Coordination Funds

细胞如何组装成组织并保持组织的完整性是生物学的中心问题。初级纤毛从大多数脊椎动物细胞的表面伸出，在那里它们感知并局部传递细胞外信号。初生纤毛不起静态细胞器的作用。相反，它们动态地整合细胞外的输入，从而在组织发育、维持和疾病重塑期间控制细胞的命运和功能。初级纤毛的功能依赖于1)纤毛内分子的动态组成，受纤毛运输机制和纤毛底部的门控的精确调节，2)细胞外刺激的上下文相关的感知和处理，以及3)以细胞和组织特有的方式动态组装和拆卸。我们推测，在组织组织和功能过程中，整合这三种初级纤毛动力学对于控制细胞过程至关重要。剖析初级纤毛动力学如何支配组织组织不是一个单独的实验室就能解决的，而是需要一个研究单位(RU)的合作研究努力，并拥有涵盖不同组织类型的纤毛动力学的综合专业知识。因此，RU将在共同努力中解决共同目标，这超出了单个项目或调查人员所能实现的范围。我们的研究组由七个项目(P1至P7)组成。P2和P3将定义纤毛内分子的动力学如何控制细胞的命运、形态发生和组织结构。P4和P5将揭示细胞外刺激如何调节初级纤毛动力学，以控制细胞命运和功能。最后，P6和P7将确定初级纤毛组装/拆解动力学和纤毛信号动力学的变化如何调节组织结构的分子机制。重要的是，每个项目至少涵盖两个层面的纤毛动力学，使用2D细胞培养和3D有机物或活体动物模型，并使用高含量的数据和特定的假设来获得机制理解。RU还将包括一名墨卡托研究员，他将提供标准化的技术和定量程序，使用成像分析纤毛动力学。我们的共同目标是分析不同细胞和组织之间的纤毛动力学，并揭示调节组织发育和功能的共同和特定于上下文的机制。从长远来看，我们的共同努力将使我们能够破译纤毛疾病中损害纤毛动力学的机制，并确定潜在的治疗靶点。

How cells assemble into tissues and maintain tissue integrity are central questions in biology. Primary cilia project from the surface of most vertebrate cells, where they sense and locally transduce extracellular signals. Primary cilia do not function as static organelles. Instead, they dynamically integrate extracellular input, thereby controlling cell fates and functions during tissue development, maintenance, and remodeling in disease. Primary cilia function relies on i) the dynamic composition of molecules within the cilium, precisely regulated by the ciliary trafficking machinery and gating at the ciliary base, ii) the context-dependent sensing and processing of extracellular stimuli, and iii) the dynamic assembly and disassembly in a cell- and tissue-specific manner. We hypothesize that integrating this triad of primary cilia dynamics is critical to control cellular processes during tissue organization and function. Dissecting how primary cilia dynamics govern tissue organization cannot be addressed by an individual lab but requires a collaborative research effort in a Research Unit (RU) with combined expertise covering ciliary dynamics in different tissue types. Thus, the RU will address the common goal in a joint effort, which goes beyond what could be achieved by individual projects or investigators. Our RU consists of seven projects (P1 to P7). P1, P2, and P3 will define how the dynamics of intraciliary molecules control cell fate, morphogenesis, and tissue organization. P4 and P5 will reveal how extracellular stimuli regulate primary cilia dynamics to control cell fate and function. Finally, P6 and P7 will identify the molecular mechanisms underlying how primary cilia assembly/disassembly dynamics and the changes in ciliary signaling dynamics regulate tissue organization. Importantly, every project covers at least two levels of cilia dynamics, uses 2D cell culture and 3D organoids or in vivo animal models, and employs high-content data and specific hypotheses to gain mechanistic understanding. The RU will also include a Mercator fellow who will provide standardized technological and quantitative procedures to analyze cilia dynamics using imaging. Our common goal is to analyze cilia dynamics across different cells and tissues and uncover common and context-specific mechanisms that regulate tissue development and function. On the long term, our combined efforts will allow to decipher the mechanisms that impair cilia dynamics in ciliopathies, and identify potential therapeutic targets.