Manipulating Stem Cells to Provide Long Term Regeneration of Irradiated Salivary Glands

操纵干细胞以提供受辐射唾液腺的长期再生

• 批准号: 10180935
• 负责人: Isabelle M.A. Lombaert
• 金额: $ 35.93万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10180935
• 关键词: Acinar Cell; Acinus organ component; Adult; Affect; Age; Aging; Allogenic; Binding Proteins; Cell Line; Cell Lineage; Cell Maintenance; Cell Proliferation; Cell Therapy; Cell Transplantation; Cells; Clinic; Clinical; Clonality; Cloning; Data; Development; Ductal Epithelial Cell; Epithelial; Epithelial Cells; Future; Gene Expression Profile; Gene Proteins; Genes; Genetic; Gland; Goals; Hematopoietic stem cells; Heterogeneity; Human; Immune; Immunoprecipitation; In Vitro; Knowledge; Life; Longevity; Maintenance; Mass Spectrum Analysis; Microarray Analysis; Molecular; Molecular Profiling; Multipotent Stem Cells; Mus; Natural regeneration; Pain; Peer Review; Population; Proliferating; Proto-Oncogene Protein c-kit; Publishing; Quality of life; Radiation; Reporter; Role; Saliva; Salivary; Salivary Glands; Signal Transduction; Speech; Submandibular gland; Sum; Syndrome; Taste Perception; Therapeutic; Tissues; Translating; Transplantation; Treatment Protocols; Work; Xerostomia; base; cancer therapy; experimental study; fetal; fetus cell; fibroblast growth factor receptor 2b; head and neck cancer patient; improved; in vivo; irradiation; mouse model; multipotent cell; novel therapeutics; oral infection; overexpression; repaired; self-renewal; stem; stem cell population; stem cell replacement; stem cell self renewal; stem cell therapy; stem cells; tissue repair; transcription factor; translational approach

PROJECT SUMMARY/ABSTRACT Worldwide, the quality of life of over half a million surviving head-and-neck cancer patients per year is drastically decreased due to co-irradiation of healthy saliva-secreting salivary glands. Current therapies to rescue hypo-salivation only provide temporary relief; hence new therapies for permanent tissue repair are needed. In a mouse model, we induced successful repair of irradiated salivary glands by transplanting KIT+ stem/progenitor cells. However, this population of stem/progenitor cells decreases with age and is heterogeneous; hence, currently compromising our ability to efficiently use these cells for therapy. Recent discoveries in our lab have shown that transcription factor SOX10 tightly regulates proliferation and differentiation in fetal KIT+ cells. In this proposal we hypothesize that only a subpopulation of adult KIT+ cells, which express SOX10, retain stem cell self-renewal capacity. Thus, we aim to: (1) characterize the multipotent stem cells within the KIT+ cell population, (2) define the role of transcription factor SOX10 in maintaining adult KIT+ cells, and (3) characterize the molecular heterogeneity and SOX10 signature in human KIT+ cells. Overall, the scientific ideas proposed here will expand our knowledge of salivary gland stem cell populations, and will significantly improve future hypo-salivation rescuing by stem cell-based therapies.

项目概要/摘要 在全球范围内，每年超过 50 万存活的头颈癌患者的生活质量 由于健康分泌唾液的唾液腺的共同照射而急剧下降。目前的治疗方法 抢救唾液分泌不足只能暂时缓解；因此，永久性组织修复的新疗法是 需要。在小鼠模型中，我们通过移植 KIT+ 成功诱导了受辐射唾液腺的修复 干/祖细胞。然而，干细胞/祖细胞的数量随着年龄的增长而减少，并且 异质;因此，目前损害了我们有效利用这些细胞进行治疗的能力。最近的 我们实验室的发现表明转录因子 SOX10 严格调节增殖和 胎儿 KIT+ 细胞的分化。在此提议中，我们假设只有成人 KIT+ 细胞的一个亚群， 表达SOX10，保留干细胞自我更新能力。因此，我们的目标是：（1）表征多能 KIT+细胞群中的干细胞，(2)定义转录因子SOX10在维持成体中的作用 KIT+ 细胞，(3) 表征人类 KIT+ 细胞中的分子异质性和 SOX10 特征。 总的来说，这里提出的科学想法将扩大我们对唾液腺干细胞群的了解， 并将显着改善未来基于干细胞疗法的唾液分泌不足的拯救。