Identification of Stromal Responses During Castration Mediated Thymic Regrowth

描述(申请人提供)：在正常情况下，大多数T淋巴细胞是在胸腺中产生的。然而，胸腺会随着年龄的增长而退化，从青春期开始。由于胸腺输出的新T细胞与其质量成正比，与年龄相关的胸腺萎缩会导致幼稚T细胞的产生逐渐减少。在外周淋巴系统中，胸腺输出的减少被现有T细胞的稳态扩张所补偿。虽然这避免了坦率的T细胞淋巴细胞减少，但结果是T细胞库具有越来越多的寡克隆性谱系，而不是由新生成的幼稚胸腺T细胞产生的广谱免疫。因此，衰老与T细胞免疫缺陷(或免疫缺陷)的积累有关，导致对传染病的易感性增加，疫苗反应降低，抗肿瘤监视减少，自身免疫力增强，以及其他疾病。生成新T细胞的能力下降也是造血干细胞移植的一个重大限制。造血干细胞移植是一种治疗白血病等疾病的老牌疗法，也是一种治疗红斑狼疮和多发性硬化症等自身免疫性疾病的新兴疗法。因此，纠正/预防与年龄相关的胸腺退化(萎缩)对于提高成年人和老年人的生活质量和降低医疗费用具有重要意义。值得注意的是，胸腺可以被诱导完全再生，但最有效的方法(手术去势)是不切实际的。尽管如此，这种可塑性显示了设计出诱导再生的实用方法的潜力。这个项目的目的是使用最近设计的健壮的物理方法(激光显微解剖、微阵列)和计算建模来创建其自然状态下胸腺基质基因的准确全球列表，包括萎缩的胸腺和去势诱导的不同再生阶段(起始、对数、峰值)。然后将分析基质基因表达特征，以揭示萎缩和再生反应期间发生的变化。将使用信息学和生物学验证来确定这些过程中的关键调控因素，并将通过传统的生物学方法进行后续处理。除了深入了解胸腺基质生物学和再生过程外，我们还希望揭示胸腺再生治疗方法的潜在靶点。

DESCRIPTION (provided by applicant): Under normal conditions, most T lymphocytes are made in the thymus. However, the thymus degenerates with age, beginning around puberty. Because output of new T cells from the thymus is proportional to its mass, age-related thymic atrophy results in a progressive decline in production of naive T cells. In the peripheral lymphoid system, decreased thymic output is compensated by homeostatic expansion of existing T cells. While this avoids frank T cell lymphopenia, the result is a T cell pool with an increasingly oligoclonal repertoire, rather than the broad spectrum of immunity conferred by newly generated, naive thymic T cells. Thus, aging is associated with accumulation of T cell immunodeficiencies (or immunoinsufficiencies), resulting in increased susceptibility to infectious disease, decreased vaccine response, decreased anti- tumor surveillance, increased autoimmunity, and other disorders. Decreased capacity to make new T cells is also a substantial limitation in hematopoietic stem cell transplantation, which is an established therapy for diseases like leukemia, and an emerging therapy for autoimmune disorders like lupus erythematosus and multiple sclerosis. Correcting/preventing age-related thymic degeneration (atrophy) is thus of substantial importance for enhancing quality of life, and decreasing health care costs in adults and the elderly. Notably, the thymus can be induced to completely regrow, but the most efficient means for this (surgical castration) is impractical. Nonetheless, this plasticity shows the potential for devising practical means for inducing regeneration. The aims of this project are to use recently devised, robust physical methods (laser microdissection, microarray) and computational modeling to create accurate global lists of thymic stromal genes in their native state, both in the atrophied thymus, and during various regrowth phases (initiation,log, peak) induced by castration. Stromal gene expression signatures will then be analyzed to reveal changes that occur in atrophy, and during the regrowth response. Informatic and biological validations will be used to identify key regulators in these processes, which will be followed-up by conventional biological approaches. In addition to an in-depth understanding of thymic stromal biology and the regrowth process, we expect to reveal potential targets for therapeutic approaches for thymic regeneration.