Functional Genomics of Lrig1+ Colonic Stem Cells in DSS-induced Colitis Repair

项目摘要 在这项申请中提出的研究将集中在了解结肠干细胞如何 在上皮损伤后的修复中的作用。已知表皮生长因子受体(EGFR) 信号在受伤后被激活，这有助于修复；然而，这种激活和 随后的增长和扩散必须受到严格监管，以避免异常的过度增长。我们 已经发现，EGFR抑制剂Lrig1标志着我们的建议中的一组结肠干细胞 旨在阐明Lrig1+干细胞在伤口愈合中的作用。目前，它还相对鲜为人知 哪些特定的结肠祖细胞群负责再生上皮 损伤性结肠炎。为了理解这一点，我们进行了一系列短期的血统追踪 小鼠口服葡聚糖硫酸钠(DSS)的实验，建议 在我们的NIDDK导师研究科学家奖(K01)资助中。通过直接观察Lrig1+ 通过短期谱系追踪实验，在结肠损伤修复期间祖细胞的激活， 很明显，Lrig1+祖细胞负责产生大量的 受损的结肠上皮细胞。有趣的是，Lrig1+祖细胞的激活 起源于结肠隐窝的+4位置，这与图案不同 未损伤状态下隐窝基底部的Lrig1+细胞。这些观察结果表明 Lrig1在那些存在于+4区的细胞中是重要的，与它在 这可能是结肠再生和修复的关键。这个 这里提出的研究试图了解这些Lrig1+祖细胞的转录组学 作为结肠再生和修复的基本驱动力。这些研究是明确的“下一步” 对于我们在NIDDK指导研究科学家的指导下提出并进行的研究 奖励(K01)奖品。

Project Summary The research proposed in this application will focus on understanding how colonic stem cells function in repair after epithelial injury. It is known that epidermal growth factor receptor (Egfr) signaling is activated after injury and this contributes to repair; however, this activation and subsequent growth and proliferation, must be tightly regulated to avoid aberrant overgrowth. We have found that an Egfr inhibitor, Lrig1, marks a population of colonic stem cells our proposal seeks to clarify the role of Lrig1+ stem cells in wound healing. Currently, it is relatively unknown which specific colonic progenitor cell populations are responsible for regenerating an epithelium damaged colitis. To understand this, we have executed a series of short-term lineage-tracing experiments in mice undergoing oral administration of dextran-sodium-sulfate (DSS), proposed in our NIDDK Mentored Research Scientist Award (K01) grant. By directly observing Lrig1+ progenitor cell activation during colonic injury repair, via short-term lineage tracing experiments, it is readily apparent that Lrig1+ progenitor cells are responsible for generating large numbers of cells in the damaged colonic epithelium. Interestingly, Lrig1+ progenitor cell activation appears to originate around the +4 position of the colonic crypts, which is distinct from the pattern observed from Lrig1+ cells in the crypt-base in uninjured states. These observations suggest that Lrig1 is important in those cells present in the +4 region, independent from it’s role in the crypt-base compartment, and this is perhaps crucial for colonic regeneration and repair. The studies proposed here seek to understand the transcriptomics of these Lrig1+ progenitor cells as fundamental drivers of colonic regeneration and repair. These studies are a clear “next step” to the studies we have proposed and conducted under our NIDDK Mentored Research Scientist Award (K01) grant.