BRCA1在慢性间歇性低氧所致心脏损伤中的作用及其机制的研究

基本信息
批准号:81770372
项目类别:面上项目
资助金额:60.00
负责人:周珊珊
学科分类:
依托单位:吉林大学
批准年份:2017
结题年份:2021
起止时间:2018-01-01 - 2021-12-31
项目状态: 已结题
项目参与者:金景鹏,郝守艳,李婧,汤小强,许慧娟,陈凤敏
关键词:
NFE2相关因子2慢性间歇性低氧金属硫蛋白BRCA1心脏重构
结项摘要

Obstructive sleep apnea (OSA) is the most common type of sleep-disorderedbreathing. Chronic intermittent hypoxia (CIH) is considered to be the main event of OSA to induce cardiac damage. Our preliminary studies showed that (1) Endogenous metallothionein (MT) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression was up-regulated with no obviously cardiac damage in response to early stage of CIH, but significantly decreased with significantly cardiac oxidative damage, remodeling and dysfunction in response to late stage of CIH exposures, the changes of cardiac BRCA1 expression was in parallel with MT and Nrf2 expression; (2) In support of MT and Nrf2 as a major compensatory component, mice with cardiac-specific overexpression of MT gene (MT-TG) and cardiac-specific overexpression of Nrf2 (Nrf2-TG) were completely resistant and mice with global deletion of MT gene (MT-KO) and global deletion of Nrf2 (Nrf2-KO) were highly sensitive to CIH-induced cardiac effects, respectively. (3) Reciprocal regulation of cardiac Nrf2 and MT expressions in response to IH. In this study, therefore, we will interbreed BRCA1-KO mice, in combination of Nrf2-KO and MT-KO mouse models, to investigate CIH-induced cardiac damage. The objective of this study is to define the role of BRCA1 in CIH-induced cardiac damage and dissect whether BRCA1 as a compensatory component prevents intermittent hypoxia-induced cardiomyopathy and the relationship among BRCA1, Nrf2 and MT. We explored the whether SFN can protect IH-induced cardiomyopathy without BRCA1.

呼吸睡眠暂停(OSA)是常见的睡眠呼吸疾病,OSA模式的慢性间歇性低氧(CIH)是引发心脏损伤的主要原因。前期工作中我们发现:①CIH条件下,小鼠心肌组织BRCA1的表达与金属硫蛋白(MT)和NF-E2相关因子2 (Nrf2)相同,均呈现早期升高、晚期下降的趋势;②MT过表达转基因(MT-TG)和 Nrf2-TG小鼠保护CIH所致的心肌损伤,而MT基因敲除(MT-KO)和Nrf2-KO小鼠使损伤提前出现且程度加重;③CIH条件下MT与Nrf2相互协同作用。本课题拟通过构建BRCA1心脏特异性基因敲除(BRCA1-KO)小鼠,同时应用Nrf2-KO和MT-KO小鼠,阐明BRCA1在CIH所致心脏损伤中的作用并探讨BRCA1、Nrf2和MT之间的关系及相关机制,同时应用Nrf2激动剂莱菔硫烷(SFN),明确其是否可挽救BRCA1基因突变所加重的CIH所致的心脏损伤。

项目摘要

阻塞性睡眠呼吸暂停(obstructive sleep apnea, OSA)低通气综合征,是一种最常见的严重危害人类健康的睡眠疾病之一。慢性间歇性低氧(chronic intermittent hypoxia, CIH)是OSA的主要病理特征,目前众多学者应用CIH的动物模型研究OSA所致的心脏损伤,发现CIH是引发包括心室重构在内的心脏损伤的主要原因。目前认为,氧化应激是OSA所致心血管疾病的主要发病机制之一。前期工作中我们发现:①CIH条件下,小鼠心肌组织BRCA1的表达与金属硫蛋白(MT)和NF-E2相关因子2 (Nrf2)相同,均呈现早期升高、晚期下降的趋势;②MT过表达转基因(MT-TG)和 Nrf2-TG小鼠保护CIH所致的心肌损伤,而MT基因敲除(MT-KO)和Nrf2-KO小鼠使损伤提前出现且程度加重 ③CIH条件下MT与Nrf2相互协同作用。我们研究发现BRCA1与MT和Nrf2之间存在协同作用,在CIH所致心脏损伤中发挥作用,并且发现SFN在CIH所致心脏损伤中发挥保护作用,并且这一保护作用依赖Nrf2的存在。

项目成果
{{index+1}}

{{i.achievement_title}}

{{i.achievement_title}}

DOI:{{i.doi}}
发表时间:{{i.publish_year}}

暂无此项成果

数据更新时间:2023-05-31

其他相关文献

1

High Performance Van der Waals Graphene-WS2-Si Heterostructure Photodetector

High Performance Van der Waals Graphene-WS2-Si Heterostructure Photodetector

DOI:10.1002/admi.201901304
发表时间:2019
2

中温固体氧化物燃料电池复合阴极材料LaBiMn_2O_6-Sm_(0.2)Ce_(0.8)O_(1.9)的制备与电化学性质

中温固体氧化物燃料电池复合阴极材料LaBiMn_2O_6-Sm_(0.2)Ce_(0.8)O_(1.9)的制备与电化学性质

DOI:10.11862/CJIC.2019.081
发表时间:2019
3

Influence of calcination temperature on the photocatalytic performance of the hierarchical TiO2 pinecone-like structure decorated with CdS nanoparticles

Influence of calcination temperature on the photocatalytic performance of the hierarchical TiO2 pinecone-like structure decorated with CdS nanoparticles

DOI:https://doi.org/10.1016/j.ceramint.2018.09.243
发表时间:2018
4

Functionalization and Fabrication of Soluble Polymers of Intrinsic Microporosity for CO2 Transformation and Uranium Extraction

Functionalization and Fabrication of Soluble Polymers of Intrinsic Microporosity for CO2 Transformation and Uranium Extraction

DOI:
发表时间:2018
5

贵州织金洞洞穴CO2的来源及其空间分布特征

贵州织金洞洞穴CO2的来源及其空间分布特征

DOI:
发表时间:2016

相似国自然基金

1

Nrf2在金属硫蛋白保护慢性间歇性低氧所致心脏损伤中的作用

批准号:81400281
批准年份:2014
负责人:周珊珊
学科分类:H0207
资助金额:23.00
项目类别:青年科学基金项目
2

PGC-1α在慢性间歇性低压低氧适应心脏保护中的作用及机制

批准号:81200070
批准年份:2012
负责人:马会杰
学科分类:H0201
资助金额:23.00
项目类别:青年科学基金项目
3

氢气对慢性间歇性低氧所致血管内皮细胞损伤的保护作用及机制研究

批准号:81700084
批准年份:2017
负责人:林莹妮
学科分类:H0110
资助金额:20.00
项目类别:青年科学基金项目
4

活性氧在慢性间歇性低压低氧适应心脏保护中的作用及信号转导机制的研究

批准号:31100832
批准年份:2011
负责人:马慧娟
学科分类:C1101
资助金额:22.00
项目类别:青年科学基金项目