Molecular Regulation of Aging Thymus Atrophy

说明(申请人提供)：免疫衰老始于胸腺退化，而与年龄相关的胸腺退化是胸腺微环境受多基因调控的结果。我们的假设是，衰老萎缩的胸腺一定表现出目前未知的分子特征和细胞形态的变化，调控胸腺微环境的转录因子可能参与了与衰老相关的胸腺退化过程。我们的方法是研究老年萎缩胸腺的分子特征和细胞学特征，重点是K5/K8在胸腺上皮细胞上的共定位，基于cKit和Has的造血祖细胞亚群Tn1的表达，以及两类Foxn1转录的表达；同时，利用部位和时间特异性的CRE重组酶小鼠模型，测试成年胸腺髓质、皮质和总TECs中Foxn1信号的下调是否足以诱导衰老相关胸腺退化。这些研究可能最终导致了解与年龄相关的胸腺退化的分子机制，并可能制定逆转衰老胸腺功能的策略。

DESCRIPTION (provided by applicant): Immunosenescence starts from thymic involution, while age-related thymic involution results from thymic microenvironment changes regulated by multiple genes. Our hypothesis is the aged atrophic thymus must show changes in molecular features and cellular profiles that are not currently known, and transcription factors regulating thymic microenvironment built up mostly by thymic epithelial cells might be involved in the aging-related thymic involution process. Our approach is to investigate the aged atrophic thymus molecular features and cellular profiles focusing on K5/K8 co-localization on thymic epithelial cells, TN.1 hematopoietic progenitor cell subsets based on cKit and HAS expression, as well as the expression of two classes of Foxnl transcription; meanwhile test whether down regulation of the Foxnl signal in medulla, cortex and total TECs in adult thymus can sufficiently induce aging-related thymic involution with site- and time- tissue-specific Cre-recombinase mouse model. These studies may ultimately lead to understanding the molecular mechanisms of age-related thymic involution and make possible strategies to reverse the function of the aged thymus.