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: 10322423
• 负责人: Anthony W De Tomaso
• 金额: $ 51.59万
• 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/10322423
• 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; Play; Process; Property; Reaction; Regenerative response; Research; Resources; Role; 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 cell self renewal; 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.

抽象的 我们的实验室致力于免疫学、干细胞生物学和再生的交叉领域，并获得资助 资助这项工作（GM123267 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，以及移动之间发生的基因决定的细胞竞争事件 生殖系干细胞占据生态位。此外，我们最近发现这些相同的种系 干细胞在正常条件下谱系受限，负责再生 对受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、中枢和周围神经、内分泌和生殖组织再生 novo 是从分离的血管碎片中分离出来的，我们建议将我们的研究工作扩展到这个强大的领域 脊索动物再生模型系统。正如提案中所述，在过去 18 个月中，这些 研究得出了许多令人兴奋的发现，我们将在即将到来的资助期间跟进 期间，包括：剖析同种异体识别特异性的分子基础及其保护 脊椎动物免疫力；种系归巢所需的自分泌刺激的新机制 干细胞并可能在竞争表型中发挥作用；以及救援和谱系追踪分析 对于全身再生，研究表明单个生殖干细胞可以产生 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，而且 为快速创建灰霉病转基因品系提供了独特的机会。我们的长期 目标是利用Botryllus独特的生物学特性来进行创新的分子研究 机制研究和 MIRA 奖将使我们能够将我们的努力从资助转向承载 对这些生物医学重要主题进行更多更好的创新研究。