Identification of Stromal Responses During Castration Mediated Thymic Regrowth

描述（由申请方提供）：在正常条件下，大多数T淋巴细胞在胸腺中产生。然而，胸腺随着年龄的增长而退化，大约从青春期开始。由于胸腺新T细胞的输出与其质量成正比，因此年龄相关性胸腺萎缩导致幼稚T细胞产生的进行性下降。在外周淋巴系统中，减少的胸腺输出通过现有T细胞的稳态扩增来补偿。虽然这避免了明显的T细胞淋巴细胞减少症，但结果是T细胞池具有越来越多的寡克隆库，而不是由新产生的幼稚胸腺T细胞赋予的广谱免疫。因此，衰老与T细胞免疫缺陷（或免疫不敏感性）的积累相关，导致对感染性疾病的易感性增加、疫苗应答降低、抗肿瘤监视降低、自身免疫增加和其他病症。造血干细胞移植是白血病等疾病的既定疗法，也是红斑狼疮和多发性硬化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变性（萎缩）对于提高生活质量和降低成人和老年人的医疗保健费用具有实质性的重要性。值得注意的是，胸腺可以诱导完全再生，但最有效的方法（手术阉割）是不切实际的。尽管如此，这种可塑性显示了设计诱导再生的实用方法的潜力。该项目的目的是使用最近设计的，强大的物理方法（激光显微切割，微阵列）和计算建模，以创建准确的全球名单胸腺基质基因在其原生状态，无论是在萎缩的胸腺，并在各种再生阶段（启动，日志，峰值）诱导去势。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。信息学和生物学验证将用于确定这些过程中的关键监管机构，这些监管机构将通过常规生物学方法进行跟踪。除了深入了解胸腺基质生物学和再生过程，我们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.