CONSTITUTIVE STRESS PROTEINS AND STRESS TOLERANCE
组成性应激蛋白和应激耐受性
基本信息
- 批准号:6328958
- 负责人:
- 金额:$ 18.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1998
- 资助国家:美国
- 起止时间:1998-12-09 至 2002-11-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Stress induces cells to develop Tolerance against subsequent exposure to
a diverse range of toxic insults. There are two phases of Tolerance. One
phase develops quickly and requires no protein synthesis (protein
synthesis independent Tolerance: PSIT). Stress-induced protein synthesis
is requisite for the slower developing, more protracted second phase
(protein synthesis dependent Tolerance: PSDT).
The central hypothesis is that heat shock proteins (HSPs) confer PSIT and
PSDT stress protection. We proposed a model in which stress-denatured and
aggregated proteins induce cells to develop PSIT and/or PSDT. PSIT
develops more quickly and requires constitutively expressed HSP-27 and/or
alphaB-crystallin to maintain stress-denatured and aggregated proteins in
a folding competent state, making the proteins more accessible to
disaggregation by the unfolding/refolding chaperone activity of HSC-70
and/or HSP-70. If PDT is also induced, PSIT protects cells while
additional HSP-27, alphaB-crystallin and HSP-70/HSC-70 are synthesized.
Up-regulated HSPs then provide protracted PSDT protection after PSIT
decays. In both PSIT and PSDT, HSC70 and/or HSP 70 ultimately disaggregate
large protein aggregates into smaller ones. Proteins in the smaller
aggregates are either returned to their native state by continued HSC-70
or HSP-70 unfolding/refolding, or more efficiently proteolyzed.
The specific aims and experimental design will test critical aspects pf
the model by determining how PSIT and PSDT are induced, and how HSP-27 and
alphaB-crystallin confer PSIT and PSDT stress protection. This will
include determining how stress-induced: phosphorylation, changes in
oligomer size, and changes in cellular distribution of HSP-27 and alphaB-
crystallin influence their stress protection. Experiments will also
establish if HSP-27 and alphaB-crystallin function in a cooperative manner
with HSC-70 and HSP-70 to provide stress protection, and discover the
conditions that determine whether denatured proteins are disaggregated
into a soluble state of proteolyzed.
Tolerance provides protection against many clinically relevant stresses,
e.g., ischemia, and denatured and abnormal proteins are involved in many
human diseases including, Alzheimer's disease. Thus, understanding how
HSPs function in PSIT and PSDT to protect cells against cytotoxic stresses
and to ameliorate the cytotoxicity of denatured and aggregated proteins
may lead to new and effective clinical applications for stress Tolerance.
应激诱导细胞对随后暴露于
各种各样的有毒侮辱宽容有两个阶段。一
阶段发展迅速,不需要蛋白质合成(蛋白质
合成独立容差:PSIT)。应激诱导蛋白质合成
是发展缓慢、时间更长的第二阶段所必需的
(蛋白质合成依赖性耐受性:PSDT)。
核心假设是热休克蛋白(HSP)赋予PSIT,
PSDT应力保护。我们提出了一个模型,其中应力变性和
聚集的蛋白质诱导细胞发生PSIT和/或PSDT。PSIT
发展更快,需要组成型表达HSP-27和/或
α B-晶状体蛋白维持应激变性和聚集的蛋白质,
一种折叠能力状态,使蛋白质更容易被
通过HSC-70的解折叠/重折叠伴侣活性的解聚
和/或HSP-70。如果PDT也被诱导,PSIT保护细胞,
合成另外的HSP-27、α B-晶状体蛋白和HSP-70/HSC-70。
上调的HSP然后在PSIT后提供延长的PSDT保护
腐烂在PSIT和PSDT中,HSC 70和/或HSP 70最终解聚,
大的蛋白质聚集成较小的蛋白质。蛋白质在较小的
聚集体或者通过持续的HSC-70
或HSP-70解折叠/重折叠,或更有效地蛋白水解。
具体的目标和实验设计将测试的关键方面,
通过确定PSIT和PSDT是如何诱导的,以及HSP-27和
α B-晶状体蛋白赋予PSIT和PSDT应激保护。这将
包括确定压力如何诱导:磷酸化,
寡聚体大小以及HSP-27和alphaB-
晶状体蛋白影响它们的应激保护。实验也将
确定HSP-27和α B-晶状体蛋白是否以协同方式发挥功能
HSC-70和HSP-70提供压力保护,并发现
确定变性蛋白质是否解聚的条件
转化为可溶的蛋白质水解状态
耐受性提供了对许多临床相关应激的保护,
例如,在一个实施例中,缺血,变性和异常蛋白质参与了许多
人类疾病,包括阿尔茨海默病。因此,了解如何
热休克蛋白在PSIT和PSDT中起作用,以保护细胞免受细胞毒性应激
并改善变性和聚集蛋白的细胞毒性
可能会导致新的和有效的临床应用的压力耐受。
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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Michael Jude Borrelli其他文献
Michael Jude Borrelli的其他文献
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{{ truncateString('Michael Jude Borrelli', 18)}}的其他基金
The Seventh Nanotechnology for Health Care Conference
第七届纳米技术医疗保健会议
- 批准号:
9805451 - 财政年份:2018
- 资助金额:
$ 18.4万 - 项目类别:
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第五届纳米技术医疗保健会议
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9094250 - 财政年份:2014
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$ 18.4万 - 项目类别:
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第五届纳米技术医疗保健会议
- 批准号:
8849339 - 财政年份:2014
- 资助金额:
$ 18.4万 - 项目类别:
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- 批准号:
8792651 - 财政年份:2014
- 资助金额:
$ 18.4万 - 项目类别:
Reduced Temperature Thermal Ablation for HCC and other Liver Tumors
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8114667 - 财政年份:2011
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Reduced Temperature Thermal Ablation for HCC and other Liver Tumors
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6954118 - 财政年份:2005
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- 批准号:
7111475 - 财政年份:2005
- 资助金额:
$ 18.4万 - 项目类别:
Heat Activated Gene Therapy Using Radiomimetic CdtB
使用拟放射 CdtB 的热激活基因治疗
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7279152 - 财政年份:2005
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Heat Activated Gene Therapy Using Radiomimetic CdtB
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- 批准号:
6876886 - 财政年份:2004
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