Understanding Endoplasmic Reticulum-Mitochondrial Cross-Talk in Corneal Endothelial Cells

了解角膜内皮细胞中的内质网-线粒体交互作用

基本信息

  • 批准号:
    10550019
  • 负责人:
  • 金额:
    $ 24.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-05-01 至 2025-03-31
  • 项目状态:
    未结题

项目摘要

Project Summary Fuchs endothelial corneal dystrophy (FECD) is a common, genetically complex and age-related degenerative disease affecting approximately 4 % of the U.S.A. population with a higher incidence in females. In FECD, corneal endothelial (CE) cell loss is accompanied by extracellular matrix deposition in the form of guttae. My mentor (Ula V. Jurkunas) has reported explicitly that in FECD, oxidant-antioxidant imbalance due to suboptimum Nrf-2 regulated antioxidant defense, including a decline in its transcriptional target, NAD(P)H quinone dehydrogenase 1 (NQO1), leads to oxidative DNA damage, mitochondrial dysfunction, and apoptosis. My preliminary data also suggests the significant loss of CE in NQO1-/- mice compared to WT in the mouse model of FECD. Alike oxidative stress and mitochondrial damage, my co-mentor (Albert S. Jun) and others have implicated the role of ER stress/ Unfolded protein response (UPR) in the pathogenesis of FECD. My preliminary data also suggests the significant and earlier activation of pro-apoptotic ER stress markers for NQO-/- cell line after UVA-induced FECD model in vitro. However, there has not been any study linking ER and mitochondrial stress under oxidant-antioxidant imbalance for CE in FECD. The objective of this proposal is to define the contribution of ER stress on mitochondrial stress (altered bioenergetics and dynamics) under oxidant-antioxidant imbalance in FECD. During the mentored phase (K99) of the award, I will determine whether UVA induces ER and mitochondrial stress (Aim 1a), ER stress alters mitochondrial bioenergetic (Aim 1b) and dynamics (morphology, fragmentation, translocation) all under oxidant-antioxidant imbalance (Aim 2a). I will learn to induce and quantify ER stress with my co-mentor lab’s collaboration (Albert Jun), analyze mitochondrial bioenergetics and dynamics with mentor Ula Jurkunas and co-mentor Pere Puigserver’s lab, learn in vitro and in vivo model of FECD (Jurkunas’s lab) along with the extensive career development activities offered at Harvard Medical School. During the R00 phase, with mentor and co-mentor’s support, I will perform uncompleted parts of Aim1-2 with the additional investigation of the mechanism of ER mediated-activation of mitochondrial intrinsic apoptotic pathway (Aim 1c) via Ca+2 signaling and microtubular rearrangement (Aim 2b). Collectively, these studies will provide new insights and perspectives into the ER-Mitochondrial cross talk for corneal endothelial biology, which will advance our understanding of FECD pathogenesis. A K99 award will allow me to receive additional training in ER and Mitochondria biology along with novel training in corneal endothelial cell biology. The extensive resources and career development opportunities available at Harvard Medical School, Jurkunas, Puigserver, and Jun’s lab, as well as the research activities planned in the K99 phase, will enable me to achieve the long-term goal of becoming an independent investigator dedicated to the study of ER-Mitochondrial cross talk in corneal endothelial biology.
项目摘要 Fuchs角膜内皮营养不良(FECD)是一种常见的、遗传复杂的、与年龄相关的退行性角膜病变, 影响约4%的美国人口的疾病,女性发病率较高。在FECD中, 角膜内皮(CE)细胞损失伴随着滴胶形式的细胞外基质沉积。我 mentor(Ula V. Jurkunas)明确报道,在FECD中,由于次优的氧化-抗氧化失衡, Nrf-2调节抗氧化防御,包括其转录靶点NAD(P)H醌的下降 脱氢酶1(NQO 1)导致氧化性DNA损伤、线粒体功能障碍和细胞凋亡。我 初步数据还表明,与小鼠模型中的WT相比,NQO 1-/-小鼠中的CE显著损失 的FECD。与氧化应激和线粒体损伤一样,我的共同导师(阿尔伯特S。Jun)和其他人有 提示ER应激/未折叠蛋白反应(UPR)在FECD发病机制中的作用。我的初步 数据还表明NQO-/-细胞系的促凋亡ER应激标志物的显著和早期活化 在体外UVA诱导的FECD模型后。然而,还没有任何研究将ER与线粒体 氧化-抗氧化剂失衡下的应激对FECD中CE的影响。本提案的目的是界定 氧化-抗氧化剂作用下内质网应激对线粒体应激的贡献(改变的生物能量学和动力学) 幼儿发展不平衡。在奖励的指导阶段(K99),我将确定UVA是否会诱导ER 和线粒体应激(Aim 1a),ER应激改变线粒体生物能量(Aim 1b)和动力学 (形态学、断裂、移位)都在氧化剂-抗氧化剂失衡下(目的2a)。我会学会诱导 并与我的共同导师实验室的合作(Albert Jun)量化ER压力,分析线粒体生物能量学 与导师Ula Jurkunas和共同导师Pere Puigserver的实验室一起学习体外和体内模型, FECD(Jurkunas的实验室)沿着哈佛医学院提供的广泛的职业发展活动。 在R 00阶段,在导师和共同导师的支持下,我将与 ER介导的线粒体内源性凋亡途径激活机制的补充研究 (Aim 1c)通过Ca+2信号传导和微管重排(Aim 2b)。总的来说,这些研究将提供新的 对ER-线粒体串扰的角膜内皮生物学的见解和观点,这将促进 我们对FECD发病机制的理解。K99奖将允许我在ER接受额外的培训, 线粒体生物学沿着角膜内皮细胞生物学的新训练。广泛的资源和 职业发展机会,可在哈佛医学院,Jurkunas,Puigserver,和君的实验室,作为 以及K99阶段计划的研究活动,将使我能够实现以下长期目标: 成为一名独立的研究者,致力于研究角膜上皮细胞中的ER-线粒体串扰, 内皮生物学

项目成果

期刊论文数量(0)
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Varun Kumar其他文献

Varun Kumar的其他文献

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{{ truncateString('Varun Kumar', 18)}}的其他基金

Understanding Endoplasmic Reticulum-Mitochondrial Cross-Talk in Corneal Endothelial Cells
了解角膜内皮细胞中的内质网-线粒体交互作用
  • 批准号:
    10597212
  • 财政年份:
    2020
  • 资助金额:
    $ 24.9万
  • 项目类别:

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