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

项目摘要 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起作用。已知表皮生长因子受体（Egfr） 损伤后信号被激活，这有助于修复;然而，这种激活和 随后的生长和增殖必须严格调控以避免异常的过度生长。我们 我们发现，一种Egfr抑制剂Lrig 1标记了结肠干细胞群， 旨在阐明Lrig 1+干细胞在伤口愈合中的作用。目前，它还相对未知 哪些特定的结肠祖细胞群负责上皮再生 受损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， 在小鼠中进行口服葡聚糖硫酸钠（DSS）的实验，提出了 在我们的NIDDK指导研究科学家奖（K 01）授予。通过直接观察Lrig 1 + 通过短期谱系追踪实验， 很明显，Lrig 1+祖细胞负责产生大量的 受损结肠上皮细胞。有趣的是，Lrig 1+祖细胞活化似乎 起源于结肠隐窝的+4位置，这与模式不同 从未损伤状态下的隐窝基底中的Lrig 1+细胞观察到。这些观察结果表明 Lrig 1在+4区域的细胞中很重要，与它在细胞中的作用无关。 这可能是结肠再生和修复的关键。的 这里提出的研究试图了解这些Lrig 1+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” 我们在NIDDK指导研究科学家指导下提出和进行的研究 奖励（K 01）赠款。

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.