The Mucolipin TRP Ion Channels

Mucolipin TRP 离子通道

基本信息

  • 批准号:
    8416389
  • 负责人:
  • 金额:
    $ 31.32万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-01-15 至 2015-12-31
  • 项目状态:
    已结题

项目摘要

The mucolipin family of Transient Receptor Potential (TRPML) proteins is predicted to encode ion channels of intracellular endosomes and lysosomes. Mutations of human TRPML1 cause type IV mucolipidosis (ML4), a devastating neurodegenerative disease in young children. ML4 patients exhibit motor defects, mental retardation, retinal degeneration, and iron-deficiency anemia. Mice with mutations in TRPML3 (the varitint-waddler, Va mice) are deaf and exhibit circling behavior and pigmentation defects. The broad-spectrum phenotypes of both ML4 and Va appear to result from certain aspects of endosomal/lysosomal dysfunction. Lysosomes, traditionally believed to be the terminal ¿recycle center¿ for biological ¿garbage¿, have recently been revealed to play indispensable roles in multiple intracellular signaling pathways. The putative lysosomal function(s) of TRPML proteins, however, has been unclear largely due to the lack of a reliable functional assay for these intracellularly-localized proteins. We have now made a technical breakthrough by developing a patch-clamp method to directly measure the functions of TRPML proteins in the isolated late endosome/lysosome. We found that TRPML1 is an inwardly-rectifying (cations flowing out of the lysosome) cation channel conducting both Ca2+ and Fe2+. These findings molecularly and electrophysiologically identified the first Ca2+/Fe2+ channel in the lysosome. Mutations found in ML4 patients impair TRPML1¿s ability to permeate Ca2+ and Fe2+ at degrees that correlate well with the severity of the ML4 disease. To expand our findings, the goal of the proposed research is to apply a multidisciplinary approach using electrophysiology, Ca2+ imaging, immunochemistry, biochemistry, and fluorescence imaging to test our central hypotheses that TRPML1 mediates cation efflux from endosomes and lysosomes and that impaired ion homeostasis underlies lysosomal dysfunction and ML4 phenotypes. Our first aim is to determine the role of TRPML1 in endolysosomal iron release. Using iron imaging and iron staining methods, we will determine whether iron release from endo-lysosomes is impaired in TRPML1-deficient skin fibroblasts. Our second aim is to investigate the roles of TRPML1 in the lysosome-mediated cell biological functions that have been shown to involve Fe2+/Ca2+ efflux from lysosomes. Using cell death assays, we will investigate whether TRPML1-deficient cells are susceptible to oxidative stress. Using bacteria killing assays, we will determine whether TRPML1-deficient macrophages exhibit reduced bactericidal activity. Our third aim is to investigate the role of TRPML1 in lysosomal Ca2+ signaling. Like the endoplasmic reticulum (ER), lysosomes are also believed to be the Ca2+ release sites during certain cellular signaling. Using electrophysiology and Ca2+ imaging, we will specifically test whether TRPML1 is activated by known lysosome Ca2+-release activators, and whether the induced lysosomal Ca2+ release is absent in TRPML1-deficient fibroblasts. In the long term, the results should provide clinical insights into therapeutic approaches for both iron-related disorders (anemia and iron overload) and degenerative diseases (retinal and neural degeneration).
瞬时受体电位(TRPML)蛋白的粘脂家族被预测为 编码细胞内核内体和溶酶体的离子通道。人类突变 TRPML 1导致IV型粘脂沉积症(ML 4),这是一种破坏性的神经退行性疾病, 年幼的孩子。ML 4患者表现出运动缺陷、智力迟钝、视网膜变性, 和缺铁性贫血TRPML 3突变小鼠(varitint-waddler,Va小鼠) 耳聋并表现出绕圈行为和色素缺陷。广谱 ML 4和Va的表型似乎都是由以下某些方面引起的: 内体/溶酶体功能障碍。溶酶体,传统上被认为是 <$回收中心<$生物<$垃圾<$,最近被揭示发挥不可或缺的 在多种细胞内信号通路中的作用。假定的溶酶体功能 然而,TRPML蛋白一直不清楚,主要是由于缺乏可靠的功能性蛋白质。 检测这些细胞内定位的蛋白质。我们现在已经做了一个技术性的 通过开发膜片钳方法直接测量功能的突破, 分离的晚期内体/溶酶体中的TRPML蛋白。我们发现TRPML 1是一种 内向整流(阳离子流出溶酶体)阳离子通道传导Ca 2 + Fe2+。这些发现在分子和电生理学上鉴定了第一个Ca 2 +/Fe 2 + 溶酶体中的通道。在ML 4患者中发现的突变损害了TRPML 1的能力, 渗透Ca 2+和Fe 2+的程度与ML 4疾病的严重程度密切相关。 为了扩大我们的发现,拟议研究的目标是应用多学科的 使用电生理学、Ca 2+成像、免疫化学、生物化学和 荧光成像来测试我们的中心假设,即TRPML 1介导阳离子流出, 内体和溶酶体,以及受损的离子稳态是溶酶体 功能障碍和ML 4表型。我们的第一个目标是确定TRPML 1在内溶酶体中的作用, 铁释放使用铁成像和铁染色方法,我们将确定 在TRPML 1缺陷的皮肤成纤维细胞中,内溶体的铁释放是否受损。 我们的第二个目的是研究TRPML 1在溶酶体介导的细胞凋亡中的作用。 已显示涉及来自溶酶体的Fe 2 +/Ca 2+流出的生物学功能。使用 细胞死亡测定,我们将研究TRPML 1缺陷细胞是否对 氧化应激使用细菌杀伤试验,我们将确定TRPML 1缺陷型 巨噬细胞表现出降低的杀菌活性。我们的第三个目标是研究 TRPML 1在溶酶体Ca 2+信号转导中的作用像内质网(ER)一样,溶酶体是 也被认为是某些细胞信号传导过程中的Ca 2+释放位点。使用 电生理学和Ca 2+成像,我们将专门测试TRPML 1是否被激活, 已知的溶酶体Ca 2+释放激活剂,以及诱导的溶酶体Ca 2+释放是否是 在TRPML 1缺陷的成纤维细胞中不存在。从长远来看,结果应该提供临床 对铁相关疾病(贫血和铁缺乏)的治疗方法的见解 超负荷)和变性疾病(视网膜和神经变性)。

