Decreased Protein Degradation in Aging
Decreased Protein Degradation in Aging
批准号:
10393546
负责人:
ANA MARIA CUERVO
金额:
$44.58万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
未结题
起止时间:
2018-04-01 至 2025-03-31
关键词:
AgeAgingAreaAutophagocytosisBiology of AgingCellular biologyCharacteristicsComplexCustomDefectDeteriorationDiseaseEndoplasmic ReticulumEnvironmentEquilibriumFailureFellowshipFundingFutureGoalsHealthHomeostasisImpairmentInternationalInterventionJournalsLaboratoriesLipidsLiverLysosomesMaintenanceManuscriptsMediatingMedicalMentorsMetabolicMetabolic DiseasesMinorityMolecular ChaperonesMuscle WeaknessNerve DegenerationOrganOrgan PreservationOrganismPathway interactionsPostdoctoral FellowPreparationProcessProteinsQuality ControlReadingRegulationResearchRodentSeveritiesStudy modelsSystemTrainingTraining ProgramsTranslatingWorkWritingage relatedagedanti agingbasecareercell growth regulationdesignexperimental studyfunctional declinegenetic manipulationimprovedlipid metabolismmeetingsnovel strategiesparent grantpost-doctoral trainingpreventprotein degradationrestorationskillstherapy designtherapy development
中文摘要
这项建议的重点是伴侣介导的自噬(CMA),这是一种介导自噬的分解代谢途径。
溶酶体中胞质蛋白的选择性降解。CMA有助于维持细胞
通过参与细胞质量控制来维持体内平衡。我们以前发现CMA活性降低
随着年龄的增长,老年啮齿动物肝脏中适当CMA活性的恢复可防止器官退化,
保持器官功能。我们认为,CMA的失败有助于功能衰退的特点,
衰老的生物体,并延缓与年龄有关的疾病的进程。
该提案的总体目标是:1)确定CMA随年龄增长而功能失效的原因,
2)了解不同器官中CMA活性随年龄增长而降低的后果; 3)
探索基因操作的替代干预措施,以增强衰老生物体中的CMA活性。
为此,在下一个资助期内,我们打算:1)确定溶酶体的贡献,
分子伴侣和辅助分子伴侣通过CMA对底物蛋白质的溶酶体内化
阐明CMA对细胞脂质代谢的调节作用
通过维持内质网和脂滴的稳态和3)分析系统和
CMA活性随着年龄的增长而降低的器官特异性后果与这种功能有关。
在细胞质量控制和代谢平衡的调节途径。
意义:这项研究将阐明CMA的功能下降如何促进衰老,
确定新的方法来纠正旧生物体中有缺陷的CMA,
和器官的稳态特征
一个研究补充,以促进健康相关研究的多样性(行政增刊)是要求这一点
家长补助金,以支持少数民族博士后研究员。
英文摘要
This proposal focuses on chaperone-mediated autophagy (CMA), a catabolic pathway that mediates the
selective degradation of cytosolic proteins in lysosomes. CMA contributes to the maintenance of cellular
homeostasis by participating in cellular quality control. We have previously found that CMA activity decreases
with age and that restoration of proper CMA activity in livers of old rodents prevents organ deterioration and
preserves organ function. We propose that failure of CMA contributes to the functional decline characteristic of
old organisms and aggravates the course of age-related diseases.
The overall goal of this proposal is 1) to identify the causes behind the functional failure of CMA with age,
2) to understand the consequences of the decrease in CMA activity with age in different organs and 3) to
explore alternative interventions to the genetic manipulation to enhance CMA activity in aging organisms.
With this purpose, during the next period of funding we intend to: 1) determine the contribution of lysosomal
chaperones and co-chaperones to the lysosomal internalization of substrate proteins through the CMA
translocation complex; 2) elucidate the contribution of CMA to the regulation of cellular lipid metabolism
through maintenance of endoplasmic reticulum and lipid droplet homeostasis and 3) analyze the systemic and
organ-specific consequences of the decrease in CMA activity with age in relation to the function of this
pathway in cellular quality control and in the regulation of the metabolic balance.
Significance: This study will elucidate how functional decline of CMA contributes to aging and could help
identifying new approaches to correct defective CMA in old organisms and prevent the alterations in cellular
and organ homeostasis characteristics of aging
A research Supplement to Promote Diversity in Health-Related Research (Admin Suppl) is requested for this
parent grant to support a minority post-doctoral fellow.
