波兰医学博士招聘-托伦哥白尼大学-细胞铁死亡

发布时间：2020/9/22 12:49:04

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邮箱：cxw@med.tj.cn

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微信公众号链接：https://mp.weixin.qq.com/s?__biz=MzU5NTk2OTE2Mw==&mid=2247485711&idx=1&sn=8769823e9f8559857e1edd5689bf99d9&chksm=fe689cebc91f15fd61d39b0ea8a98ed835bf73f776994a28af1ced2b8bdf717816b241800d35&token=177111913&lang=zh_CN#rd

学校：托伦哥白尼大学 Nicolaus Copernicus University

院系：Faculty of Physics, Astronomy and Applied Informatics

教授：Prof. dr hab. Wieslaw Nowak

申请邮箱： karolamik@fizyka.umk.pl

截止日期：Sep. 28, 2020

介绍

项目名称：Computational studies of regulatory mechanism and inhibition of ferroptotic cell death signal

项目介绍：

铁死亡（Ferroptosis）是一种新的，近期被认可的，非细胞凋亡的细胞死亡形式，其特征是脂质过氧化物的积累。在癌症的治疗中起着至关重要的作用，并且可以促进脑部创伤，肾脏疾病和哮喘中组织的降解。当前，全球有超过3.65亿人患有哮喘，目前尚无有效的预防方法。对铁死亡的深入了解可能对他们来说是新的希望。

在由波兰国家科学中心资助的SONATA研究项目中，我们想验证以下假设：在分子水平上了解铁死亡过程的机制可能带来新的化合物，从而对抗细胞铁死亡。我们最近的研究（S. Wenzel et. al., Cell, 2017）表明，具有15LOX蛋白复合物的PEBP1的形成会引发细胞铁死亡信号，即导致脂质过氧化。这一发现引起了研究界的极大兴趣，尽管事实上这种关联的分子机制还知之甚少。因此，我们希望填补这一空白，并使用多种高级计算方法带来有关15LOX-PEBP1复杂动力学及其重要功能区域的新知识。

本研究项目的主要目的是开发新型计算机抑制剂，以保护细胞免受由PEBP1-15LOX络合激活的铁死亡信号的影响，而PEBP1-15LOX络合又是脂质过氧化的第一步。这类抑制剂可能会导致新药的开发。在该项目中获得的结果将对生物医学领域产生重大影响。成功的结果将与美国合作者共享，从而对我们的计算预测进行生化验证。

项目目标：

为了表征触发PEBP1-15LOX蛋白复合物活性的其他调节机制以及其他成分在铁死亡中的作用。

确定15LOX和PEBP1-15LOX中的配体扩散途径。

开发计算机模拟新抑制剂，该抑制剂将终止由PEBP1-15LOX络合引发的细胞铁死亡信号。

主要职责包括：

1）掌握分子动力学，配体参数化，分子对接和Python编程技能。

2）寻找一种基于增强采样（在PLUMED中实现）的最新开发方法的通用方法，以揭示分离的15LOX蛋白和与PEBP1复合的15LOX中的新条目和新通道。

3）使用可用的和/或新颖的计算工具和分析方法找到变构调制和动力学的热点和关键部位。

4）掌握药效团模型的制备和虚拟筛选的使用。

5）基于任务#2-4所获得的信息，为15LOX和15LOX-PEBP1复合物提供了一组新的潜在抑制剂。

6）美国合作者将在生化研究中对最有发展前景的化合物进行测试。

博士生还将参与：

1.以书面和口头方式（出版物，会议）介绍项目成果。

2.与小组的其他成员合作，使项目取得成功。

要求

物理学，化学，生物学或类似专业的硕士学位。

具备入读托伦哥白尼大学AST博士学院 （Academia Scientiarum Thoruniensis）的资格（https://www.phd.umk.pl/ast/）。

参与科学工作。

具有良好的英语（口语和书面）能力和良好的表达能力。

对科学活动有很高的动力和热情。

分析性思维方式。

此外，以下是个人优势：

编程经验（例如Python）和计算机方法知识，例如分子动力学，对接，蛋白质弹性模型。

有关Linux / Unix操作系统的基本知识。

参与科研课题。

出版科学刊物（最好是在同行评审期刊中）。

申请

充分考虑2020年9月11日之前收到的申请，但在职位填补之前将继续接受申请。选定的申请人需要参加在NCU的面试或通过电话会议进行的面试。

所需文件如下，请将所有申请文件和推荐信发送至：karolamik@fizyka.umk.pl：

简历以及出版物和会议清单。

扫描硕士学位文凭。

求职信。

可以提供推荐人员的联系方式（例如，论文的指导者）。

简要介绍迄今为止参与过的研究活动。

请在您的录取通知中附上以下句子：

“I hereby give consent for my personal data included in my application to be processed for the purposes of the recruitment process under the Personal Data Protection Act as of 29 August 1997, consolidated text: Journal of Laws 2016, item 922 as amended.”

Job description

Project title: Computational studies of regulatory mechanism and inhibition of ferroptotic cell death signal

Project description:

Ferroptosis is new, recently recognized, non-apoptotic form of cell death characterized by the accumulation of lipid peroxides. Is plays a vital role in the treatment of cancers, and can contribute to the degradation of tissue in brain trauma, kidney disease and asthma. Currently, over 365 million people globally are affected by asthma and there is no effective prevention for it. Better insight into ferroptosis may be new hope to them.

In SONATA research project, funded by National Science Centre Poland, we would like to verify hypothesis that the understanding of mechanisms of ferroptosis process at the molecular level may bring novel chemical compounds acting against the ferroptotic cell death. Our recent studies (S. Wenzel et. al., Cell, 2017) showed that formation of PEBP1 with 15LOX protein complex initiate the ferroptotic cell death signal i.e. leads to lipids peroxidation. This discovery sparked substantial interest in research community, despite the fact that molecular mechanism of this association in poorly understand yet. Thus, we would like to fulfill this gap and bring new knowledge about 15LOX-PEBP1 complex dynamics and its functionally important regions using multiple advanced computational approaches.

The main goal of present research project is to develop in silico new inhibitors which will protect a cell against ferroptotic death signal activated by the PEBP1-15LOX complexation, which in turn is an initial step of lipids peroxidation. Such inhibitors may potentially lead to new drugs developments. The results obtained during this project will have significant impact on the biomedical field. Promising outcome will be shared with the US collaborators for biochemical verification of our computational predictions.

Project goals:

To characterize the regulatory mechanisms triggering the activity of the PEBP1-15LOX protein complex and roles of other components in the ferroptosis process.

To identify ligands diffusion pathways in 15LOX and PEBP1-15LOX.

To develop in silico new inhibitors which will stop ferroptotic cell death signal initiated by the PEBP1-15LOX complexation.

Key responsibilities include:

1) Mastering molecular dynamics, ligand parametrization, molecular docking and Python programing skills.

2) Finding a general approach for recently developed method based on the enhance sampling (implemented in PLUMED) to reveal new entries and tunnels in isolated 15LOX protein and 15LOX complexed with PEBP1.

3) Finding hot spots and crucial sites for allosteric modulation and dynamics using available and/or novel computational tools and analysis methods.

4) Mastering pharmacophore model preparation and usage of virtual screening.

5) Based on knowledge from tasks #2-4 providing a new set of potential inhibitors for 15LOX and 15LOX-PEBP1 complex.

6) The most promising compounds will be tested in biochemical studies by the US collaborators.

PhD student will also be expected:

1. To present results of the project in written and oral manner (publications, conferences).

2. To collaborate with other members of the group towards the success of the project.

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