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

常染色体显性多囊肾病 (ADPKD) 心脏中的 mTORC1/2 信号转导

• 批准号: 10481528
• 负责人: CHARLES Louis EDELSTEIN
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10481528
• 关键词: Antisense Oligonucleotide Therapy; Apoptosis; Attention; Autophagocytosis; Autosomal Dominant Polycystic Kidney; Binding; Blood Pressure; CD3 Antigens; CD8B1 gene; Cardiac; Cause of Death; Cell Count; Cells; Clinical Research; Complex; Cyclic AMP; Cyst; Data; Development; EIF4EBP1 gene; FRAP1 gene; Functional disorder; Future; Generations; Genetic; Genetic study; Glucose; Glucose tolerance test; Goals; Growth; Heart; Heart Diseases; Heart Function Tests; Heart Hypertrophy; Hypertension; Immune; Intervention; Knock-out; Link; Lipids; Mediating; Modeling; Mus; Muscle Cells; Myocardium; Output; PRKCA gene; Palmitates; Pathway interactions; Patients; Penetration; Phosphorylation; Phosphorylation Inhibition; Plasma; Proteins; Proto-Oncogene Proteins c-akt; Protocols documentation; Publishing; Role; Signal Pathway; Signal Transduction; Sirolimus; Structure; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Translations; Weight; clinical practice; cytotoxic; experimental study; human disease; improved; in vivo; inhibition of autophagy; inhibitor; insight; kinase inhibitor; mTOR Inhibitor; mouse model; novel; novel therapeutics; overexpression; pharmacologic; pre-clinical; restraint; side effect; targeted agent

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.

心脏病是PKD患者死亡的常见原因。研究心脏机制 超出高血压的肥大是未满足的需求。此外，对阻止的新型药物的测试 MTORC1/2输出，例如第二，第三和第四代MTORC1/2抑制剂和棕榈酸酯连接的ASOS 剧烈穿透心肌，通常是心脏肥大和PKD的需求 具体来说。 MTOR抑制剂领域最令人兴奋的发展是发展 与第一代MTOR抑制剂相比，高度MTORC1且具有较小副作用的化合物。 发现DL001的MTORC1选择性是细胞和体内的雷帕霉素的40倍，并且与众不同。 雷帕霉素对葡萄糖耐量测试没有影响，不会影响血浆脂质，其较小 对总T细胞数量的影响，对CD3+ CD8+（抑制/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。该实验挑战了先前存在的范式，即高血压是主要发起者 PKD中心脏肥大和舒张功能障碍。我们建议MTORC1/2增加 PKD1RC/RC小鼠中高血压之前的心脏，心脏肥大和舒张功能障碍的信号传导。 基于MTORC1/2对在心脏中删除或保护的机制的已知影响 肥大，总体假设是MTORC1在PKD中引起心脏肥大，而MTORC2为 保护的。我们提出了MTORC1光基化的遗传或药物抑制（4E-BP1， EIF4E，PS6）将改善心脏肥大，而MTORC2的药理或遗传抑制（Rictor，Rictor， AKT，PKCα）在心脏肥大中有害。在短期内，遗传研究将提供机械 对心脏中新型MTORC1和2个信号通路的见解。了解 与MTORC1/2有关的心脏肥大的病理生理学，以提供有关开发的见解 治疗心脏肥大的新疗法。从长远来看，新颖的未来使用 PKD中的药理学MTOR抑制剂/活化剂将在小鼠模型中进行测试，直系同源 疾病。新型MTORC1和2抑制剂的发展，可能具有更好的治疗特征，并且 副作用比现有MTOR抑制剂少，可能会改变有关使用的未来临床实践 心脏肥大中的MTOR抑制剂。该提议很重要，因为它探讨了未解决的问题 心脏肥大中的MTORC1/2信号传导：1）遗传基因敲除，ASO疗法和 4E-BP1/EIF4E途径的不同组件的药理抑制作用，2）新2nd的效果，第三名 和第四代MTOR抑制剂，3）MTORC2药物抑制/激活的影响。 4） 抑制MTORC2输出，AKT或PKCα的影响。 5）MTORC1/2抑制对自噬通量的影响 在心脏中，6）AMPK激活剂在已经增加p- AMPK激活。成功完成研究目标将导致更多关注 PKD临床前/临床研究的心脏，PKD患者的心脏功能和临床的早期测试 对心脏肥大和PKD的靶向MTORC1/2的新型药物的研究。