调控固有淋巴细胞分化—miR-181b抑制动脉粥样硬化新机制

We and others have reported that miR-181b can maintain vascular homeostasis and inhibit atherosclerosis(AS) by regulating innate and adaptive immunity. Innate lymphoid cell (ILC) is a newly discovered subset of innate immune cells. Different ILC subgroups are involved in the development of many immune-related diseases, including AS. But it's not clear whether or not miR-181b can reduce AS by regulating ILCs differentiation. Our previous studies showed that over-expression of miR-181b can inhibit ILC1 expression and reduce plaque areas. These results suggest that miR-181b may inhibit AS by regulating ILCs differentiation. This project is intended to further clarify our hypothesis and its mechanism. First, the expression pattern of miR-181b and ILCs differentiation during the progress of AS will be investigated. Second, the effect of over-expression or down-regulation of miR-181b on ILCs differentiation and AS will be examined. Third, the related mechanism for miR-181b modulating ILCs differentiation will be studied. These results will reveal the role of this novel immunoregulatory mechanism by miR-181b on AS. It will help to improve the pathogenesis of AS and provide the basis for miR-181b translational medicine research.

包括我们在内的研究表明，miR-181b能够通过调控天然免疫和获得性免疫维持血管稳态，抑制动脉粥样硬化(AS)。固有淋巴细胞（ILCs）是一类新发现的天然免疫细胞，不同ILCs亚群参与了包括AS在内的多种免疫炎症相关疾病的发生发展。miR-181b是否通过调控ILCs分化而抑制AS发生尚不清楚。我们的预实验研究发现，在体过表达miR-181b能够减少ILC1，同时减少动脉斑块面积，提示miR-181b可能通过调控ILCs分化而抑制AS。本项目拟进一步明确其作用及机制。项目将通过观察AS时miR-181b和ILCs亚群的变化规律；探讨在体过表达/拮抗miR-181b对ILCs分化和AS的影响；以及研究miR-181b调控ILCs分化的作用和分子机制，来揭示miR-181b介导的这种全新的免疫调节机制在AS形成中的作用。结果将有助于完善AS发病机制，并为miR-181b的转化医学研究提供依据。

包括我们在内的研究表明，miR-181b能够通过调控天然免疫和获得性免疫维持血管稳态，抑制动脉粥样硬化(AS)。固有淋巴细胞（ILCs）是一类新发现的天然免疫细胞，不同ILCs亚群参与了包括AS在内的多种免疫炎症相关疾病的发生发展。miR-181b是否通过调控ILCs分化而抑制AS发生尚不清楚。我们的预实验研究发现，在体过表达miR-181b能够减少ILC1，同时减少动脉斑块面积，提示miR-181b可能通过调控ILCs分化而抑制AS。本项目进一步的，成功验证ILC2s对小鼠动脉粥样硬化的影响，发现ILC2具有动脉粥样硬化保护性作用；离体及在体证实miR-181b对ILC2s的影响，miR-181b能够增加ILC2表达；机制上，发现Notch1是miR-181b的靶点：miR-181b能抑制Notch1的表达。本研究揭示miR-181b通过Notch1调控ILC2的表达进而影响AS。