Regulation of lysosome positioning and function by the unfolded protein response
通过未折叠蛋白反应调节溶酶体的定位和功能
基本信息
- 批准号:10705590
- 负责人:
- 金额:$ 32.26万
- 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:2016-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAlzheimer&aposs DiseaseAutophagocytosisBrainCell physiologyCellsCellular StressDataDiabetes MellitusDiseaseEndoplasmic ReticulumGoalsHomeostasisHuntington DiseaseHuntington geneLysosomesMalignant NeoplasmsMammalian CellMediatingMessenger RNANerve DegenerationNeurodegenerative DisordersOrganellesParkinson DiseasePathway interactionsPatientsPositioning AttributeProcessProteinsRegulationResearch ProposalsStressTherapeuticbiological adaptation to stressdesignendoplasmic reticulum stresshuman diseaseinsightlate endosomemisfolded proteinnovel therapeutic interventionprotein aggregationresponsetooltrafficking
项目摘要
Project Summary/Abstract
The broad goals of this research proposal are to understand how cells mitigate the aggregation
of proteins that underlie neurodegenerative diseases, and how these mechanisms are influenced by
stress pathways and organelle trafficking. There are no cures for Huntington’s, Parkinson’s, and
Alzheimer’s diseases, so exploring new mechanisms for how cells respond to protein aggregation is
important for offering new therapeutic approaches. The first goal of this proposal is to understand how
cells degrade the disease-causing form of the Huntington protein, in particular as it misfolds but before
it forms the large aggregates that are found in the brains of patients. These intermediate, oligomeric
forms of the Huntington protein are thought to be the most toxic, yet we do not know the mechanisms
through which cells most effectively degrade them. Guided by preliminary data, we will explore how
cells employ late endosome-mediated microautophagy in this degradation. Microautophagy is not well-
understood at a mechanistic level, especially in mammalian cells, and this proposal is also designed to
provide more general insights and tools to study this fundamental cellular process. The second overall
goal of this proposal is to understand the relationships between protein aggregation, stress in the
endoplasmic reticulum (ER), and organelle trafficking/positioning. Many neurodegenerative diseases
induce ER stress, yet the complicated interplay between ER stress response pathways and
neurodegeneration is not well-understood enough to provide a clear path for manipulating these stress
pathways therapeutically. This proposal seeks to understand how a particular aspect of the ER stress
response, involving the degradation of a specific mRNA and subsequent repositioning of late
endosomes and lysosomes, affects the degradation and aggregation of the Huntington protein.
Investigating this stress response will also help us to understand how cells maintain homeostasis in the
ER, which is important in many human diseases including cancer and diabetes.
项目概要/摘要
该研究计划的主要目标是了解细胞如何减轻聚集
神经退行性疾病背后的蛋白质,以及这些机制如何受到影响
应激途径和细胞器贩运。亨廷顿舞蹈症、帕金森舞蹈症和帕金森舞蹈症无法治愈
阿尔茨海默病,因此探索细胞如何响应蛋白质聚集的新机制是
对于提供新的治疗方法非常重要。该提案的首要目标是了解如何
细胞会降解亨廷顿蛋白的致病形式,特别是当它错误折叠但之前
它形成在患者大脑中发现的大聚集体。这些中间体、寡聚体
亨廷顿蛋白的形式被认为是毒性最强的,但我们不知道其机制
细胞通过这种方式最有效地降解它们。以初步数据为指导,我们将探讨如何
细胞在这种降解过程中利用晚期内体介导的微自噬。微自噬不太好——
从机械层面上理解,特别是在哺乳动物细胞中,该提案还旨在
提供更一般的见解和工具来研究这一基本的细胞过程。总成绩第二名
该提案的目标是了解蛋白质聚集、压力之间的关系
内质网(ER)和细胞器运输/定位。许多神经退行性疾病
诱发 ER 应激,但 ER 应激反应途径与
对神经退行性疾病的了解还不够深入,无法为控制这些压力提供明确的途径
治疗途径。该提案旨在了解 ER 压力的某个特定方面如何
反应,涉及特定 mRNA 的降解和随后的晚期重新定位
内体和溶酶体,影响亨廷顿蛋白的降解和聚集。
研究这种应激反应也将帮助我们了解细胞如何维持体内平衡
ER,在许多人类疾病中很重要,包括癌症和糖尿病。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Regulation of Blos1 by IRE1 prevents the accumulation of Huntingtin protein aggregates.
- DOI:10.1091/mbc.e22-07-0281
- 发表时间:2022-11-01
- 期刊:
- 影响因子:3.3
- 作者:Bae, Donghwi;Jones, Rachel Elizabeth;Piscopo, Katherine M.;Tyagi, Mitali;Shepherd, Jason D.;Hollien, Julie
- 通讯作者:Hollien, Julie
{{
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 }}
JULIE HOLLIEN其他文献
JULIE HOLLIEN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('JULIE HOLLIEN', 18)}}的其他基金
Regulation of lysosome positioning and function by the unfolded protein response
通过未折叠蛋白反应调节溶酶体的定位和功能
- 批准号:
10202203 - 财政年份:2016
- 资助金额:
$ 32.26万 - 项目类别:
Regulation of mRNA decay and metabolism during endoplasmic reticulum stress
内质网应激过程中 mRNA 衰变和代谢的调节
- 批准号:
10005415 - 财政年份:2016
- 资助金额:
$ 32.26万 - 项目类别:
Regulation of lysosome positioning and function by the unfolded protein response
通过未折叠蛋白反应调节溶酶体的定位和功能
- 批准号:
10468021 - 财政年份:2016
- 资助金额:
$ 32.26万 - 项目类别:
mRNA decay mechanisms for ER stress recovery
内质网应激恢复的 mRNA 衰减机制
- 批准号:
7907770 - 财政年份:2007
- 资助金额:
$ 32.26万 - 项目类别:
mRNA decay mechanisms for ER stress recovery
内质网应激恢复的 mRNA 衰减机制
- 批准号:
7673496 - 财政年份:2007
- 资助金额:
$ 32.26万 - 项目类别:
mRNA decay mechanisms for ER stress recovery
内质网应激恢复的 mRNA 衰减机制
- 批准号:
7658474 - 财政年份:2007
- 资助金额:
$ 32.26万 - 项目类别:
mRNA decay mechanisms for ER stress recovery
内质网应激恢复的 mRNA 衰减机制
- 批准号:
7297253 - 财政年份:2007
- 资助金额:
$ 32.26万 - 项目类别:
Consequences of the metazoan unfolded protein response
后生动物未折叠蛋白反应的后果
- 批准号:
6743139 - 财政年份:2003
- 资助金额:
$ 32.26万 - 项目类别:
Consequences of the metazoan unfolded protein response
后生动物未折叠蛋白反应的后果
- 批准号:
6644428 - 财政年份:2003
- 资助金额:
$ 32.26万 - 项目类别: