Heterogeneity of medullary thymic epithelium

描述（由申请人提供）：胸腺髓上皮（TE）参与胸腺细胞阴性选择。这种TE室的异质性主要与髓质TE室影响耐受性的能力有关。髓质TE异质性的基础尚不清楚，尽管主流模型认为髓质TE表现出组织特异性基因的“混杂”表达，这是由aire转录因子调节的基因表达的随机和可逆的抑制的结果。本文提出的研究将验证一个新的假设，即胸腺上皮的异质性反映了祖上皮细胞的不同发育命运，从而使髓质TE亚群分化表达其他上皮组织的分子特征。该模型解释了先前观察到的髓质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。本文提出的工作将检验相应的假设，即胸腺中组织特异性基因表达的调节方式与外周上皮组织相同。这里提出的工作也将提供对髓质TE室如何发展的理解，并将为调节这些细胞发育的细胞相互作用和信号通路的本质提供新的见解。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。这里讨论的问题主要与临床重要的一个主要问题有关，即上皮隔室如何有助于建立对自身上皮分子的免疫耐受性。了解控制胸腺内潜在耐受抗原表达的机制将是必要的，以便设计基本的治疗策略来增强胸腺功能的这一重要方面。除了提供对这一问题的见解外，本文提出的髓质性TE发展模型的验证将从根本上改变TE发展的主流二元发展模型，并为增强胸腺功能的其他方面提供新的机会，这些方面在与年龄相关的胸腺退化或由于HIV感染而下降。

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.