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（ETPs）。它们来自罕见的循环造血祖细胞，其身份以前是未知的。我们在之前的资助期内的工作确定了称为早期淋巴祖细胞（ELPs）的祖细胞群循环，并在生理上定居胸腺。在我们目前的提案中，我们希望了解定居胸腺的罕见elp是如何产生etp和其他下游群体的，这些群体最终衍生出成熟的、具有免疫能力的T细胞。我们假设在胸腺沉降后发生大量增殖，通过这种方式，罕见的胸腺elp沉降产生大量的早期胸腺祖细胞（etp）。事实上，我们认为在胸腺沉降后立即发生的增殖可能比T淋巴形成的任何后续阶段都要多。我们目前提议的一个目标是量化这种扩散，并确定如何对其进行监管。由于定居胸腺的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是一种参与多种细胞命运决定的细胞表面受体，我们希望探索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。总之，这些研究将使我们能够拼凑出从骨髓造血干细胞到胸腺内etp的细胞谱系，并了解引导细胞沿着T细胞发育途径的信号。我们的具体目的是：具体目的1：测量胸腺沉降和etp产生之间的增殖。具体目标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细胞发育的早期阶段描述增殖和分化事件。Notch在这一早期阶段起着关键作用，我们建议阐明Notch信号在早期T细胞发育中的功能，并确定其协调早期T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.