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Autophagic flux regulation by the cholesterol/H+ antiporter PTCH1

胆固醇/H 逆向转运蛋白 PTCH1 调节自噬流

基本信息

批准号：
BB/S01716X/1
负责人：
Natalia Riobo-Del Galdo
金额：
$ 58.82万
依托单位：
University of Leeds
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FS01716X%2F1
关键词：
Autophagic flux regulation cholesterol H+

项目摘要

Development of a fertilized egg into a properly formed embryo requires a number of signals that perfectly orchestrate the formation of tissues and organs. One of those important signalling events is the so-called "Hedgehog" pathway that when absent provokes very serious congenital defects incompatible with life. Conversely, excessive activity of the Hedgehog pathway after birth is a common cause of childhood brain tumours and adult brain, skin, lung, prostate, and gut cancers. My group has contributed to the understanding of how the Hedgehog signals are perceived by cells and transmitted into different outcomes, depending on the tissue type and the context. Here, we propose to investigate a novel function of the Hedgehog pathway in regulating autophagy, the "self-eating" behaviour of cells. We found that the Hedgehog receptor PTCH1, a tumour suppressor, inhibits autophagy. Cells normally feed themselves from available nutrients; however, in conditions of starvation like those encountered by tumour cells that grow faster that the vasculature that nourishes them, cells degrade part of their contents to survive. Autophagy is essential for cancer cells survival. We will investigate how the Hedgehog pathway regulates autophagy at the molecular level. We will build onto our recent publication that shows that interaction between the C-terminal domain of PTCH1 and ATG101 is necessary for inhibition of autophagy, characterised by reduced number of acidic vesicles where degradation occurs. We propose that PTCH1 acts as a transporter, dissipating the proton gradient of those vesicles (autolysosomes) by a mechanism coupled to cholesterol transport. We will test this hypothesis and will investigate if this function of PTCH1 is lost by mutations of the C-terminal domain frequently found in cancer. We hope that our findings will increase the knowledge on new targets for cancer therapy and will reveal new ways in which cells adapt and survive to different stressors.

受精卵发育成正确形成的胚胎需要许多信号，这些信号完美地协调了组织和器官的形成。这些重要的信号事件之一是所谓的“刺猬”途径，当缺乏时会引起与生命不相容的非常严重的先天性缺陷。相反，出生后Hedgehog通路的过度活动是儿童脑肿瘤和成人脑，皮肤，肺，前列腺和肠道癌症的常见原因。我的团队有助于理解细胞如何感知Hedgehog信号并根据组织类型和背景将其传递到不同的结果。在这里，我们建议调查一个新的功能的刺猬途径在调节自噬，“自食”行为的细胞。我们发现Hedgehog受体PTCH 1是一种肿瘤抑制因子，可以抑制自噬。细胞通常从可用的营养物质中喂养自己;然而，在饥饿的条件下，如肿瘤细胞生长得比覆盖它们的脉管系统更快，细胞会降解部分内容物以生存。自噬对于癌细胞的存活至关重要。我们将研究刺猬途径如何在分子水平上调节自噬。我们将建立在我们最近的出版物上，该出版物表明PTCH 1和ATG 101的C-末端结构域之间的相互作用对于抑制自噬是必要的，其特征在于降解发生的酸性囊泡数量减少。我们认为PTCH 1作为一种转运蛋白，通过与胆固醇转运偶联的机制消散这些囊泡（自溶酶体）的质子梯度。我们将测试这一假设，并将调查PTCH 1的这种功能是否因癌症中常见的C-末端结构域突变而丧失。我们希望我们的发现将增加对癌症治疗新靶点的了解，并揭示细胞适应和存活于不同压力源的新方式。

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）

Ubiquitin-protein ligase Ubr5 cooperates with hedgehog signalling to promote skeletal tissue homeostasis.

DOI：
10.1371/journal.pgen.1009275
发表时间：
2021-04
期刊：
PLoS genetics
影响因子：
4.5
作者：
Mellis D;Staines KA;Peluso S;Georgiou IC;Dora N;Kubiak M;Van't Hof R;Grillo M;Farquharson C;Kinsella E;Thornburn A;Ralston SH;Salter DM;Riobo-Del Galdo NA;Hill RE;Ditzel M
通讯作者：
Ditzel M

Partial Truncation of the C-Terminal Domain of PTCH1 in Cancer Enhances Autophagy and Metabolic Adaptability.

PTCH1中C末端结构域的部分截断可增强自噬和代谢适应性。