Unveiling the molecular mechanisms to modulate peroxisome dynamics and abundance for improvement of cell performance

真核细胞的标志之一是存在膜结合区室（细胞器），它们创造不同的优化环境，以促进维持生命所需的各种代谢反应。为了适应细胞或生物体不断变化的生理需求，细胞器必须不断调整其数量，形状，位置和代谢功能。这需要通过细胞器形成（生物发生）、降解（自噬）或遗传（细胞分裂）来调节细胞器丰度的动态过程。过氧化物酶体是多功能的亚细胞细胞器，对人类健康和发育至关重要。过氧化物酶体在脂质代谢、信号传导、抗氧化应激和衰老中的重要保护作用最近已经出现。我们的工作表明，过氧化物酶体是非常动态的，可以形成从预先存在的细胞器在一个多步骤的过程中，需要改造的过氧化物酶体膜，形成管状膜延伸，随后收缩，并分为几个新的过氧化物酶体。过氧化物酶体动力学和增殖的缺陷与年龄相关的疾病有关，包括神经变性、失明和耳聋。尽管它们对细胞生理学具有根本重要性，但对介导和调节过氧化物酶体膜动力学和人类丰度的机制知之甚少，并且缺少生物物理模型。了解这些机制不仅对于理解基本的生理过程，而且对于理解疾病病因学中的致病过程是重要的。本项目的总体目标是对正常和疾病状态下过氧化物酶体丰度、膜动力学和细胞器合作的机制和调控获得新的见解。在本研究项目中，我们将（1）评估过氧化物酶体分裂中的关键蛋白质的作用，以揭示调节过氧化物酶体丰度的分子机制，（2）应用生物物理方法研究蛋白质-脂质相互作用和膜重塑，（3）鉴定调节关键蛋白质的表达和过氧化物酶体动力学以改善细胞性能的机制，以及（4）开发生物物理/数学模型以理解和预测健康和疾病状况下的过氧化物酶体动力学。在这个跨学科项目中，我们将结合联合收割机在细胞器生物学和细胞器方面独特互补专业知识，基于生物物理和数学方法以及人类细胞生物学的新工具和模型的疾病。我们将应用分子细胞生物学，生物物理学，生物化学和筛选方法，数学建模和尖端成像技术来揭示介导和调节细胞器膜动力学和细胞器丰度的分子机制和途径。具体而言，该研究项目将提高我们对细胞器动态/丰度及其对健康老龄化和常见退行性疾病的影响的理解。我们将开发新的工具和模型来评估和调节细胞器动力学，这可能有助于提高细胞性能。了解如何调节细胞器的动力学和丰度，并利用细胞器的保护功能将具有重要的生物学和医学意义。它可能有助于健康老龄化和年龄相关疾病的新治疗方法的发展。

One of the hallmarks of eukaryotic cells is the presence of membrane-bound compartments (organelles), which create different optimised environments to promote various metabolic reactions required to sustain life. To adapt to the changing physiological requirements of a cell or organism, organelles have to constantly adjust their number, shape, position, and metabolic functions accordingly. This requires dynamic processes which modulate organelle abundance by organelle formation (biogenesis), degradation (autophagy), or inheritance (cell division). Peroxisomes are multifunctional subcellular organelles that are essential for human health and development. Vital, protective roles of peroxisomes in lipid metabolism, signalling, the combat of oxidative stress and ageing have emerged recently. Our work has revealed that peroxisomes are extremely dynamic and can form from pre-existing organelles in a multistep process which requires remodelling of the peroxisomal membrane, the formation of tubular membrane extensions which subsequently constrict and divide into several new peroxisomes. Defects in peroxisome dynamics and multiplication have been linked to age related disorders involving neurodegeneration, loss of sight and deafness. Despite their fundamental importance to cell physiology, the mechanisms that mediate and regulate peroxisome membrane dynamics and abundance in humans are poorly understood and a biophysical model is missing. Understanding these mechanisms is not only important for comprehending fundamental physiological processes but also for understanding pathogenic processes in disease etiology. The overall aim of this project is to acquire novel insights into the mechanism and regulation of peroxisome abundance, membrane dynamics and organelle cooperation in normal and disease conditions.In this research project, we will (1) assess the role of key proteins in peroxisome division to unveil the molecular mechanisms modulating peroxisome abundance, (2) apply biophysical approaches to investigate protein-lipid interaction and membrane remodelling, (3) identify mechanisms to modulate expression of key proteins and peroxisome dynamics for improvement of cell performance, and (4) develop a biophysical/mathematical model to understand and predict peroxisome dynamics in health and disease conditions.In summary, in this interdisciplinary project we will combine unique complementary expertise in organelle-biology and organelle-based disorders with biophysical and mathematical approaches as well as novel tools and models in human cell biology. We will apply molecular cell biology, biophysical, biochemical and screening approaches, mathematical modelling and cutting edge imaging techniques to reveal the molecular mechanisms and pathways that mediate and regulate organelle membrane dynamics and organelle abundance. Specifically, this research project will improve our understanding of organelle dynamics/abundance and its impact on healthy ageing and common, degenerative disorders. We will generate new tools and models for assessing and modulating organelle dynamics, which may help to improve cell performance. Understanding how to modulate organelle dynamics and abundance and to use the protective functions of organelles will be of significant biological and medical importance. It may contribute to the development of new therapeutic approaches in healthy ageing and age-related disorders.