Sorting, topology, and structural control in cells

细胞中的排序、拓扑和结构控制

• 批准号: 2737807
• 金额: --
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2737807
• 关键词: Sorting; topology; structural; control; cells

The Golgi Apparatus, a key organelle in eukaryotic cells, processes and traffics molecules. Modifying proteins/lipids and then distributing them, it is essential to the operation of the cell. It is not surprising then that structural issues in the Golgi are linked to neurodegenerative diseases, cardiovascular disease and cancer, to name but a few. Membrane bound organelles exhibit robust regulatory response; despite supporting a constant flux of molecules the structure of the Golgi is very stable and reforms rapidly if destroyed or after a mitotic event. Yet after a century of research, how this organelle regulates its morphology and function is poorly understood. We will tackle this problem using a physical approach. The Golgi, consisting of the Golgi complex and Trans Golgi Network (TGN), can be modelled as acollection of surfaces with very different topological characteristics. The complex is comprised of many sac-like cisternae- picture a stack of pancakes. It has positive curvature in the sense of the integral of its Gaussian curvature. This is in stark contrast to the very negative curvature of the TGN, a network of cups and tubules with many handles. Our preliminary research provided understanding of how a physical approach could explain the stability of this structure. We will build this into a robust model using a physical description of the membrane energy. Achieving this relies on a background of mathematical knowledge but also benefits from the biological insights that partners in Institut Curie provide, ensuring the theory can be tested against experimental observations. These include, but are not limited to, the up-regulation of vesicular traffic on the Golgi or ER. In our approach we characterise events such as vesiculation, when a small sphere of membrane buds off the Golgi, based on the resulting changes to the free energy of the system. The free energy can be described as the bending energy of the membrane and vesicle, given by an integral form known as the Helfrich Hamiltonian, plus entropy contribution arising from preferential recruitment of surface proteins. These are driven onto the vesicle by a preference for its (highly positive) Gaussian curvature, leaving behind molecules with a higher propensity for negative curvature. By invoking a near-equilibrium approximation we can calculate the vesicle composition that minimises the free energy. We must then embed this into the architecture of a dynamical system representing the supply and removal of membrane. We seek analytical insights and so consider a deterministic system first, which will facilitate the description of the trafficking steady state. The next task is to model deeper levels of complexity until we are accurately describing the real world system.

高尔基体是真核细胞中一个重要的细胞器，负责处理和运输分子。修饰蛋白质/脂质，然后分配它们，这对细胞的运作至关重要。因此，高尔基体的结构问题与神经退行性疾病、心血管疾病和癌症有关也就不足为奇了。膜结合的细胞器表现出强大的调节反应;尽管支持恒定的分子流量，但高尔基体的结构非常稳定，并且如果被破坏或在有丝分裂事件后迅速重组。然而，经过世纪的研究，人们对这种细胞器如何调节其形态和功能知之甚少。我们将使用物理方法来解决这个问题。高尔基体由高尔基复合体和跨高尔基体网络（TGN）组成，可以被建模为具有非常不同拓扑特征的表面的集合。这个复合体由许多囊状的池组成--想象一下一堆煎饼。它在高斯曲率的积分意义下具有正曲率。这与TGN的非常负的曲率形成鲜明对比，TGN是一个具有许多手柄的杯和小管网络。我们的初步研究提供了物理方法如何解释这种结构的稳定性的理解。我们将使用膜能量的物理描述将其构建成一个强大的模型。实现这一目标依赖于数学知识的背景，但也受益于居里研究所合作伙伴提供的生物学见解，确保理论可以根据实验观察进行测试。这些包括但不限于高尔基体或ER上囊泡运输的上调。在我们的方法中，我们根据系统自由能的变化来解释囊泡形成等事件，当一个小的膜球从高尔基体上发芽时。自由能可以被描述为膜和囊泡的弯曲能，由被称为Helfrich Hamiltonian的积分形式给出，加上由表面蛋白的优先募集产生的熵贡献。这些被驱动到囊泡的偏好，其（高度积极的）高斯曲率，留下的分子具有较高的倾向，负曲率。通过调用近平衡近似，我们可以计算囊泡的组成，使自由能最小化。然后，我们必须将其嵌入到代表膜的供应和移除的动力系统的架构中。我们寻求分析的见解，所以考虑一个确定性的系统第一，这将有助于描述的贩运稳定状态。下一个任务是对更深层次的复杂性进行建模，直到我们准确地描述真实的世界系统。