Allorecognition, parasitic stem cells and regeneration in a basal chordate

摘要 我们的实验室致力于免疫学、干细胞生物学和再生的交叉学科，而赠款 为这项工作(GM123267和GM 123255)提供资金，我们要求将其合并到MIRA计划中 为自我/非自我背后的分子机制提供了大量的见解 识别，以及发生在移动设备之间的遗传决定的细胞竞争事件 生殖系干细胞为利基占据。此外，我们最近发现，这些相同的生殖系 干细胞在正常情况下是受血统限制的，负责再生 对伤害的反应称为全身再生，在此期间，整个身体，包括 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来自分离的血管片段，我们建议将我们的研究努力扩展到这个强大的 脊索再生模型系统。正如建议书所述，在过去18个月，这些 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金期间跟进 时期，包括：剖析同种异体识别特异性的分子基础及其保守性 脊椎动物免疫；一种新的自分泌刺激机制，这是生殖系归巢所必需的 干细胞和可能在竞争表型中扮演的角色；以及挽救和谱系追踪分析 对于全身再生的研究表明，单个生殖系干细胞可以产生 全身--这一结果可能对理解生殖细胞肿瘤有重大意义，而且 为快速创建Botryllus转基因品系提供了独特的机会。我们的长期合作 目标是利用Botryllus独特的生物学特性进行创新的分子 机械研究，和Mira奖将使我们的努力从资助转向执行 在这些生物医学重要课题上开展更多、更好的创新研究。

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.