转录因子Islet1 在心脏起搏细胞的发育和功能中的调控机制

Rhythmic contraction of the heart is controlled by the electrical impulses generated by pacemaker cells of the sinoatrial node (SAN). Abnormalities in SAN development lead to cardiac arrhythmia and sudden death, the leading cause of death in the adult. The LIM homeodomain transcription factor Islet1 is expressed in pacemaker cells of the SAN. However, a potential role of Islet1 in the SAN is unknown. We have generated several Islet1 mutant mouse lines, including an Islet1 hypomorphic mutant with reduced Islet1 expression and a mutant in which Islet1 expression was ablated specifically in the SAN utilizing an inducible HCN4-CreERT2. We found that Islet1 is required for the survival, proliferation and pacemaker function of the pacemaker cells and its progenitors. We hypothesized that Islet1 plays important roles in the formation and pacemaker function of the SAN. At the early stages, Islet1 is required for the proliferation, differentiation, survival and pacemaker function of the SAN. At the later stages, Islet1 is required for pacemaker function of the SAN. To test this, we will: 1) to investigate the role of Islet1 in the proliferation, differentiation and survival of pacemaker cells of the SAN; 2) to investigate the role of Islet1 in pacemaker function of the SAN; 3) to examine the expression of potential candidate genes known to play a role in the SAN, and to FACS-sort SAN cells to perform microarray analysis to define molecular mechanisms of Islet1 in SAN formation and function. ChIP assay will be performed to define direct targets of Islet1 in pacemaker cells. Our proposed study will define the role of Islet1 in the SAN, and provide novel insight into mechanisms of SAN formation and function, which will advance our understanding of human arrhythmia.

心脏起搏传导系统的形成和功能的异常导致心律失常和猝死。转录因子Islet1是第二心脏区域前体细胞的标志，在心脏的形成中起重要作用。Islet1在起搏器（即窦房结）中的起搏细胞中表达，但其作用和调控机制尚不明。我们建立了Islet1低表达和起搏细胞特异性敲除的小鼠模型。前期研究初步揭示了Islet1在起搏器器前体细胞细胞及特异性细胞的形成和起搏功能中的特异性作用。本研究将进一步探讨不同发育时期Islet1在窦房结起搏细胞的增殖、分化和存活以及起搏功能中的调控作用；分离纯化窦房结起搏细胞，进行基因芯片分析；筛选潜在靶基因进行Chip分析，建立相关的转基因小鼠模型证实Chip的分析数据，以阐明Islet1的调控网络及其在起搏器形成和起搏功能中的作用和机制。本研究将加深我们对起搏细胞形成和功能的调控及人类心律失常发生机制的理解，为开发新的治疗方法奠定基础。

心脏起搏传导系统的形成和功能异常导致心律失常和猝死。Islet1是第二心脏领域前体细胞的标志蛋白和重要的转录调控因子。Islet1在窦房结细胞中表达，但其作用不明。我们建立了Islet1低表达和起搏传导系统特异性敲除的小鼠模型。前期研究初步揭示了Islet1在调控窦房结细胞及其前体细胞的形成和起搏功能中的特异性作用。我们推测：Islet1在窦房结的形成和功能中起着重要作用。Islet1对起搏细胞及其前体细胞的增殖、分化、存活和起搏功能中至关重要。为此，我们将：研究在窦房结不同发育时期Islet1在起搏细胞的增殖、分化和存活以及起搏功能中的调节作用；通过对靶基因和基因芯片分析，阐明Islet1在窦房结形成和起搏功能中作用的分子机制。本研究将加深我们对起搏器细胞的谱系，其形成的信号通路和人类心律失常的分子机理的理解，并为开发新的疗法提供基础。