乳源miR-29的肠道吸收过程及在肠道更新修复中的作用机制

MicroRNA可在转录后水平调控40-60%的人类基因表达，对人体健康具有重要作用。乳汁中富含microRNA，且存在于外泌体中不易降解，形成了天然的microRNA转运系统。申请人前期研究显示miR-29在肠隐窝底部高表达，且富含miR-29的乳汁外泌体能缓解小鼠肠道损伤，然而其抵达肠道细胞的有效性及其对肠道更新修复的作用机制尚不明确。本项目首先通过小鼠活体荧光成像进行示踪，探究口服乳源外泌体在肠道中的富集与降解规律，明确乳源外泌体递送miR-29的有效性；其次，利用miR-29基因敲除小鼠及回补实验，从肠道结构损伤、炎症浸润程度、细胞增殖、肠道更新速度四个层面，确证在炎症损伤条件下miR-29对肠道更新修复的影响；最后，锁定miR-29直接作用的靶基因，并明确下游的信号通路，以揭示miR-29调控肠道更新的分子机制，为乳源miR-29的开发利用及其在配方乳粉中的添加策略提供科学证据。

MicroRNAs are responsible for regulating 40% to 60% of human gene expression at the post-transcriptional level, and play an essential role in human health. MicroRNAs are abundant in milk, encapsulated within exosomes that ensure their stability and bioavailability, forming a natural microRNA transfection system. In our previous studies, miR-29 was highly expressed at the bottom of the intestinal crypts, and milk-derived exosomes contain miR-29 can alleviate intestinal damage in mice. However, whether miR-29 could effectively reach intestinal cells and accelerate intestinal renewal and repair are unclear. In this study, the intestinal absorption of oral milk-derived exosomes and its effectiveness to deliver miR-29 will be investigated using Small Animal In Vivo Imaging System. Then, miR-29-knockout mice and rescue experiments will be used to investigate whether miR-29 could regulate intestinal regeneration with colitis, by evaluating intestinal structural damage, inflammatory infiltration degree, cell proliferation, and intestinal renewal speed. Finally, the direct target gene and the downstream signaling pathway of miR-29 will be elucidated, to reveal the molecular mechanism how miR-29 regulats intestinal renewal. Our study will provide insight for illuminating the biological activity of milk-derived miR-29 and guiding its utilization in infant formula.