Dissecting the Molecular Mechanism of Intraflagellar Transport Motors

组成人体的30万亿个细胞可分为约200种主要类型。几乎所有这些类型的细胞都长出一种叫做纤毛的天线状结构，它从细胞表面伸出到环境中。远亲生物，如原生动物和绿藻也有纤毛，这表明它们是古老的细胞器，比所有真核生物的最后一个共同祖先还要早。纤毛具有重要的感官作用，检测和处理环境刺激，如光、嗅觉、形态因子和流体流动。纤毛的一个子集以波状运动主动搏动以产生细胞推进，例如在精子细胞中，或液体在气道和输卵管上皮上的运动。纤毛的结构和组成缺陷引起了大量的疾病，统称为纤毛病。因此，破译纤毛的组装和功能机制是理解广泛的生物过程和疾病状态的分子基础的基础。我们对支持纤毛形成和功能的中心机制特别感兴趣。这构成了一个运输系统，它将构件从细胞质移动到纤毛尖端，并将产物返回到细胞体。它由两种以atp为燃料的运动蛋白提供动力，它们沿着纤毛朝相反的方向运动。我们希望揭示运动蛋白产生力和运动、协调往返运输以及在穿过纤毛时避免相互碰撞的独特机制。为了实现这一目标，我们将使用新的工具来生产和操作电机以进行详细的研究。

The 30 trillion cells that make up the human body fall into ~200 major types. Virtually all of these cell types grow an antenna-like structure called the cilium, which projects from the cell surface into the environment. Distantly related organisms such as protozoa and green algae also possess cilia, suggesting that they are ancient organelles that pre-date the last common ancestor of all eukaryotes. Cilia serve vital sensory roles, detecting and processing environmental stimuli such as light, olfactants, morphogens and fluid flow. A subset of cilia actively beat with a wave-like motion to generate cell propulsion, for example in sperm cells, or movement of fluid over the epithelia lining the airways and oviduct. Defects in the architecture and composition of cilia cause a plethora of disorders collectively known as ciliopathies. Hence, deciphering the mechanisms by which cilia are assembled and function is fundamental to understanding a wide array of biological processes and the molecular basis of disease states. We are particularly interested in the central mechanism underpinning cilia formation and function. This constitutes a transport system that moves building blocks from the cytoplasm to the tip the cilium and returns products to the cell body. It is powered by two types of ATP-fueled motor protein, which move in opposite directions along the cilium. We wish to uncover the unique mechanisms through which the motor proteins generate force and movement, coordinate round trips of transportation, and avoid colliding with each other as they traverse the cilium. To achieve this, we will use new tools to produce and manipulate the motors for detailed study.