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:
- 金额:$ 22.1万
- 依托单位:
- 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:
- 关键词:Adverse effectsAgeAgingAmino AcidsAnimalsBlood VesselsBranched-Chain Amino AcidsCardiacCardiovascular DiseasesCell Culture TechniquesChronicClinical TrialsComplexConsumptionCuesDataDefectDietDietary InterventionDiseaseDisease ProgressionEchocardiographyEssential Amino AcidsFRAP1 geneFarnesyl Transferase InhibitorFibroblastsGenesGeneticGrowth FactorHealthHereditary DiseaseHumanImmunityImmunosuppressionInborn Errors Amino Acid MetabolismInsulinIntakeInterventionIsoleucineLaboratoriesLamin Type ALeucineLongevityLysineMacronutrients NutritionMediatingMetabolicMethionineMethodsMolecularMorphologyMusMutationNuclearNuclear EnvelopeNuclear LaminNutrientPathologyPatientsPhenotypePhenylalaninePremature aging syndromeProgeriaProtein KinaseProtein-Restricted DietPublishingRNA SplicingReducing dietResearchRoleSignal TransductionSirolimusSyndromeTechniquesTestingTherapeuticThinnessThreonineTissuesTryptophanValineWild Type Mousediabetogenicdietary restrictiondisease phenotypeeffective therapyfeedingglucose tolerancehealthy aginghuman diseaseimprovedin vivoinsulin sensitivitymTOR InhibitormTOR Signaling PathwaymTOR inhibitionmalemedical foodmouse modelmutantnegative affectnormal agingpreventresponse
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Dudley William Lamming其他文献
Dudley William Lamming的其他文献
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