Early T lineage progenitors

描述（由申请人提供）：成年小鼠胸腺中最早描述的祖细胞称为早期胸腺祖细胞（ETP）。它们来源于罕见的循环造血祖细胞，其身份以前是未知的。我们在前一个资助期的工作确定了一群称为早期淋巴样祖细胞（ELP）的祖细胞循环，并在生理上定居胸腺。在我们目前的建议中，我们希望了解如何罕见的ELP解决胸腺引起ETP和其他下游群体，从成熟的，免疫活性的T细胞最终衍生。我们假设，巨大的增殖发生后，胸腺沉降，罕见的ELP解决胸腺产生大量的早期胸腺祖细胞（ETP）。事实上，我们认为胸腺沉降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。我们目前建议的一个目标是量化这种扩散，并确定如何对其进行监管。由于胸腺沉降的ELP具有多种细胞类型的谱系潜力，另一个目标是解决替代谱系命运，特别是骨髓命运在胸腺沉降后如何受到约束的问题。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谱系定型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中的造血干细胞延伸到胸腺内的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。我们的具体目标是：具体目标1：测量胸腺沉降和ETP产生之间的增殖。具体目标2：确定Notch信号传导在ETP中的功能。具体目标3：确定Notch信号导致T谱系进展和定型的机制。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描述增殖和分化事件。Notch在这个最早的阶段起着至关重要的作用，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细胞系进展和定型的机制。

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.