Targeting mechanisms of inter-organelle communication to promote healthy aging
细胞器间通讯的靶向机制促进健康衰老
基本信息
- 批准号:9242811
- 负责人:
- 金额:$ 12.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-30 至 2018-05-31
- 项目状态:已结题
- 来源:
- 关键词:5&apos-AMP-activated protein kinaseAddressAdverse effectsAgeAge of OnsetAgingAnimalsAutomobile DrivingBehaviorBiologicalBiological ProcessCREB1 geneCaenorhabditis elegansCardiovascular DiseasesCellsCellular Metabolic ProcessCellular biologyCommunicationComorbidityCoupledDataDefectDiabetes MellitusDietary InterventionDiseaseElderlyEndoplasmic ReticulumFertilityGene ExpressionGenesGeneticGenetic ModelsGoalsGrowthHealthHomeostasisImmunityIndividualInterventionKnowledgeLifeLinkLongevityMalignant NeoplasmsMammalian CellMediatingMediator of activation proteinMembraneMetabolicMetabolismMicroscopyMitochondriaModelingMolecularMonitorMorbidity - disease rateMorphologyNeurodegenerative DisordersNuclearOrganellesOsteoporosisOutputPathologyPathway interactionsPatientsPhasePhysiologyPlayProteinsPublic HealthRegulationReproductionResolutionRisk FactorsRoleShapesSignal TransductionSiteStrokeSystemTestingTherapeuticTrainingTranscription CoactivatorTransgenic OrganismsTranslatingabstractingage relatedageddesigndetection of nutrientdifferential expressionfunctional declinegene therapyhealthy agingimprovedin vivoinsightlipid metabolismmetabolomicsmitochondrial metabolismnovelpreventresponsesensortherapeutic developmenttooltranscription factor
项目摘要
Project Summary/Abstract
Age-onset diseases including cancer, neurodegenerative disease, diabetes, cardiovascular disease, stroke,
and osteoporosis are generating a public health burden that is quickly becoming insurmountable. Exacerbating
this problem, co-morbidities are common among the elderly. The ideal therapeutic strategy to confront this
crisis is to target a unifying risk factor, but patient age is the only risk factor common to all these diseases.
Fortunately, it is increasingly clear that the biological processes of aging are malleable, thus the rate and
quality of aging may be improved. Genetic and nutritional interventions causing real or perceived energy-
depletion are robust, conserved mechanisms to promote healthier aging. Unfortunately these interventions,
e.g. activation of the molecular low-energy sensor AMPK, also carry clinically unacceptable side effects, such
as suppressed immunity and fertility. Translating these findings into therapeutics thus requires identification of
downstream mechanisms that are sufficient for healthier aging. Through a genetic model of longevity in C.
elegans via activation of AMPK, we demonstrated that the negative side-effects of energy-depletion can be
uncoupled from the positive effects on healthy aging. Using unbiased, systems-level approaches, we found
that the longevity-specific mechanism involves downstream regulation of mitochondrial dynamics and
metabolic functions, and we now demonstrate that regulation of mitochondrial dynamics is causal to AMPK
longevity. New data indicate that perturbing the unfolded protein response (UPR), which mediates homeostasis
of the endoplasmic reticulum (ER), interacts with the AMPK pathway to extend lifespan through a mechanism
that also requires mitochondrial remodeling. Given recent studies showing that the ER physically interacts with
mitochondria to regulate organelle morphology and metabolic signaling, these data suggest a new paradigm in
aging: ER/mitochondrial regulation of longevity occurs through an integrated metabolic mechanism. Physical
changes in mitochondrial networks are a hallmark of aging, but how organelle dynamics are mechanistically
involved in longevity is unknown. By genetically inactivating mediators of mitochondrial remodeling
(fission/fusion), Aim 1 will define how mitochondrial dynamics drive the changes in mitochondrial metabolism
associated with low-energy longevity. Through novel transgenics and training in high-resolution microscopy in
Aim 2, I will test the hypothesis that UPRER perturbations promote altered mitochondrial morphology and
signaling between organelles. Finally in the R00 phase, Aim 3 will build on the tools and insights developed in
Aims 1 and 2 to identify genetic mechanisms in C. elegans by which ER-mitochondrial inter-organelle
communication can be directly targeted to extend healthy lifespan and protect metabolic homeostasis. Taken
together, the goal of this proposal is to identify how evolutionarily conserved energy-sensing pathways
coordinately modulate inter-organelle signaling and metabolic function to promote longevity.
项目总结/摘要
包括癌症、神经退行性疾病、糖尿病、心血管疾病、中风、
和骨质疏松症正在产生一种公共卫生负担,这种负担正迅速变得难以克服。加剧
这个问题,合并症在老年人中很常见。面对这种情况的理想治疗策略
危机是针对一个统一的风险因素,但病人的年龄是唯一共同的风险因素,所有这些疾病。
幸运的是,越来越清楚的是,衰老的生物过程是可塑性的,因此,
可以改善老化的质量。遗传和营养干预导致真实的或感知的能量-
消耗是促进更健康衰老的稳健、保守的机制。不幸的是,这些干预措施,
例如分子低能传感器AMPK的激活也带来临床上不可接受的副作用,例如
免疫力和生育能力受到抑制因此,将这些发现转化为治疗方法需要确定
这些下游机制足以让老年人更健康。通过C.
