Aging of Early B Cell Precursors

描述(由申请人提供)：年龄相关的造血干细胞(HSC)功能缺陷可能会阻碍基于HSC的治疗在老年人中的应用。我们已经开展了一系列研究，以探讨HSC在老年小鼠中的功能。在这个模型系统中，我们已经确定了衰老导致从HSCs产生早期B淋巴细胞前体细胞的效率显著低下。我们建议通过四个特定的目标进一步探索这种缺陷的细胞和分子基础。在目标1中，我们将确定早期B系前体细胞何时开始随着年龄的增长而衰退，并确定受衰老过程影响的B系分化的最早阶段。在目标2中，我们将测试早期淋巴祖细胞的年龄相关性丢失是否是由于HSCs的细胞固有缺陷，以及非规范淋巴祖细胞是否对老年人的B细胞谱系做出贡献。在目标3中，我们将阐明HSC老化对早期B细胞前体细胞应答细胞因子IL-7和维持B细胞系分化能力的影响。最后，在目标4中，我们将确定E2A和EBF转录因子在与年龄相关的非常早期的B系祖细胞丧失中的作用。总之，这些研究将增强我们对干细胞生物学的了解，并为早期淋巴细胞发育中与年龄相关的缺陷奠定基础。

DESCRIPTION (provided by applicant): Age-related defects in hematopoietic stem cell (HSC) function may hamper the application of HSC-based therapies for elderly individuals. We have undertaken a series of studies investigating HSC function in aged mice. With this model system, we have determined that aging leads to markedly inefficient generation of early B lymphocyte progenitor cells from HSCs. We propose to further explore the cellular and molecular basis for this defect via four specific aims. In Aim 1, we will determine when early B-lineage precursors first decline with age and define the earliest stage in B-lineage differentiation affected by the aging process. In Aim 2, we will test whether age-associated loss of early lymphoid progenitors is due to cell intrinsic defects in HSCs, and test whether noncanonical lymphoid progenitors contribute to the B cell lineage in the elderly. In Aim 3, we will elucidate the impact of HSC aging on the capacity of early B cell precursors to respond to the cytokine IL-7 and sustain B-lineage differentiation. Finally, in Aim 4, we will define the role of the E2a and EBF transcription factors in the age-associated loss of very early B-lineage progenitors. Together, these studies will enhance our knowledge of stem cell biology and the basis for age-related defects in early lymphocyte development.