 PKD的临床前/临床研究中的心脏，PKD患者和临床的心功能早期测试 靶向mTORC1/2的新药物在一般心肌肥厚以及PKD特异性中的研究。

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.