Dissecting the Molecular Mechanism of Intraflagellar Transport Motors

构成人体的30万亿个细胞分为大约200种主要类型。几乎所有这些细胞类型都生长出一种称为纤毛的触角状结构，它从细胞表面投射到环境中。亲缘关系较远的生物，如原生动物和绿色藻类也有纤毛，这表明它们是所有真核生物最后共同祖先之前的古老细胞器。纤毛起着重要的感觉作用，检测和处理环境刺激，如光，嗅觉，形态发生素和流体流动。纤毛的一个子集以波浪状运动积极地跳动以产生细胞推进，例如在精子细胞中，或在气道和输卵管内衬的上皮上的流体运动。纤毛结构和组成的缺陷会导致大量的疾病，统称为纤毛病。因此，破译纤毛组装和功能的机制对于理解广泛的生物过程和疾病状态的分子基础至关重要。我们对纤毛形成和功能的中枢机制特别感兴趣。这构成了一个运输系统，将构建块从细胞质移动到纤毛顶端，并将产物返回到细胞体。它由两种类型的ATP驱动的运动蛋白提供动力，它们沿着纤毛向相反的方向运动。我们希望揭示马达蛋白产生力和运动的独特机制，协调运输的往返行程，并避免在穿过纤毛时相互碰撞。为了实现这一目标，我们将使用新的工具来生产和操纵电机进行详细的研究。

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.