Heterogeneity of medullary thymic epithelium

描述（由申请方提供）：胸腺髓质上皮（TE）参与胸腺细胞阴性选择。这种TE隔室的异质性与髓质TE隔室影响耐受性的能力密切相关。这种髓质TE异质性的基础知之甚少，虽然流行的模型认为，髓质TE表现出组织特异性基因的“混杂”表达，这是由aire转录因子调控的基因表达的随机和可逆的去抑制的结果。这里提出的研究将测试新的假设，即胸腺上皮细胞的异质性反映了替代的祖上皮细胞的发育命运，这样的髓质TE分化表达分子的其他上皮组织的特征。该模型解释了先前观察到的髓TE异质性模式，并将允许以有组织和合理的方式评估这种异质性。这里提出的工作将测试的推论假设，组织特异性基因表达在胸腺中的调节方式与外周上皮组织中相同。这里提出的工作也将提供一个了解如何髓TE隔室的发展，并将提供新的见解的细胞相互作用和信号通路的性质，调节这些细胞的发展。最后，本文提出的研究将重新评估aire转录因子对组织发育和髓室发育的影响。这里解决的问题是集中有关的一个重大问题的临床重要性，上皮细胞室如何有助于建立免疫耐受自我上皮分子。为了设计合理的治疗策略来增强胸腺功能的这一重要方面，了解胸腺内潜在的致耐受性抗原表达的控制机制将是必要的。除了提供深入了解这个问题，验证模型的髓质TE发展提出的将从根本上改变流行的二元发展模式TE发展，并提供新的机会，以提高其他方面的胸腺功能下降，在与年龄相关的胸腺退化或作为一个后果的HIV感染。

DESCRIPTION (provided by applicant): Medullary thymic epithelium (TE) participates in thymocyte negative selection. Heterogeneity of this TE compartment is centrally related to the ability of the medullary TE compartment to effect tolerance. The basis for this medullary TE heterogeneity is poorly understood, although the prevailing model holds that medullary TE exhibit "promiscuous" expression of tissue-specific genes as a consequence of a random and reversible derepression of gene expression that is regulated by the aire transcription factor. Studies proposed here will test the novel hypothesis that the heterogeneity of thymic epithelium reflects alternative developmental fates of progenitor epithelial cells, such that subsets of medullary TE differentiate to express molecules characteristic of other epithelial tissues. This model accounts for the patterns of medullary TE heterogeneity that have been previously observed and will allow an assessment of this heterogeneity in an organized and rational manner. Work proposed here will test the corollary hypotheses that tissue specific gene expression in the thymus is regulated in the same manner as in peripheral epithelial tissues. The work proposed here will also provide an understanding of how the medullary TE compartment develops and will provide new insight into the nature of the cellular interactions and signaling pathways that regulate the development of the these cells. Finally, studies proposed here will re-evaluate the impact of the aire transcription factor on the development of the organization and development of the medullary compartment. The questions addressed here are centrally related to a major question of clinical importance how the epithelial compartment contributes to the establishment of immunological tolerance to self-epithelial molecules. Understanding the mechanisms controlling the expression of potentially toleragenic antigens within the thymus will be necessary in order to design rationale therapeutic strategies to enhance this important aspect of thymic function. In addition to providing insight into this problem, validation of the model of medullary TE development proposed here will fundamentally alter the prevailing binary developmental model of TE development and provide new opportunities to enhance other aspects of thymic function that decline during age-related thymic involution or as a consequence of HIV infection.