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

Lrig1 结肠干细胞在 DSS 诱导的结肠炎修复中的功能基因组学

• 批准号: 9535992
• 负责人: Anne E Zemper
• 金额: $ 7.26万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9535992
• 关键词: Acute; Address; Affect; Cell Count; Cell Proliferation; Cell physiology; Cells; Cessation of life; Chronic; Colitis; Data; Disease; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epithelial; Epithelium; Genetic Transcription; Genomics; Goals; Grant; Growth; Growth Factor; Heterogeneity; Homeostasis; Hour; Immunoglobulin Domain; Impaired wound healing; Individual; Inflammation; Injury; Intestines; LGR5 gene; Leucine-Rich Repeat; Maintenance; Malignant - descriptor; Mentors; Mesenchyme; Microscopy; Molecular; Mucous Membrane; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Natural regeneration; Oral Administration; Pattern; Phase; Play; Population; Positioning Attribute; Premalignant Cell; Process; Production; Property; Proteins; Receptor Signaling; Recovery; Regenerative response; Regulation; Reporter; Repression; Research; Research Project Summaries; Research Proposals; Research Scientist Award; Resolution; Role; Series; Signal Transduction; Sodium Dextran Sulfate; Stem cells; Tamoxifen; Time; Tissues; Work; Wound Healing; base; cell growth; colonic crypt; differential expression; experimental study; functional genomics; human tissue; improved; injury and repair; insight; migration; new technology; progenitor; protein expression; regenerative; repaired; response; response to injury; single-cell RNA sequencing; stem; stem cell population; tissue regeneration; tissue repair; transcriptome sequencing; transcriptomics

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.

项目摘要 本应用程序中提出的研究将集中于了解结肠干细胞 上皮损伤后修复的功能。众所周知，表皮生长因子受体（EGFR） 受伤后激活信号，这有助于修复；但是，这种激活和 随后的生长和增殖必须严格调节，以避免异常过度生长。我们 已经发现EGFR抑制剂LRIG1标志着结肠干细胞的种群我们的建议 试图阐明LRIG1+干细胞在伤口愈合中的作用。目前，这是相对未知的 哪些特定的结肠祖细胞群负责再生上皮 结肠炎受损。为了理解这一点，我们执行了一系列短期谱系追踪 在接受口服葡萄糖 - 硫酸盐（DSS）的小鼠中进行的实验，提议 在我们的NIDDK指导研究科学家奖（K01）的资助中。通过直接观察LRIG1+ 结肠损伤修复过程中的祖细胞激活，通过短期谱系追踪实验， 很明显，LRIG1+祖细胞负责生成大量 结肠上皮受损的细胞。有趣的是，出现LRIG1+祖细胞激活 起源于结肠隐窝的+4位置，这与模式不同 在未受伤状态的隐窝基碱中观察到的LRIG1+细胞。这些观察表明 该LRIG1在+4区域中存在的细胞中很重要，与其在其中的作用无关 地穴基室，这对于结肠再生和修复可能至关重要。 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因素。这些研究是一个明显的“下一步” 我们在NIDDK指导研究科学家的研究中提出和进行的研究 奖项（K01）赠款。