Aging and thymopoiesis: Changes in stroma, T-presursors

描述（由申请人提供）：胸腺在人类和啮齿动物外周初始T细胞库中大多数初始T细胞的发育中具有关键功能。尽管有这种基本功能，胸腺随着年龄的增长而逐渐退化，导致幼稚T细胞输出的急剧减少。因此，衰老与潜在威胁生命的感染和自身免疫性疾病的发病率增加有关。我们最近的发现和建议的研究表明，有可能改善这种减少的胸腺功能。要做到这一点，我们必须首先了解导致胸腺退化的细胞和分子变化，这是我们研究的长期目标。在临床上，这些知识将帮助我们开发新的策略来恢复胸腺的活力，增加老年或慢性病患者，艾滋病等免疫缺陷疾病患者以及接受化疗或骨髓移植的患者的胸腺幼稚T细胞的输出。胸腺内T细胞或胸腺细胞的发育依赖于胸腺上皮基质，并受转录因子的调控，转录因子的时间表达受到严格调控。我们假设Notch信号位于信号级联的顶端，该信号级联协调转录因子的协调表达，对T谱系的承诺和分化以及胸腺上皮细胞功能成熟至关重要。控制未成熟三阴性（TN）胸腺细胞发育的转录因子的时间表达变化导致胸腺初始T细胞输出降低。我们还假设胸腺上皮基质调节这些转录因子表达的变化。TN胸腺细胞的发育需要T细胞系承诺、细胞扩增以及T细胞受体β和α的重排。我们提出了四个具体目的：目的1，确定T细胞的承诺是否在衰老的胸腺中改变；目的2，确定DN胸腺细胞发育过程中细胞扩增是否发生改变；目的3，确定老年胸腺DN发生过程中T细胞受体β和α的重排是否发生改变；目的4，确定Notch信号如何调控FoxN1转录。我们已经产生了具有上皮特异性转录因子Foxn1的转基因小鼠。这些小鼠在DN发育中没有年龄相关的变化，这是描述衰老胸腺细胞中转录因子表达的控制和胸腺上皮基质在这一过程中的功能的独特工具。

DESCRIPTION (provided by applicant): The thymus has crucial functions in the development of most naive T cells for the peripheral naive T cell pool in humans and rodents. Despite this essential function, the thymus involutes with age, leading to a dramatic reduction in naive T cell output. Thus, aging is associated with increased incidence of potentially life-threatening infections and autoimmune diseases. Our recent findings and the proposed studies indicate that it might be possible to ameliorate such reduced thymopoiesis. To do so, we must first understand the cellular and molecular changes that lead to thymic involution, which is the long-term goal of our research. Clinically, this knowledge will help us develop novel strategies to rejuvenate the thymus and increase thymic output of naive T cells in the elderly or chronically ill, in patients with immunodeficiency diseases such as HIV, and in patients undergoing chemotherapy or bone marrow transplant. The development of T cells or thymocytes in the thymus depends on thymic epithelial stroma and is regulated by transcription factors whose temporal expression is tightly regulated. We hypothesize that Notch signaling is at the apex of the signal cascade that orchestrates the coordinated expression of transcription factors critical for T lineage commitment and differentiation as well as thymic epithelial cell functional maturation. Changes in the temporal expression of transcription factors that control the development of the immature triple negative (TN) thymocytes result in lower thymic naive T cell output. We also hypothesize that thymic epithelial stroma modulates changes in the expression of these transcription factors. The development of TN thymocytes requires T lineage commitment, cell expansion, and rearrangement of T cell receptors beta and alpha. We propose four specific aims: Aim 1, to determine whether T cell commitment is altered in the aged thymus; Aim 2, to determine whether cell expansion is altered during DN thymocyte development; Aim 3, to determine whether rearrangement of T cell receptors beta and alpha are altered in DN development in the aged thymus; Aim 4, to determine how Notch signaling regulates FoxN1 transcription. We have generated transgenic mice for the epithelium-specific transcription factor Foxn1. These mice show absence of age- associated changes in DN development and are a unique tool for delineating the control of expression of transcription factors in aged thymocytes and the function of thymic epithelial stroma in this process.