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: 9375979
• 负责人: Anne E Zemper
• 金额: $ 7.03万
• 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/9375979
• 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; 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; 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.

项目概要 本申请中提出的研究将侧重于了解结肠干细胞如何 具有修复上皮损伤后的功能。据了解，表皮生长因子受体（Egfr） 损伤后信号传导被激活，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过度生长。我们 我们发现 Egfr 抑制剂 Lrig1 标记了结肠干细胞群 旨在阐明 Lrig1+ 干细胞在伤口愈合中的作用。目前还比较不为人所知 哪些特定的结肠祖细胞群负责上皮的再生 受损的结肠炎。为了理解这一点，我们执行了一系列短期谱系追踪 口服葡聚糖硫酸钠（DSS）的小鼠实验提出 在我们的 NIDDK 指导研究科学家奖 (K01) 资助中。通过直接观察Lrig1+ 通过短期谱系追踪实验，在结肠损伤修复过程中激活祖细胞， 很明显，Lrig1+ 祖细胞负责产生大量 受损结肠上皮细胞。有趣的是，Lrig1+祖细胞激活出现 起源于结肠隐窝的 +4 位置，这与模式不同 在未受伤状态下的隐窝基底中的 Lrig1+ 细胞中观察到。这些观察表明 Lrig1 在 +4 区域的细胞中很重要，独立于它在 隐窝基部隔室，这可能对于结肠再生和修复至关重要。这 这里提出的研究旨在了解这些 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” 我们在 NIDDK 指导研究科学家的指导下提出并进行的研究 奖（K01）授予。