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Nanoelectrode arrays for study of the molecular mechanisms, triggers, and inhibit

用于研究分子机制、触发和抑制的纳米电极阵列

基本信息

批准号：
8220900
负责人：
PETER J. BURKE
金额：
$ 19.37万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-15 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8220900
关键词：
Action Potentials Address Adenine Nucleotides Apoptosis Apoptosis Inhibitor Apoptosis Regulator Apoptotic Binding Biochemical Caliber Cancer Biology Cell Death Cells Charge Cholesterol Cytosol Defect Diamide Down-Regulation Electrodes Functional disorder Generations Genes Glucose Heme Hepatocyte Hexokinase 2 Individual Induction of Apoptosis Infusion procedures Inner mitochondrial membrane Ions Kinetics Lipids Maintenance Measures Membrane Membrane Potentials Metabolism Metals Microfluidics Mitochondria Mitochondrial DNA Mitochondrial Proteins Mitochondrial Proton-Translocating ATPases Mitochondrial Swelling Molecular Monitor Mutation Neurons Normal Cell Oxidative Stress Oxygen Peroxides Phase Phospholipids Potential Energy Primary carcinoma of the liver cells Process Production Protein Family Protein Isoforms Regulation Repression Resolution Signal Transduction Signal Transduction Pathway Source Surface Swelling System Technology Testing Variant Vesicle aerobic glycolysis cancer cell cell killing coproporphyrinogen III cytochrome c oxidase falls functional status high throughput technology inhibitor/antagonist macromolecule miniaturize mitochondrial dysfunction mitochondrial membrane mitochondrial permeability transition pore nano nanowire oligomycin sensitivity-conferring protein response seal sensor single walled carbon nanotube theories tumorigenesis uptake

项目摘要

DESCRIPTION (provided by applicant): Mitochondria are the central regulator of apoptosis, a process initiated by the activation of the mitochondrial permeability transition pore (mtPTP), an aggregate of several mitochondrial proteins. When this pore opens, the critical membrane polarization of the mitochondrial inner membrane disappears and ions equilibrate between the matrix and cytosol resulting in mitochondrial swelling. This leads to release of the contents of the mitochondrial intermembrane space into the cell cytosol, including a number of cell death promoting factors killing the cell. The mtPTP can be activated by uptake of excessive Ca++; increased oxidative stress; decreased mitochondrial membrane potential, and reduced ADP and ATP. It is generally agreed upon that repression of apoptosis is one of the fundamental steps in tumorigenesis. Cancer cells acquire unresponsiveness to apoptosis facilitating signals, thus enabling uncontrolled proliferation. For this reason, the induction of apoptosis is one of the modes of actions of chemotherapeutic compounds. In order to allow further high throughput studies of the biochemical facilitators and inhibitors, of apoptosis, and to determine if changes in individual mitochondrial membrane potential P are important to cellular metabolism, we need to develop a system to monitor P in individual mitochondria. To accomplish this objective, we propose to extend studies that have monitored the action potentials in neurons using an array of parallel electrodes to which the mitochondria are adhered. Our thesis is that a nanoelectrode technology can be developed to capacitively measure membrane potential across the mitochondrial inner membrane phospholipid bilayer without actually penetrating the membrane. We propose to develop nano-electrical transduction sensor arrays with sufficiently high spatial and temporal resolution to monitor the charge changes on the surface of a mitochondrion sized lipid vesicle and the individual mitoplast. With this technology, we will then interrogate the regulation of P in normal and cancer cells. Several key features on mitochondrial metabolism are now recognized as important to the alteration of cancer cell mitochondrial function: changes in the Akt signal transduction pathway, induction of hexokinase II, alteration an adenine nucleotide translocator (ANT) isoform expression, down regulation of the SOC2 cytochrome c oxidase (complex IV, COX) assembly factor, mutation in mitochondrial DNA (mtDNA) genes, and modulation of the mitochondrial permeability transition pore (mtPTP) and its interaction with the pro- and anti- apoptotic Bcl2 family proteins. While all of these are important factors in the alteration of cancer cell metabolism, they still fall short of explaining the near universal alterations in mitochondrial function observed in cancer cells. A high throughput technology to monitor P in mitochondria will allow further studies of these issues in cancer biology.

