Identifying the role of serotonin receptor 4 and trefoil factor 3 in intestinal wound repair

确定血清素受体 4 和三叶因子 3 在肠道伤口修复中的作用

• 批准号: 10336138
• 负责人: Melinda Anne Engevik
• 金额: $ 12.21万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-13 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10336138
• 关键词: Actins; Address; Adult; Agonist; Animal Model; Award; Bifidobacterium; Biological Assay; Biopsy; C57BL/6 Mouse; CXCR4 Receptors; CXCR4 gene; Colitis; Collaborations; Colon; Colonoscopy; Critical Illness; Cytoskeleton; Data; Development; Distal; Enterochromaffin Cells; Enterocutaneous Fistula; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; F-Actin; Failure; Filopodia; Foundations; Funding; Future; Gastric ulcer; Gastrointestinal tract structure; Germ-Free; Gnotobiotic; Goals; Goblet Cells; HTR3A gene; Hospitalization; Human; Ileitis; Image; In Vitro; Infection; Inflammatory; Inflammatory Bowel Diseases; Institution; Intestines; K-Series Research Career Programs; Link; Literature; Mediating; Medicine; Mentors; Mentorship; Microbiology; Modeling; Molecular; Mucous Membrane; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Ondansetron; Outcome; Peripheral Nervous System; Physiological; Process; Property; Publications; Recombinants; Research; Research Personnel; Resources; Role; Scientific Advances and Accomplishments; Scientist; Secure; Serotonin; Serotonin Production; Serotonin Receptors 5-HT4; Signal Transduction; Signaling Molecule; Site; Skin; Skin injury; Surgical Anastomosis; Techniques; Testing; Therapeutic Agents; Tissues; Training; Ulcer; Work; Wound models; base; college; commensal bacteria; epithelial repair; epithelial wound; experimental study; healing; in vivo; inhibitor/antagonist; innovation; intestinal epithelium; microbial; monolayer; mouse model; novel therapeutics; prevent; receptor; release factor 3; repaired; response; sensor; serotonin receptor; tegaserod; trefoil factor; wound; wound closure; wound healing

PROJECT SUMMARY Background and aims: Serotonin (5-HT) exerts numerous physiological functions in the gastrointestinal tract via activation of 14 different serotonin receptor subtypes. Elevated serotonin levels are noted in response to tissue damage, indicating that serotonin release may mediate important repair mechanisms. Serotonin has been shown to have reparative effects on skin injury and gastric ulcers, and serotonin receptor 4 (5-HTR4) specifically has been shown to have anti-ulcerogenic action after colon tissue damage. However, the mechanism behind this phenomenon is unclear. Recently 5-HTR4 has been identified on goblet cells, which are known to produce trefoil factor 3 (TFF3); a key compound in intestinal repair. Currently the link between 5-HTR4 and TFF3 is unknown. Preliminary data generated using human intestinal enteroids has demonstrated that exogenous serotonin stimulates TFF3 release to promote repair in live imaging wound healing assays. This effect was mitigated by inhibition of the TFF3 receptor CXCR4. In a microbial-centered approach, our lab has also identified a single commensal bacterium, Bifidobacterium dentium, which in gnotobiotic mice and in mouse and human enteroids is able to stimulate serotonin release from enterochromaffin cells. Additionally, treatment of human enteroids with B. dentium metabolites also enhance epithelial restitution in a wound healing assay, similar to exogenous serotonin. The overall hypothesis of this proposal is that serotonin activates 5-HTR4 on goblet cells to stimulate TFF3 release, which acts on its receptor CXCR4 to mediate signaling cascades responsible for epithelial repair. Aim 1 seeks to define the requirement of TFF3 for 5-HTR4 mediated epithelial repair in vivo using mouse models and colonoscopy-induced colonic wounds. Aim 2 seeks to examine a microbial approach for stimulating serotonin production and wound healing in vivo. Finally, Aim 3 addresses the signaling cascade required for TFF3 mediated restitution in intestinal epithelial cells in mouse and human colonic enteroids in vitro. Mucosal healing is critical for in the treatment of ulcers, surgical anastomoses, enterocutaneous fistulae and inflammatory bowel disease wounds. Failure to properly heal wounds can result in complications including infection, prolonged hospitalization, and critical illness. Long-term objective and aims: My long-term goal is to become a productive independent investigator at research institution. Receiving a K01 Career Development Award would better equip me to achieve this goal. My research is well suited for the National Institute of Diabetes and Digestive and Kidney Diseases as it relates to intestinal wound repair. My current institution, Baylor College of Medicine, offers the scientific resources required to complete this proposal. Additionally, I have assembled a group of renowned scientists to serve on my mentorship committee and leaders in the fields of microbiology and wound repair to serve as my mentors. In collaboration with my mentors, I have developed a training plan that will allow me master advanced scientific techniques, increase my publication record and secure independent funding. At the completion of this award, I believe I will have the resources and expertise required to transition to an independent principle investigator.

项目总结