The Role of SOX10 in Stemness of KIT+ Cells and Repairing Irradiated Salivary Glands

SOX10 在 KIT 细胞干细胞和修复辐照唾液腺中的作用

基本信息

批准号：
9469922
负责人：
Harleen Athwal
金额：
$ 3.63万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9469922
关键词：
Acinar Cell Adenoviruses Adherent Culture Adult Age Biology C-KIT Gene Cell Differentiation process Cell Line Cell Therapy Cells Clinical Critical Thinking Data Dental caries Dentists Deposition Development Duct (organ) structure Ductal Epithelial Epithelial Cells Epithelium Faculty Fetal Development Follow-Up Studies Functional disorder Future Genetic Goals Grant Homologous Transplantation Human Immune In Vitro Knowledge Mediating Modeling Molecular Morphology Multipotent Stem Cells Mus Mycoses Names Natural regeneration Oral health Organ Pain Patients Play Population Production Proto-Oncogene Protein c-kit Quality of life Radiation Radiation therapy Receptor Protein-Tyrosine Kinases Regenerative Medicine Role Saliva Salivary Glands Scientist Signal Transduction Stem Cell Research Submandibular gland Syndrome System Taste Perception Technical Expertise Testing Tetanus Helper Peptide Therapeutic Tissues Training Transplant Recipients Transplantation Virus Work Xerostomia base career cell type effective therapy fetal fibroblast growth factor receptor 2b head and neck cancer patient improved in vivo irradiation multipotent cell novel therapeutics offspring oral infection overexpression progenitor prospective regenerative repaired skills stem stem cell population stem cells stemness tissue repair transcription factor

项目摘要

ABSTRACT Each year, over half a million head and neck cancer patients are treated with radiotherapy, which results in the severe dry mouth syndrome, xerostomia, due to co-radiation of healthy salivary glands. Poor quality of life in such patients is a result of conditions associated with xerostomia such as hyposalivation, dental caries, fungal infections, decaying teeth, and taste and masticatory dysfunctions. Current therapies to rescue hyposalivation provide temporary relief and are largely ineffective; thus, new therapies for permanent tissue repair are needed. Our lab has deep expertise in cutting-edge salivary glands stem cell research, and was the first to demonstrate the clinical potential of KIT+ (c-Kit, CD117) stem/progenitor cells in rescuing hyposalivation. However, this population of stem/progenitor cells decreases with age, currently compromising our ability to efficiently use these cells for therapy. Our current work shows that transcription factor SOX10 plays a major role in the proliferation and differentiation potential of KIT+ cells. For example, epithelial depletion of Sox10 results in loss of KIT+ and pro-acinar cells in the fetal stages. However, it is unclear whether SOX10 is required for expansion and multi-potency, i.e. the ability to differentiate into all epithelial cell types, of KIT+ cells through adulthood. Based on existing evidence, we hypothesize that SOX10 plays a central role in the expansion and differentiation of all KIT+ cells. To test this hypothesis, we will lineage trace epithelial KIT+SOX10+ cells in the submandibular gland using inducible mouse systems. We will also assess forced overexpression of SOX10 to expand KIT+ cells. Overall, these studies will elucidate whether SOX10 marks multi-potent KIT+ stem cells, and can be applied to expand KIT+ stem cells. The scientific ideas proposed here will expand our knowledge of salivary gland stem cells, and will significantly improve future hyposalivation rescue stem cell-based therapies.

抽象的每年有超过 50 万头颈癌患者接受放射治疗，这导致由于健康唾液腺的共同辐射而导致严重的口干综合症、口干症。生活质量差此类患者是由与口干症相关的疾病引起的，例如唾液分泌不足、龋齿、真菌感染、蛀牙、味觉和咀嚼功能障碍。目前挽救唾液分泌不足的疗法提供暂时的缓解，但基本上无效；因此，永久性组织修复的新疗法是需要。我们的实验室在尖端唾液腺干细胞研究方面拥有深厚的专业知识，并且是第一个证明 KIT+（c-Kit、CD117）干/祖细胞在挽救唾液分泌不足方面的临床潜力。然而，干细胞/祖细胞的数量随着年龄的增长而减少，目前损害了我们的能力有效地利用这些细胞进行治疗。我们目前的工作表明转录因子 SOX10 在 KIT+细胞的增殖和分化潜力中的作用。例如，Sox10 的上皮细胞耗竭导致胎儿阶段 KIT+ 和前腺泡细胞的损失。然而，尚不清楚 SOX10 是否是 KIT+ 细胞的扩增和多效性（即分化为所有上皮细胞类型的能力）所需通过成年期。根据现有证据，我们假设 SOX10 在所有 KIT+ 细胞的扩增和分化。为了检验这个假设，我们将追踪上皮细胞的谱系使用诱导型小鼠系统在颌下腺中 KIT+SOX10+ 细胞。我们还将评估强制过表达 SOX10 以扩增 KIT+ 细胞。总体而言，这些研究将阐明 SOX10 是否标志着多能KIT+干细胞，可用于扩增KIT+干细胞。这里提出的科学想法将扩大我们对唾液腺干细胞的认识，并将显着改善未来的唾液分泌不足救援干细胞疗法。