Notch signaling in B cell development and survival

Notch1的人类同源物最初是在t细胞白血病复发性染色体易位的染色体断点上发现的。我们之前已经证明，激活的Notch1的组成性表达导致小鼠t细胞白血病，并且它在白血病中的作用可能与其在淋巴细胞发育中的正常功能有关。作为我们了解Notch在白血病中的作用的长期计划的一部分，我们已经开始研究Notch在造血中的功能。Notch蛋白是一个保守的家族，在许多谱系中调节细胞命运选择，包括干细胞。最近，我们提供的证据表明Notch在调节造血干细胞的淋巴样细胞命运决定中起关键作用。为了进一步了解这一过程，我们进行了研究，以了解Notch在B细胞发育中的功能。我们的初步结果表明，在体内和器官培养中，Notch信号通路促进B细胞凋亡，抑制Notch信号通路以牺牲T细胞发育为代价导致B细胞发育。目前研究的重点是Notch信号在B细胞发育和存活中的作用。在Aim 1中，我们将重点关注Notch信号的一种特殊调节剂，它可以拮抗Notch信号并促进造血干细胞的B细胞发育。这项研究将结合体内、器官培养和体外方法来了解这种蛋白质在B细胞发育中的功能。在特异性目标2中，我们将描述B淋巴细胞亚群中的Notch信号传导，并确定Notch信号传导特异性促进B细胞死亡的机制。这些研究将导致对淋巴细胞发育和功能的更好理解，并在此过程中，将为治疗白血病和其他免疫和造血系统疾病提供治疗见解。

The human homologue of Notch1 was originally identified at the chromosomal breakpoint in a recurrent chromosomal translocation in T-cell leukemia. We have previously shown that constitutive expression of activated Notch1 causes T-cell leukemia in mice and that its role in leukemia may be related to its normal function in lymphoid development. As part of our long term plan to understand the role of Notch in leukemia, we have initiated studies to understand Notch function in hematopoiesis. Notch proteins are a conserved family that regulates cell fate choice in many lineages, including stem cells. Recently, we have provided evidence that Notch plays a key role in regulating lymphoid cell fate decisions from hematopoietic stem cells. To further understand this process, we have undertaken studies to understand Notch function in B cell development. Our preliminary results suggest that Notch signaling promotes apoptosis of B cells and that inhibition of Notch signaling leads to B cell development at the expense of T cell development, both in vivo and in organ cultures. The proposed studies focus on the role of Notch signaling in B cell development and survival. In Aim 1, we will focus on a particular modulator of Notch signaling that antagonizes Notch signaling and promotes B cell development from hematopoietic stem cells. The studies in this aim will use a combination of in vivo, organ culture, and in vitro methods to understand the function of this protein in B cell development. In Specific Aim 2, we will characterize Notch signaling in B lymphoid subsets and determine the mechanism by which Notch signaling specifically promotes B cell death. These studies will lead to an improved understanding of lymphoid development and function, and in doing so, will provide therapeutic insights into treating leukemia and other diseases of the immune and hematopoietic systems.