期刊论文(15)
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会议论文
Decreased Protein Degradation in Aging
-
批准号:9905323
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项目类别:
-
资助金额:$44.58万
-
财政年份:2018
-
负责人:ANA MARIA CUERVO
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依托单位:
Molecular and Cellular Mechanisms of the Lysosomal Storage Disease Cystinosis
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批准号:10434057
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项目类别:
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资助金额:$72.53万
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财政年份:2017
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负责人:ANA MARIA CUERVO
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依托单位:
Molecular and Cellular Mechanisms of the Lysosomal Storage Disease Cystinosis
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批准号:10683169
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项目类别:
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资助金额:$72.53万
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财政年份:2017
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负责人:ANA MARIA CUERVO
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依托单位:
Project 3: Autophagy dysfunction and neuronal activity in FTD
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批准号:9292170
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项目类别:
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资助金额:$29.46万
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财政年份:2016
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负责人:ANA MARIA CUERVO
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Understanding Alzheimer's Disease in the Context of the Aging Brain
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批准号:9856238
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项目类别:
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资助金额:$123.17万
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财政年份:2016
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负责人:ANA MARIA CUERVO
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依托单位:
Project 3: Autophagy dysfunction and neuronal activity in FTD
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批准号:10011929
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项目类别:
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资助金额:$31.95万
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财政年份:2016
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负责人:ANA MARIA CUERVO
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依托单位:
Functional Consequences of Impaired Autophagy in Aging
-
批准号:8792022
-
项目类别:
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资助金额:$16.7万
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财政年份:2014
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负责人:ANA MARIA CUERVO
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依托单位:
Control of vesicular trafficking in the hepatocyte.
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批准号:8633455
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项目类别:
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资助金额:$71.99万
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财政年份:2013
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负责人:ANA MARIA CUERVO
-
依托单位:
Control of vesicular trafficking in the hepatocyte
-
批准号:9888362
-
项目类别:
-
资助金额:$68.55万
-
财政年份:2013
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负责人:ANA MARIA CUERVO
-
依托单位:
Control of vesicular trafficking in the hepatocyte.
-
批准号:8838778
-
项目类别:
-
资助金额:$30.0万
-
财政年份:2013
-
负责人:ANA MARIA CUERVO
-
依托单位:
Control of vesicular trafficking in the hepatocyte.
-
批准号:9858827
-
项目类别:
-
资助金额:$1.95万
-
财政年份:2013
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负责人:ANA MARIA CUERVO
-
依托单位:
Control of vesicular trafficking in the hepatocyte.
-
批准号:8479622
-
项目类别:
-
资助金额:$71.99万
-
财政年份:2013
-
负责人:ANA MARIA CUERVO
-
依托单位:
Control of vesicular trafficking in the hepatocyte.
-
批准号:9135764
-
项目类别:
-
资助金额:$42.0万
-
财政年份:2013
-
负责人:ANA MARIA CUERVO
-
依托单位:
Control of vesicular trafficking in the hepatocyte
-
批准号:10376295
-
项目类别:
-
资助金额:$68.55万
-
财政年份:2013
-
负责人:ANA MARIA CUERVO
-
依托单位:
Einstein's Nathan Shock Center of Excellence in Basic Biology of Aging
-
批准号:10434970
-
项目类别:
-
资助金额:$21.91万
-
财政年份:2010
-
负责人:ANA MARIA CUERVO
-
依托单位:
Einstein's Nathan Shock Center of Excellence in Basic Biology of Aging
-
批准号:10260406
-
项目类别:
-
资助金额:$21.91万
-
财政年份:2010
-
负责人:ANA MARIA CUERVO
-
依托单位:
Einstein's Nathan Shock Center of Excellence in Basic Biology of Aging
-
批准号:10675109
-
项目类别:
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资助金额:$21.77万
-
财政年份:2010
-
负责人:ANA MARIA CUERVO
-
依托单位:
Einstein's Nathan Shock Center of Excellence in Basic Biology of Aging
-
批准号:10045033
-
项目类别:
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资助金额:$27.35万
-
财政年份:2010
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负责人:ANA MARIA CUERVO
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依托单位:
2010 Biology of Aging Gordon Research Conference and/or Gordon Research Seminar
-
批准号:7901910
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项目类别:
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资助金额:$7.5万
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财政年份:2010
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负责人:ANA MARIA CUERVO
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依托单位:
Functional Consequences of Impaired Autophagy in Aging
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批准号:8053240
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项目类别:
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资助金额:$200.29万
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财政年份:2009
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负责人:ANA MARIA CUERVO
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依托单位:
海外基金