Identification of stromal responses during castration-induced 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。不幸的是，胸腺的大小随着年龄的增长而逐渐退化，在青春期左右出现明显的发病。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新的、幼稚的T细胞的产生终生递减。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，但最终的结果是，随着时间的推移，T细胞库越来越代表着一种寡克隆谱系，而不是由新生成的、幼稚的胸腺T细胞赋予的广泛、公正的免疫谱。因此，衰老与T细胞免疫缺陷(或免疫缺陷)的积累有关，这反过来会导致对传染病的易感性增加，对疫苗的反应降低，抗肿瘤监视减少，自身免疫力增强，以及其他相关的疾病。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，纠正和/或预防与年龄相关的胸腺退化(萎缩)对于提高成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，尽管最有效的方法(手术去势)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可能性。该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)和计算模拟来在原位生成原始状态下胸腺基质基因的准确全局列表，包括在未经修改的萎缩胸腺中以及在去势诱导的再生的不同阶段(启动、对数阶段、终止)。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，随后将采用传统的生物学方法(转基因、基因敲除)。除了深入了解胸腺基质生物学和再生过程外，该项目有望最终揭示胸腺再生治疗方法的潜在新靶点。公共卫生相关性：T细胞免疫功能下降是年龄相关性胸腺退化的直接后果，并与一系列不良情况有关，包括感染风险增加、感染严重程度增加、对疫苗接种的反应性降低、肿瘤监视减少、自身免疫力增强等。因此，再生胸腺对人类健康具有重大意义。这项应用为理解萎缩胸腺再生的生物学提供了一种新的方法。除了深入了解再生过程外，该项目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.