Dissecting the molecular crosstalk between mechanotransduction and primary cilia in models of congenital valvulopathies

剖析先天性瓣膜病模型中机械转导和初级纤毛之间的分子串扰

• 批准号: MR/X019837/1
• 负责人: Julien Vermot
• 金额: $ 79.94万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX019837%2F1
• 关键词: Dissecting; molecular; crosstalk; between; mechanotransduction

Primary cilia are versatile microtubule-based protrusions located at the surface of nearly every cell of the human body. In addition to important functions in adults, PC are important regulators of embryonic development. PC are considered as dynamic cellular antenna that sense environmental cues via multiple signalling pathways in different tissues and across developmental stages. Their microtubule-based axoneme can remodel by assembling, maintaining, and disassembling in response to environmental stimuli during tissue differentiation. Nevertheless, the link between PC ultrastructure and its signalling activities is unclear. Furthermore, while PC composition seems to be conserved among cell types, it is unclear why ciliary defects alter specific tissues like the retina or the heart and not others. Hence, understanding the mechanisms through which mutated proteins alter PC structure and signalling is essential to understand how ciliary defects can lead to pathologies, including CHD.Cardiac cells sense mechanical forces through mechanotransduction. For instance, we recently found that stretch sensitive channels and mechanosensitive purinergic signalling are key to cardiogenesis. These and our further preliminary evidence prompted us to question the current paradigm of cilia related function during cardiac morphogenesis, and to formulate an alternative hypothesis: We postulate that cardiac primary cilia and cilia related proteins control cardiac cells properties required for successful morphogenesis by modulating these mechanosensitive pathways. The proposal has two complimentary objectives:Objective 1. To identify the mechanosensitive pathway(s) acting in the EdCs in response to mechanical forces and relationship with ciliary proteins.Objective 2. To define the cellular functions of ciliary proteins in the process of cardiac valve formation with a specific focus on mechanosensitive processes.We will have a particular focus on the ciliary protein Dzip1. Dzip1 is a gene involved in cardiac valvulopathy and mutations of dzip1 are responsible for ciliary defects in humans. To date, the cellular mechanism leading to defective valves in the dzip1 mutant is unknown. Our objective is to understand how DZIP1 affects cilia remodelling and regulatory functions in EdCs during cardiac valve development. We plan to tackle this question from organelle to tissue-scale in the entire organism.

原发性纤毛是多功能微管的突起，位于人体几乎每个细胞的表面。除了成年人的重要功能外，PC是胚胎发育的重要调节剂。 PC被认为是动态细胞天线，通过不同组织和跨发育阶段的多个信号通路感知环境线索。它们的基于微管的轴突可以通过在组织分化过程中对环境刺激组装，维持和拆卸来重塑。然而，PC超微结构与其信号活动之间的联系尚不清楚。此外，尽管PC组成似乎在细胞类型中是保守的，但尚不清楚为什么睫状缺陷会改变视网膜或心脏等特定组织，而不是其他组织。因此，了解突变蛋白改变PC结构和信号传导的机制对于了解睫状缺损如何导致病理学，包括chd.cardiac细胞通过机械传导来感知机械力。例如，我们最近发现，拉伸敏感的通道和机械敏感的嘌呤能信号传导是心脏病发生的关键。这些以及我们进一步的初步证据促使我们质疑心脏形态发生过程中纤毛相关功能的当前范式，并提出另一种假设：我们假设心脏原发性纤毛和纤毛相关的蛋白质控制心脏细胞的特性通过调节这些机械效应途径来成功形态发生所需的成功形态。该提案具有两个免费目标：目标1。确定对EDC中作用的机械敏感途径，响应于机械力和与睫状蛋白的关系。目标2。定义纤毛蛋白在心脏瓣膜形成过程中的细胞功能，并以特定的重点对机械敏感的过程进行了特定的蛋白质。 DZIP1是参与心脏瓣膜病的基因，DZIP1突变是人类纤毛缺陷的原因。迄今为止，导致DZIP1突变体中导致瓣膜缺陷的细胞机制尚不清楚。我们的目标是了解DZIP1如何影响心脏瓣膜开发过程中EDC中纤毛的重塑和调节功能。我们计划在整个生物体中解决从细胞器到组织尺度的这个问题。