描述（由申请人提供）：线粒体是细胞凋亡的中心调节因子，细胞凋亡是由线粒体通透性过渡孔（mtPTP）激活启动的过程，mtPTP是几种线粒体蛋白的集合。当这个孔打开时，线粒体内膜的临界膜极化消失，离子在基质和细胞质溶胶之间平衡，导致线粒体膨胀。这导致线粒体膜间空间的内容物释放到细胞质中，包括许多杀死细胞的细胞死亡促进因子。mtPTP可以通过摄取过量的ca++而被激活；氧化应激增加；线粒体膜电位降低，ADP和ATP降低。人们普遍认为抑制细胞凋亡是肿瘤发生的基本步骤之一。癌细胞获得对凋亡促进信号的无反应性，从而使不受控制的增殖成为可能。因此，诱导细胞凋亡是化疗药物的作用模式之一。为了进一步高通量研究细胞凋亡的生化促进剂和抑制剂，并确定单个线粒体膜电位P的变化是否对细胞代谢重要，我们需要开发一个系统来监测单个线粒体中的P。为了实现这一目标，我们建议扩展使用线粒体粘附的平行电极阵列监测神经元动作电位的研究。我们的论文是，可以开发一种纳米电极技术，在不实际穿透膜的情况下，通过线粒体内膜磷脂双分子层电容测量膜电位。我们建议开发具有足够高空间和时间分辨率的纳米电转导传感器阵列，以监测线粒体大小的脂质泡和单个线粒体质体表面的电荷变化。有了这项技术，我们将研究正常细胞和癌细胞中P的调控。线粒体代谢的几个关键特征现在被认为对癌细胞线粒体功能的改变很重要：Akt信号转导通路的改变、己糖激酶II的诱导、腺嘌呤核苷酸易位子（ANT）异构体表达的改变、SOC2细胞色素c氧化酶（复合物IV， COX）组装因子的下调、线粒体DNA （mtDNA）基因的突变、线粒体通透性过渡孔（mtPTP）的调节及其与促凋亡和抗凋亡Bcl2家族蛋白的相互作用。虽然所有这些都是癌细胞代谢改变的重要因素，但它们仍然无法解释在癌细胞中观察到的线粒体功能几乎普遍的改变。在线粒体中监测P的高通量技术将允许在癌症生物学中进一步研究这些问题。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Resistive flow sensing of vital mitochondria with nanoelectrodes.

使用纳米电极对重要线粒体进行电阻流传感。

DOI：
10.1016/j.mito.2017.06.003
发表时间：
2017
期刊：
Mitochondrion
影响因子：
4.4
作者：
Zand,Katayoun;Pham,TedDA;Li,Jinfeng;Zhou,Weiwei;Wallace,DouglasC;Burke,PeterJ
通讯作者：
Burke,PeterJ

Detection of single ion channel activity with carbon nanotubes.

DOI：
10.1038/srep09208
发表时间：
2015-03-17
期刊：
Scientific reports
影响因子：
4.6
作者：
Zhou W;Wang YY;Lim TS;Pham T;Jain D;Burke PJ
通讯作者：
Burke PJ

Charging the quantum capacitance of graphene with a single biological ion channel.

用单个生物离子通道充电石墨烯的量子电容。

DOI：
10.1021/nn501376z
发表时间：
2014-05-27
期刊：
ACS NANO
影响因子：
17.1
作者：
Wang, Yung Yu;Pham, Ted D.;Zand, Katayoun;Li, Jinfeng;Burke, Peter J.
通讯作者：
Burke, Peter J.

Acute exercise remodels mitochondrial membrane interactions in mouse skeletal muscle.

DOI：
10.1152/japplphysiol.00819.2013
发表时间：
2013-11
期刊：
Journal of applied physiology (Bethesda, Md. : 1985)
影响因子：
0
作者：
Picard M;Gentil BJ;McManus MJ;White K;St Louis K;Gartside SE;Wallace DC;Turnbull DM
通讯作者：
Turnbull DM

Sensing the electrical activity of single ion channels with top-down silicon nanoribbons.

使用自上而下的硅纳米带感测单离子通道的电活动。