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.

项目总结