Identification of stromal responses during castration-induced 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。不幸的是，胸腺的大小随着年龄的增长而逐渐退化，在青春期左右明显开始。由于胸腺产生的新T细胞与其质量成正比，因此年龄相关性胸腺萎缩导致新的初始T细胞产生终身进行性下降。在外周淋巴系统中，这种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，但最终结果是，随着时间的推移，T细胞库越来越多地代表寡克隆库，而不是由新产生的幼稚胸腺T细胞赋予的广泛的、无偏见的免疫谱。因此，衰老与T细胞免疫缺陷（或免疫不敏感性）的积累相关，这反过来导致对感染性疾病的易感性增加、对疫苗的应答降低、抗肿瘤监视降低、自身免疫增加和其他相关病症。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，纠正和/或预防年龄相关的胸腺变性（萎缩）对于提高生活质量和降低成年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，胸腺可以被诱导完全再生，尽管最有效的方法（手术阉割）有点不切实际。尽管如此，这种可塑性强调了设计其他更实用的方法来诱导胸腺再生的潜力。这个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，以产生准确的全球名单的胸腺基质基因在其原生状态原位，无论是在未经修改的萎缩胸腺，并在再生的各个阶段（启动，对数期，终止）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调控因子，随后将采用常规生物学方法（转基因、敲除）。除了深入了解胸腺基质生物学和再生过程外，该项目预计最终将揭示胸腺再生治疗方法的潜在新靶点。公共卫生相关性：T细胞免疫力的下降是年龄相关性胸腺退化的直接后果，并且与许多不良状况有关，包括感染风险增加、感染严重程度增加、对疫苗接种的反应降低、肿瘤监视降低、自身免疫增加等。本申请提出了一种新的方法来了解萎缩胸腺再生的生物学。除了对再生过程的深入了解外，该项目还有望最终揭示胸腺再生治疗的潜在新靶点。

DESCRIPTION (provided by applicant): Under normal conditions, most T lymphocytes are made in the thymus. Unfortunately, the size of the thymus degenerates progressively with age, with a noticeable onset at around the time of puberty. Because the output of new T cells from the thymus is directly proportional to its mass, age-related thymic atrophy results in a lifelong, progressive decline in the production of new, naive T cells. In the peripheral lymphoid system, this decreased thymic output is compensated by homeostatic expansion of existing T cells. While this avoids frank T cell lymphopenia, the end result is that, over time, the T cell pool increasingly represents an oligoclonal repertoire, rather than the broad, unbiased spectrum of immunity conferred by newly generated, naive thymic T cells. Thus, aging is associated with an accumulation of T cell immunodeficiencies (or immunoinsufficiencies) that, in turn, result in increased susceptibility to infectious disease, decreased response to vaccines, decreased anti-tumor surveillance, increased autoimmunity, and other related 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 and/or preventing age-related thymic degeneration (atrophy) is thus of substantial importance for enhancing quality of life, and for decreasing health care costs in adults and the elderly. Notably, the thymus can be induced to completely regrow, although the most efficient means for this (surgical castration) is somewhat impractical. Nonetheless, this plasticity underscores the potential for devising other more practical means for inducing thymic regrowth. The aims of this project are to use recently devised, robust physical methods (laser microdissection, microarray) and computational modeling to generate accurate global lists of thymic stromal genes in their native state in situ, both in the unmodified atrophied thymus, and during various phases of regrowth (initiation, log phase, termination) 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 (transgenics, knockouts). In addition to an in- depth understanding of thymic stromal biology and the regrowth process, this project is expected to ultimately reveal potential new targets for therapeutic approaches for thymic regeneration. PUBLIC HEALTH RELEVANCE: Decreases in T cell immunity are a direct consequence of age-related thymic degeneration, and are linked to a host of undesirable conditions, including increased risk of infection, increased severity of infection, decreased response to vaccinations, decreased tumor surveillance, increased autoimmunity, and so on. Regenerating the thymus is therefore of significant interest to human health. This application proposes a novel approach to understanding the biology of regrowth of the atrophied thymus. In addition to an in-depth understanding of the regrowth process, this project is expected to ultimately reveal potential new targets for thymic regeneration therapy.