Early T lineage progenitors

描述(由申请人提供)：成年小鼠胸腺中最早被描述的祖细胞被称为早期胸腺祖细胞(ETP)。它们来自罕见的循环造血祖细胞，其身份此前尚不清楚。我们在前一个资助时期的工作确定了一群被称为早期淋巴祖细胞(ELP)的祖细胞在胸腺循环并在生理上定居。在我们目前的建议中，我们希望了解在胸腺中定居的极少数ELP是如何产生ETP和其他下游群体的，成熟的、具有免疫活性的T细胞最终来自于这些群体。我们假设在胸腺稳定后立即发生巨大的增殖，通过这种罕见的ELP来稳定胸腺产生大量的早期胸腺祖细胞(ETP)。事实上，我们认为胸腺稳定后立即发生的增殖可能比T淋巴细胞生成的任何后续阶段都要多。我们目前提案的一个目标是量化这种扩散，并确定它是如何受到监管的。由于稳定胸腺的ELP具有多种细胞类型的谱系潜力，另一个目标是解决胸腺定居后替代谱系命运，特别是髓系命运如何受到限制的问题。Notch是一种细胞表面受体，参与多个细胞命运的决定，我们希望探讨Notch信号在这些关键早期事件中的作用。此外，我们希望确定Notch协调T谱系承诺和谱系进展的分子机制。总而言之，这些研究将使我们能够拼凑出从骨髓中的造血干细胞到胸腺中的ETP的细胞系，并了解引导细胞沿着T细胞发育途径前进的信号。我们的具体目标是：具体目标1：测量胸腺沉积和ETP产生之间的增殖。具体目的2：确定Notch信号在ETP中的功能。具体目标3：确定Notch信号导致T谱系进展和承诺的机制。公共卫生相关性：我们建议在胸腺内T细胞发育的最早阶段确定增殖和分化事件的特征。Notch在早期阶段起着关键作用，我们建议阐明Notch信号在早期T细胞发育中的作用，并确定其协调早期T细胞谱系进展和承诺的机制。

DESCRIPTION (provided by applicant): The earliest described progenitors in the adult mouse thymus are termed early thymic progenitors (ETPs). They derive from rare circulating hematopoietic progenitors, whose identity was previously unknown. Our work in the previous funding period established that a population of progenitors termed early lymphoid progenitors (ELPs) circulates, and physiologically settles the thymus. In our current proposal, we wish to understand how rare ELPs settling the thymus give rise to ETPs and other downstream populations from which mature, immunocompetent T cells are ultimately derived. We hypothesize that tremendous proliferation occurs right after thymic settling, by which rare ELPs that settle the thymus generate large numbers of early thymic progenitors (ETPs). Indeed, we think that more proliferation may occur immediately after thymic settling than at any subsequent stage of T lymphopoiesis. One goal of our current proposal is to quantify this proliferation, and to determine how it is regulated. As ELPs settling the thymus possess lineage potentials for multiple cell types, another goal is to address the question of how alternative lineage fates and in particular the myeloid fate are constrained after thymic settling. Notch is a cell surface receptor involved in multiple cell fate decisions, and we wish to probe the role of Notch signaling in these critical early events. Further, we wish to determine the molecular mechanisms by which Notch co-ordinates T lineage commitment and lineage progression. Together, these studies will allow us to piece together a lineage of cells that extends from hematopoietic stem cells in the bone marrow to ETPs within the thymus, and to understand the signals that guide cells down the T cell developmental pathway. Our specific Aims are: Specific Aim 1: To measure proliferation between thymic settling and the generation of ETPs. Specific Aim 2: To determine the function of Notch signaling in ETPs. Specific Aim 3: To determine the mechanism by which Notch signals result in T lineage progression and commitment. PUBLIC HEALTH RELEVANCE: We propose to characterize proliferative and differentiative events at the earliest stages of intrathymic T cell development. Notch plays a critical role at this earliest stage, and we propose to elucidate the function of Notch signaling in early T cell development, and to determine the mechanisms by which it co-ordinates early T lineage progression and commitment.