Allorecognition, parasitic stem cells and regeneration in a basal chordate

基底脊索动物的同种识别、寄生干细胞和再生

• 批准号: 10557096
• 负责人: Anthony W De Tomaso
• 金额: $ 51.41万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557096
• 关键词: Award; Biological; Biological Assay; Biological Models; Blood Vessels; Bone Marrow Transplantation; Cardiovascular system; Cells; Chordata; Endocrine; Event; Funding; Germ cell tumor; Goals; Grant; Growth; Homing; Human; Immunity; Immunology; Individual; Mediating; Molecular; Natural regeneration; Normal Cell; Organism; Peripheral; Phenotype; Process; Property; Reaction; Regenerative response; Research; Resources; Specificity; Transplantation; Work; autocrine; cancer cell; cell regeneration; follow-up; germline stem cells; innovation; insight; novel; novel strategies; prevent; programs; response to injury; stem cell biology; stem cell niche; stem cells; tissue regeneration; transmission process

Abstract Our lab works at the intersection of immunology, stem cell biology and regeneration, and the grants funding this work (GM123267 and GM 123255) which we are requesting to merge in the MIRA program have provided numerous insights into the molecular mechanisms underlying both self/non-self recognition, as well as a genetically determined cell competition event that occurs between mobile germline stem cells for niche occupancy. In addition, we have recently found that these same germline stem cells, which are lineage restricted under normal conditions, are responsible for a regenerative response to injury called Whole Body Regeneration, during which entire bodies, including all cardiovascular, GI, central and peripheral nervous, endocrine and germline tissues are regenerated de novo from isolated vascular fragments, and we propose to extend our research efforts into this robust model system of chordate regeneration. As described in the proposal, in the last 18 months, these studies have led to a number of exciting findings we will follow-up on during the upcoming funding period, including: dissecting the molecular basis for allorecognition specificity and its conservation with vertebrate immunity; a novel mechanism of autocrine stimulation that is required for homing of germline stem cells and likely plays a role in the competitive phenotype; and rescue and lineage tracing assays for whole body regeneration that have revealed that a single germline stem cell can give rise to an entire body- a result which may have major implications for understanding germ cell tumors, and also provides a unique opportunity for rapidly creating genetically modified lines of Botryllus. Our long-term goals are to utilize the unique biological properties of Botryllus to carry out innovative molecular mechanistic studies, and a MIRA award would allow us to redirect our efforts from funding to carrying out more and better innovative research on these biomedically important topics.

摘要 我们的实验室工作在免疫学，干细胞生物学和再生的交叉点， 资助这项工作（GM 123267和GM 123255），我们要求将其合并到MIRA计划中 对自我/非自我的分子机制提供了许多见解 识别，以及发生在移动的之间的基因决定的细胞竞争事件 生殖系干细胞的小生境占用。另外，我们最近发现， 干细胞在正常条件下是谱系受限的， 对损伤的反应称为全身再生，在此期间，整个身体，包括所有 心血管、胃肠道、中枢和外周神经、内分泌和生殖系组织再生， novo从孤立的血管碎片，我们建议将我们的研究工作扩展到这个强大的 脊索动物再生的模型系统。如提案所述，在过去18个月里， 研究已经导致了一些令人兴奋的发现，我们将在即将到来的资助期间进行跟踪。 期间，包括：解剖同种异体识别特异性的分子基础及其保护， 脊椎动物免疫;生殖系归巢所需的自分泌刺激的新机制 干细胞，并可能在竞争性表型中发挥作用;以及拯救和谱系追踪测定 对于全身再生的研究表明，单个生殖系干细胞可以产生一个 整个身体-这一结果可能对理解生殖细胞肿瘤具有重大意义， 为快速创建转基因葡萄球菌系提供了独特的机会。我们的长期 目标是利用葡萄球菌独特的生物学特性进行创新的分子生物学研究 机械研究，和MIRA奖将使我们能够重新定向我们的努力，从资金到携带 在这些重要的生物医学课题上进行更多更好的创新研究。