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.

初级纤毛是一种基于微管的多功能突起，几乎位于人体每一个细胞的表面。PC除了在成人体内具有重要的功能外，也是胚胎发育的重要调节因子。PC被认为是动态的细胞天线，通过不同组织和不同发育阶段的多个信号通路感知环境提示。它们以微管为基础的轴丝可以在组织分化过程中通过组装、维持和分解来响应环境刺激而重塑。然而，PC超微结构与其信号活动之间的联系尚不清楚。此外，虽然PC的组成似乎在细胞类型中是保守的，但尚不清楚为什么纤毛缺陷会改变特定的组织，如视网膜或心脏，而不是其他组织。因此，了解突变蛋白改变PC结构和信号传递的机制对于了解纤毛缺陷如何导致包括CHD在内的病理变化至关重要。心脏细胞通过机械转导感知机械力。例如，我们最近发现伸展敏感通道和机械敏感的嘌呤能信号是心脏发生的关键。这些和我们进一步的初步证据促使我们质疑目前心脏形态发生过程中纤毛相关功能的范式，并提出了另一种假说：我们假设心脏初级纤毛和纤毛相关蛋白通过调节这些机械敏感途径来控制成功形态发生所需的心肌细胞特性。该提案有两个互补的目标：目的1.确定作用于内皮细胞的机械敏感途径(S)对机械力的响应及其与纤毛蛋白的关系。目的2.明确纤毛蛋白在心脏瓣膜形成过程中的细胞功能，特别是机械敏感过程。我们将特别关注纤毛蛋白Dzip1。Dzip1是一种与心脏瓣膜病有关的基因，而dzip1的突变是导致人类睫状体缺陷的原因。到目前为止，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在心脏瓣膜发育过程中如何影响内皮细胞纤毛重塑和调节功能。我们计划在整个生物体中解决从细胞器到组织规模的这个问题。