Intervention in Progeria by Alterations in dietary macronutrient Composition

通过改变膳食大量营养素成分干预早衰症

• 批准号: 9317787
• 负责人: Dudley William Lamming
• 金额: $ 22.1万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9317787
• 关键词: Adverse effects; Age; Aging; Amino Acids; Animals; Blood Vessels; Branched-Chain Amino Acids; Cardiac; Cardiovascular Diseases; Cell Culture Techniques; Chronic; Clinical Trials; Complex; Consumption; Cues; Data; Defect; Diet; Dietary Intervention; Disease; Disease Progression; Echocardiography; Essential Amino Acids; FRAP1 gene; Farnesyl Transferase Inhibitor; Fibroblasts; Genes; Genetic; Growth Factor; Health; Hereditary Disease; Human; Immunity; Immunosuppression; Inborn Errors Amino Acid Metabolism; Insulin; Intake; Intervention; Isoleucine; Laboratories; Lamin Type A; Leucine; Longevity; Lysine; Macronutrients Nutrition; Mediating; Metabolic; Methionine; Methods; Molecular; Morphology; Mus; Mutation; Nuclear; Nuclear Envelope; Nuclear Lamin; Nutrient; Pathology; Patients; Phenotype; Phenylalanine; Premature aging syndrome; Progeria; Protein Kinase; Protein-Restricted Diet; Publishing; RNA Splicing; Reducing diet; Research; Role; Signal Transduction; Sirolimus; Syndrome; Techniques; Testing; Therapeutic; Thinness; Threonine; Tissues; Tryptophan; Valine; Wild Type Mouse; diabetogenic; dietary restriction; disease phenotype; effective therapy; feeding; glucose tolerance; healthy aging; human disease; improved; in vivo; insulin sensitivity; mTOR Inhibitor; mTOR Signaling Pathway; mTOR inhibition; male; medical food; mouse model; mutant; negative affect; normal aging; prevent; response

Project Summary Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, fatal genetic progeria – a disease of rapid aging. Treatment with rapamycin, an inhibitor of the mTOR (mechanistic Target Of Rapamycin) protein kinase, reverses HGPS phenotypes at the cellular level in HGPS fibroblasts and extends the health and lifespan of mice lacking Lmna. Unfortunately, rapamycin has serious side effects in humans, including both metabolic effects and immunosuppression, which may preclude its long-term use for HGPS patients. While many of the beneficial effects of rapamycin are due to its inhibition of mTOR complex 1 (mTORC1), we have found that many of negative side effects are mediated by “off-target” inhibition of a second mTOR complex, mTORC2. In this proposal, we propose to develop a dietary technique to specifically decrease mTORC1 signaling by decreasing the dietary abundance of specific amino acids. We will then test this intervention and compare to rapamycin in a newly developed HGPS mouse model with the same splicing defect found in humans HGPS patients, and which is unique in reproducing both the progeroid external phenotypes and internal lethal vascular defects found in humans with HGPS. This study will identify new avenues for promoting healthy aging and suppressing disease in the context of HGPS, and may be broadly applicable to other laminopathies as well as normal aging. This proposal will serve as a platform for an R01 application that will not only investigate the molecular mechanisms by which mTOR inhibition can slow the progression of HGPS, but examine the efficacy and mechanisms of similar interventions in normal aging.

项目摘要 Hutchinson-Gilford早衰综合征（HGPS）是一种罕见的，致命的遗传性早衰症-一种快速生长的疾病。 衰老用雷帕霉素治疗，雷帕霉素是mTOR（雷帕霉素的机械靶点）蛋白激酶的抑制剂， 在HGPS成纤维细胞的细胞水平上逆转HGPS表型， 缺乏Lmna的小鼠。不幸的是，雷帕霉素在人体内有严重的副作用，包括代谢， 影响和免疫抑制，这可能妨碍其长期用于HGPS患者。虽然许多 雷帕霉素的有益作用是由于其对mTOR复合物1（mTORC 1）的抑制，我们发现， 许多负面副作用是由第二mTOR复合物mTORC 2的“脱靶”抑制介导的。在 根据这项提议，我们建议开发一种饮食技术，通过以下方式特异性地降低mTORC 1信号传导： 减少特定氨基酸的饮食丰度。然后，我们将测试这种干预措施，并与 雷帕霉素在一个新开发的HGPS小鼠模型中的应用，该模型具有与人类HGPS相同的剪接缺陷 患者，这是独特的复制两个早老的外部表型和内部致死 HGPS患者的血管缺陷这项研究将确定促进健康老龄化的新途径 并在HGPS的背景下抑制疾病，并且也可广泛适用于其他层粘连蛋白病 正常的衰老。该提案将作为R 01应用程序的平台，该应用程序不仅将调查 mTOR抑制可以减缓HGPS进展的分子机制，但检查疗效 以及在正常衰老过程中类似干预的机制。