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

基本信息

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
项目类别：
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

项目摘要

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 progeria综合征（HGP）是一种罕见的致命遗传生产者 - 一种快速的疾病老化。用雷帕霉素（MTOR（雷帕霉素的机械靶点））蛋白激酶的抑制剂治疗，逆转HGP的成纤维细胞的细胞水平的HGP表型，并延长健康和寿命缺乏LMNA的小鼠。不幸的是，雷帕霉素在人类中具有严重的副作用，包括两种代谢作用和免疫抑制，这可能排除了其长期用于HGPS患者的使用。虽然许多雷帕霉素的有益作用是由于其对mTOR复合物1（MTORC1）的抑制作用，我们发现许多负副作用是通过对第二mTOR复合物mTORC2的“脱靶”抑制介导的。在这项建议，我们建议开发一种饮食技术，以通过减少特定氨基酸的饮食丰度。然后，我们将测试此干预措施，并进行比较雷帕霉素在新开发的HGP小鼠模型中，与人类HGPS中的剪接缺陷相同患者，这在再现后代外表型和内部致命方面是独一无二的在患有HGP的人类中发现的血管缺陷。这项研究将确定促进健康衰老的新途径并在HGP的背景下抑制疾病，并且可能广泛适用于其他椎板病正常老化。该建议将作为R01应用程序的平台，不仅会调查 MTOR抑制可以减慢HGP的进展，但检查效率的分子机制正常衰老中类似干预措施的机制。