Linking the lipid-sensing TMEM16A channel with lysosomal lipid storage mechanisms: implications for drug discovery
将脂质感应 TMEM16A 通道与溶酶体脂质储存机制联系起来:对药物发现的影响
基本信息
- 批准号:BB/T007664/1
- 负责人:
- 金额:$ 56.67万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2020
- 资助国家:英国
- 起止时间:2020 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
We run on electricity - virtually all vital functions like the beating of the heart, the activity of our brain, the function of blood vessels or muscle contractions are triggered by tiny electrical currents that occur through the surface (membrane) of each cell. Responsible for these currents are ion channels, proteins that form microscopic gated pores that selectively allow charged ions to move in and out of the cell; the electrical impulses they generate initiate the vast array of events indispensable for life, such as those mentioned above.A class of ion channels that are found in many cell types in the body are those that allow chloride ions to move across the membrane. For example, these chloride channels are found in the muscle cells that line blood vessels. When the channel is open, chloride "currents" are activated and the blood vessel contracts; when the channel is closed, the current is suppressed and the blood vessel is relaxed. In this way, the blood can be directed to various parts of the body depending on the need. One special feature of this channel is that its opening and closing is regulated by the membrane itself. The membrane is made of oily substances (such as cholesterol) and changes in the composition of the "oils" (technically "lipids") that make up the membrane can affect the function of these chloride channels and, as a consequence, affect many aspects of body biology. The lipid composition itself is controlled by other cellular compartments such as the lysosome that is a specialised part of the cell. We have discovered that if lysosomes are not working properly, the chloride channels are also affected. We now want to understand exactly how this happens and make use of this new knowledge to design new molecules that could eventually be used to control the function of the chloride channels and address many diseases such as those involving blood vessels (e.g. high blood pressure, stroke etc.) and generally diseases in which lipid content is altered (such as a debilitating rare genetic disease known as Niemann-Pick disease type C).To achieve this ambitious aim, we will use a variety of techniques from measurement of the passage of ions in single cells (when the membrane is normal or altered) to genetic modifications of the chloride channel. Importantly, we will combine our expertise in cellular biology with that of colleagues in Industry, who have specific skills in discovering and developing new medicines. Our work will shed light on new aspects of cell biology and, in the longer term, lead to the generation of new medicines.
我们靠电力运转--几乎所有的重要功能,如心脏跳动、大脑活动、血管功能或肌肉收缩,都是由通过每个细胞表面(膜)的微小电流触发的。负责这些电流的是离子通道,这种蛋白质形成微观的门控孔,选择性地允许带电离子进出细胞;它们产生的电脉冲启动了生命所必需的大量事件,如上面提到的那些。在人体的许多细胞类型中发现的一类离子通道是允许氯离子穿过细胞膜的通道。例如,这些氯离子通道存在于排列血管的肌肉细胞中。当通道打开时,氯“电流”被激活,血管收缩;当通道关闭时,电流被抑制,血管松弛。通过这种方式,血液可以根据需要被引导到身体的各个部位。这个通道的一个特殊特征是它的打开和关闭由膜本身来调节。膜是由油性物质(如胆固醇)组成的,组成膜的“油”(技术上称为“脂”)的组成变化会影响这些氯离子通道的功能,从而影响身体生物学的许多方面。脂类成分本身受其他细胞隔间的控制,如溶酶体,它是细胞的一个特殊部分。我们发现,如果溶酶体不能正常工作,氯通道也会受到影响。我们现在想确切地了解这是如何发生的,并利用这一新知识来设计新的分子,这些分子最终可能被用来控制氯离子通道的功能,并治疗许多疾病,如涉及血管的疾病(如高血压、中风等)。为了实现这一雄心勃勃的目标,我们将使用各种技术,从测量单个细胞中的离子通道(当膜正常或改变时)到氯通道的遗传修饰。重要的是,我们将把我们在细胞生物学方面的专业知识与工业界同事的专业知识结合起来,他们在发现和开发新药方面具有特殊的技能。我们的工作将揭示细胞生物学的新方面,从长远来看,将导致新药的产生。
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The TMEM16A anion channel as a versatile regulator of vascular tone
TMEM16A 阴离子通道作为血管张力的多功能调节器
- DOI:10.1126/scisignal.adk5661
- 发表时间:2023
- 期刊:
- 影响因子:7.3
- 作者:Tammaro P
- 通讯作者:Tammaro P
Identification of determinants of lipid and ion transport in TMEM16/anoctamin proteins through a Bayesian statistical analysis.