通过激活AMPK,我们证明了能量消耗的负面副作用可以被
与健康老龄化的积极影响脱钩。使用无偏的系统级方法,我们发现
长寿特异性机制涉及线粒体动力学的下游调节,
我们现在证明线粒体动力学的调节是AMPK的因果关系,
中心blog新的数据表明,干扰介导体内平衡的未折叠蛋白反应(UPR)
与AMPK通路相互作用,通过一种机制延长寿命。
也需要线粒体重塑鉴于最近的研究表明,ER与
线粒体调节细胞器形态和代谢信号,这些数据表明了一种新的范式,
衰老:ER/线粒体对寿命的调节是通过一个综合的代谢机制发生的。物理
线粒体网络的变化是衰老的标志,但细胞器动力学如何在机械上
与长寿有关的因素是未知的。通过基因失活线粒体重塑介质
(裂变/融合),目标1将定义线粒体动力学如何驱动线粒体代谢的变化
与低能量寿命有关。通过新的转基因技术和高分辨率显微镜的培训,
目的2,我将检验UPRER扰动促进线粒体形态改变的假设,
细胞器之间的信号传递最后,在R 00阶段,Aim 3将建立在
目的1和2是为了确定C.通过内质网-线粒体间细胞器
交流可以直接针对延长健康寿命和保护代谢稳态。采取
总之,这个提议的目标是确定进化上保守的能量感应途径是如何
协调调节细胞器间信号传导和代谢功能以促进长寿。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Kristopher Burkewitz其他文献
Kristopher Burkewitz的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Kristopher Burkewitz', 18)}}的其他基金
Targeting ER-mitochondrial calcium signaling to promote healthier aging
靶向 ER 线粒体钙信号传导以促进更健康的衰老
- 批准号:
10443143 - 财政年份:2022
- 资助金额:
$ 12.78万 - 项目类别:
Targeting ER-mitochondrial calcium signaling to promote healthier aging
靶向 ER 线粒体钙信号传导以促进更健康的衰老
- 批准号:
10643969 - 财政年份:2022
- 资助金额:
$ 12.78万 - 项目类别:
Targeting mechanisms of inter-organelle communication to promote healthy aging
细胞器间通讯的靶向机制促进健康衰老
- 批准号:
9812866 - 财政年份:2016
- 资助金额:
$ 12.78万 - 项目类别:
Targeting mechanisms of inter-organelle communication to promote healthy aging
细胞器间通讯的靶向机制促进健康衰老
- 批准号:
9886173 - 财政年份:2016
- 资助金额:
$ 12.78万 - 项目类别:
Targeting novel AMPK effectors in the regulation of healthy aging
靶向新型 AMPK 效应物调节健康衰老
- 批准号:
8803201 - 财政年份:2014
- 资助金额:
$ 12.78万 - 项目类别:
Targeting novel AMPK effectors in the regulation of healthy aging
靶向新型 AMPK 效应物调节健康衰老
- 批准号:
8527019 - 财政年份:2014
- 资助金额:
$ 12.78万 - 项目类别:
相似海外基金
Pharmacological targeting of AMP-activated protein kinase for immune cell regulation in Type 1 Diabetes
AMP 激活蛋白激酶对 1 型糖尿病免疫细胞调节的药理学靶向
- 批准号:
2867610 - 财政年份:2023
- 资助金额:
$ 12.78万 - 项目类别:
Studentship
Establishing AMP-activated protein kinase as a regulator of adipose stem cell plasticity and function in health and disease
建立 AMP 激活蛋白激酶作为脂肪干细胞可塑性和健康和疾病功能的调节剂
- 批准号:
BB/W009633/1 - 财政年份:2022
- 资助金额:
$ 12.78万 - 项目类别:
Fellowship
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
- 批准号:
532989-2019 - 财政年份:2021
- 资助金额:
$ 12.78万 - 项目类别:
Postdoctoral Fellowships
Metabolic control of integrin membrane traffic by AMP-activated protein kinase controls cell migration.
AMP 激活的蛋白激酶对整合素膜运输的代谢控制控制着细胞迁移。
- 批准号:
459043 - 财政年份:2021
- 资助金额:
$ 12.78万 - 项目类别:
Studentship Programs
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
- 批准号:
532989-2019 - 财政年份:2020
- 资助金额:
$ 12.78万 - 项目类别:
Postdoctoral Fellowships
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
- 批准号:
10561642 - 财政年份:2019
- 资助金额:
$ 12.78万 - 项目类别:
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
- 批准号:
532989-2019 - 财政年份:2019
- 资助金额:
$ 12.78万 - 项目类别:
Postdoctoral Fellowships
Treating Diabetic Inflammation using AMP-Activated Protein Kinase Activators
使用 AMP 激活的蛋白激酶激活剂治疗糖尿病炎症
- 批准号:
2243045 - 财政年份:2019
- 资助金额:
$ 12.78万 - 项目类别:
Studentship
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
- 批准号:
10359032 - 财政年份:2019
- 资助金额:
$ 12.78万 - 项目类别:
Investigating the therapeutic potential of AMP-activated protein kinase in myotonic dystrophy type 1
研究 AMP 激活蛋白激酶在 1 型强直性肌营养不良中的治疗潜力
- 批准号:
428988 - 财政年份:2019
- 资助金额:
$ 12.78万 - 项目类别:
Studentship Programs