项目成果

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Haoxing Xu其他文献

Haoxing Xu的其他文献

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{{ truncateString('Haoxing Xu', 18)}}的其他基金

Ion channels in the tubulovesicles
管泡中的离子通道
  • 批准号:
    9423540
  • 财政年份:
    2017
  • 资助金额:
    $ 31.32万
  • 项目类别:
TRP Ca2+ Channels in the Skin
皮肤中的 TRP Ca2 通道
  • 批准号:
    8529459
  • 财政年份:
    2012
  • 资助金额:
    $ 31.32万
  • 项目类别:
TRP Ca2+ Channels in the skin
皮肤中的 TRP Ca2 通道
  • 批准号:
    8238560
  • 财政年份:
    2012
  • 资助金额:
    $ 31.32万
  • 项目类别:
TRP Ca2+ Channels in the Skin
皮肤中的 TRP Ca2 通道
  • 批准号:
    9117392
  • 财政年份:
    2012
  • 资助金额:
    $ 31.32万
  • 项目类别:
Kinetic High Throughput Screening for Agonists and Inhibitors of the TRPML1 Ion c
TRPML1 离子 c 激动剂和抑制剂的动力学高通量筛选
  • 批准号:
    8262514
  • 财政年份:
    2011
  • 资助金额:
    $ 31.32万
  • 项目类别:
High Throughput Screening for Modulators of the TRPML1 Ion Channel
TRPML1 离子通道调制器的高通量筛选
  • 批准号:
    8402809
  • 财政年份:
    2011
  • 资助金额:
    $ 31.32万
  • 项目类别:
The Mucolipin TRP Ion Channels
Mucolipin TRP 离子通道
  • 批准号:
    8289767
  • 财政年份:
    2009
  • 资助金额:
    $ 31.32万
  • 项目类别:
The Mucolipin TRP Ion Channels
Mucolipin TRP 离子通道
  • 批准号:
    7651537
  • 财政年份:
    2009
  • 资助金额:
    $ 31.32万
  • 项目类别:
The Mucolipin TRP Ion Channels
Mucolipin TRP 离子通道
  • 批准号:
    8208216
  • 财政年份:
    2009
  • 资助金额:
    $ 31.32万
  • 项目类别:
The Mucolipin TRP Ion Channels
Mucolipin TRP 离子通道
  • 批准号:
    9222805
  • 财政年份:
    2009
  • 资助金额:
    $ 31.32万
  • 项目类别:

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