- DOI:10.1016/j.bpc.2024.107194
- 发表时间:2024-02
- 期刊:
- 影响因子:3.8
- 作者:Oscar Moran;Paolo Tammaro
- 通讯作者:Oscar Moran;Paolo Tammaro
Ion channels as convergence points in the pathology of pulmonary arterial hypertension.
- DOI:10.1042/bst20210538
- 发表时间:2021-08-27
- 期刊:
- 影响因子:3.9
- 作者:Jouen-Tachoire TRH;Tucker SJ;Tammaro P
- 通讯作者:Tammaro P
Polymodal Control of TMEM16x Channels and Scramblases.
- DOI:10.3390/ijms23031580
- 发表时间:2022-01-29
- 期刊:
- 影响因子:5.6
- 作者:Agostinelli E;Tammaro P
- 通讯作者:Tammaro P
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Paolo Tammaro其他文献
New insights into the molecular basis of allosteric activation of the TMEM16A channel and consequences for the control of vascular tone
- DOI:
10.1016/j.bpj.2022.11.2463 - 发表时间:
2023-02-10 - 期刊:
- 影响因子:
- 作者:
Rumaitha Al Hosni;Emilio Agostinelli;Zeki Ilkan;Lara F. Scofano;Kathryn Acheson;Andrew MacDonald;Dean Rivers;Martin Gunthorpe;Frances Platt;Paolo Tammaro - 通讯作者:
Paolo Tammaro
Inhibition of TMEM16A by Docosahexaenoic Acid Plays a Crucial Role in Blood Vessel Relaxation
- DOI:
10.1016/j.bpj.2018.11.956 - 发表时间:
2019-02-15 - 期刊:
- 影响因子:
- 作者:
Kathryn E. Acheson;Paolo Tammaro - 通讯作者:
Paolo Tammaro
1142-187 Three-dimensional echocardiographic and magnetic resonance assessment of the effect of telmisartan compared with carvedilol on left ventricular mass: A multicenter, randomized, controlled study
- DOI:
10.1016/s0735-1097(04)92176-6 - 发表时间:
2004-03-03 - 期刊:
- 影响因子:
- 作者:
Domenico Galzerano;Luca Del Viscovo;Paolo Tammaro;Carlo Tedeschi;Roberto Breglio;Diana Lama;Antonio Cerciello;Bernardino Tuccillo;Paolo Capogrosso - 通讯作者:
Paolo Capogrosso
Molecular Mechanism of Modulation of the TMEM16A Channel by Anthracene-9-Carboxylic Acid: Implications for Channel Gating
- DOI:
10.1016/j.bpj.2019.11.1823 - 发表时间:
2020-02-07 - 期刊:
- 影响因子:
- 作者:
Ria Dinsdale;Angela Russell;Phillip J. Stansfeld;Paolo Tammaro - 通讯作者:
Paolo Tammaro
Paolo Tammaro的其他文献
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{{ truncateString('Paolo Tammaro', 18)}}的其他基金
MICA: The molecular mechanisms of control of cerebral blood flow by the TMEM16A Cl- channel and their potential for pharmacological intervention
MICA:TMEM16A Cl-通道控制脑血流的分子机制及其药物干预的潜力
- 批准号:
MR/X010511/1 - 财政年份:2023
- 资助金额:
$ 56.67万 - 项目类别:
Research Grant
Towards an understanding of the molecular mechanisms that underlie the function of vascular ATP-sensitive potassium (KATP) channels
了解血管 ATP 敏感钾 (KATP) 通道功能的分子机制
- 批准号:
BB/H000259/1 - 财政年份:2009
- 资助金额:
$ 56.67万 - 项目类别:
Research Grant
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