线粒体GEF蛋白WBSCR16调控线粒体之间及线粒体与其它细胞器之间互作机制及功能的研究

批准号:
91854124
项目类别:
重大研究计划
资助金额:
93.0 万元
负责人:
黄国瑞
依托单位:
学科分类:
H0709.能量代谢调节异常与肥胖
结题年份:
2021
批准年份:
2018
项目状态:
已结题
项目参与者:
朱琴、张圣洁、冯杨、姚霜霜、刘珊珊、白梦瑶
国基评审专家1V1指导 中标率高出同行96.8%
结合最新热点,提供专业选题建议
深度指导申报书撰写,确保创新可行
指导项目中标800+,快速提高中标率
微信扫码咨询
中文摘要
细胞内线粒体之间的分裂与融合,线粒体与内质网、溶酶体之间的互作非常普遍并对细胞的正常功能是必须的。一旦细胞器互作有缺陷或被破坏,就可能引起细胞功能障碍,从而导致心血管疾病、衰老、神经退行性疾病等多种疾病。我们首次发现WBSCR16是一种定位于线粒体内并调节其分裂与融合的GEF蛋白, 显示了它对线粒体功能调节的独特性。但是目前对于它调节线粒体融合及介导线粒体与其它细胞器互作的机制,包括它在体内的功能都不清楚。我们后续初步的研究表明,除了参与调节线粒体的分裂与融合外,WBSCR16还参与了线粒体与内质网和溶酶体(线粒体自噬)的互作过程。本项目的目标就就是研究清楚WBSCR16调控线粒体融合的分子机制,更重要的是研究它在线粒体与内质网和溶酶体之间互作过程的机制和功能,探索调控这些过程的潜在作用靶点,了解和研究细胞器互作与疾病的关系并最终找到潜在的、可行的治疗方案。
英文摘要
Mitochondria is the organelle which is the main energy-producing system within most eukaryotic cells, and also play important roles in Ca++ signaling and apoptosis. The multiple mitochondria within cells normally interfuse to form intracellular tubular networks that are constantly remodeled by fission and then re-fusion of individual mitochondria. Additionally, the juxtaposition and contact among lysosome, endoplasmic reticulum (ER) and mitochondrial is a common structural feature, and providing the physical basis for intercommunication during Ca++ and other protein signaling. These dynamic processes are necessary to cell function. Deficits in mitochondrial fusion, mitochondrial and lysosome contact, contribute to chronic neurodegenerative conditions that include Charcot-Marie-Tooth neuropathy type 2A, dominant optic atrophy, Parkinson’s disease and various dementias. Our initial findings showed that WBSCR16 (Williams Buren syndrome critical region 16) is a putative GEF protein that regulates OPA1 activity and mitochondrial fusion, and in which mutation affects neuronal mitochondrial function. However, the function of WBSCR16 in mice and the mechanism among WBSCR16 with mitochondrial fusion regulated GTPases are still unknown, especially for the communication between mitochondrial and other organelles. Based on our primary data, it indicated that WBSCR16 involved the contacts between mitochondrial with ER and lysosome, respectively. Additionally, to further explore in vivo WBSCR16 roles in mice, we are presently raising mice with floxed WBSCR16 using inducible and tissue-specific conditional Knockout and Knock in approaches. The proposed studies are of great potential importance towards determining the details of regulated mitochondrial dynamics, contacts with mitochondrial and lysosome or ER. And it will help furthering understand the relationship between organelles contact and human disease, and finally find the potential and viable therapy strategy for them.
我们的前期工作是世界上首次对这个基因进行初步的研究,发现这一蛋白定位于线粒体,并可以调控线粒体的分裂与融合。有别于以往的几种调节线粒体分裂与融合的关键蛋白都是GTPase,WBSCR16是第一个发现存在于线粒体的GEF蛋白,显示了它在调节调控线粒体功能及线粒体与其它细胞器之间互作的独特功能与机制。线粒体自噬是细胞清除受损线粒体的有效手段,对于调节线粒体数量及维持线粒体的正常功能发挥重要作用。机体发生肥胖或者衰老时,由于线粒体自噬受损导致缺陷的线粒体不能被清除,从而导致体温和能量利用失衡。此外,我们还发现WBSCR16KO后会导致特殊形态的线粒体产生,这种特殊形态的线粒体与内质网存在非常密切的关系,其功能和机制我们正在研究中。
期刊论文列表
专著列表
科研奖励列表
会议论文列表
专利列表
DOI:10.1002/1873-3468.13291
发表时间:2018-11
期刊:FEBS Letters
影响因子:3.5
作者:Qin Zhu;W. Guo;Shengjie Zhang;Yang Feng;Xiao Wang;Libin Zhou;Guo-Ru Huang
通讯作者:Qin Zhu;W. Guo;Shengjie Zhang;Yang Feng;Xiao Wang;Libin Zhou;Guo-Ru Huang
细胞外基质蛋白α3(V)调节细胞代谢机制的研究及对相关代谢性疾病治疗策略的探索
- 批准号:81770845
- 项目类别:面上项目
- 资助金额:54.0万元
- 批准年份:2017
- 负责人:黄国瑞
- 依托单位:
国内基金
海外基金
