Early T Lineage Progenitors

描述（由申请人提供）：在胸腺内，Notch信号在多能造血祖细胞上印记T细胞身份。Notch信号必须抑制非T细胞命运（承诺）并驱动T细胞谱系特异性基因表达（规范），但其机制尚不清楚。我们最近发现T细胞因子-1 （TCF-1）是Notch信号下游协调T谱系特异性基因表达的“缺失环节”。我们进一步发现HES-1在早期T细胞祖细胞中对建立T细胞承诺很重要。我们建议研究TCF-1和HES-1建立和维持T细胞身份的分子机制。在目标1中，我们将研究HES-1和TCF-1如何共同建立对T细胞谱系的承诺。由于TCF-1在T细胞承托后继续表达，我们将研究如果TCF-1在承托的T细胞祖细胞中被切除，是否会破坏T细胞特异性基因表达。在目标2中，我们将建立TCF-1在T细胞发育中的作用机制。我们将确定由TCF-1控制的基因调控程序，我们将确定和研究与TCF-1一起工作以控制基因表达的合作伙伴。本提案的研究将提高我们对T细胞如何产生和如何维持T细胞身份的理解。它们可能为促进免疫缺陷和骨髓移植后T细胞发育和重建的治疗策略提供信息。

DESCRIPTION (provided by applicant): Within the thymus, Notch signals imprint T cell identity on multipotential hematopoietic progenitors. Notch signals must inhibit non-T cell fates (commitment) and drive T cell lineage-specific gene expression (specification), but the mechanisms have remained unclear. We recently identified T Cell Factor-1 (TCF-1) as the "missing link" that coordinates T-lineage specific gene expression downstream of Notch signals. We further discovered that HES-1 is important for establishing T cell commitment in early T cell progenitors. We propose to investigate molecular mechanisms through which TCF-1 and HES-1 establish and maintain T cell identity. In Aim 1, we will examine how HES-1 and TCF-1 together establish commitment to the T cell lineage. Because TCF-1 continues to be expressed after T cell commitment, we will investigate whether T-cell specific gene expression unravels if TCF-1 is ablated in committed T cell progenitors. In Aim 2, we will establish the mechanisms by which TCF-1 acts in T cell development. We will identify the gene regulatory program controlled by TCF-1, and we will identify and study partners that work with TCF-1 to control gene expression. Studies in this proposal will improve our understanding of how T cells are generated and how T cell identity is maintained. They may inform therapeutic strategies to boost T cell development and reconstitution in immune deficiency and after bone marrow transplantation.