Identification of stromal responses during castration-induced thymic regrowth.

描述（由申请人提供）：在正常情况下，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，在青春期左右开始明显退化。由于来自胸腺的新T细胞的产出与它的质量成正比，年龄相关的胸腺萎缩会导致新的幼稚T细胞产生的终生渐进下降。在外周淋巴系统中，胸腺输出量的减少由现有T细胞的稳态扩张来补偿。虽然这避免了明显的T细胞淋巴减少，但最终的结果是，随着时间的推移，T细胞池越来越多地代表一个寡克隆库，而不是新产生的初始胸腺T细胞所赋予的广泛、公正的免疫谱。因此，衰老与T细胞免疫缺陷（或免疫不足）的积累有关，而T细胞免疫缺陷（或免疫不足）反过来又导致对传染病的易感性增加，对疫苗的反应降低，抗肿瘤监测降低，自身免疫增强和其他相关疾病。造血干细胞移植是治疗白血病等疾病的一种成熟疗法，也是治疗红斑狼疮和多发性硬化症等自身免疫性疾病的一种新兴疗法。造血干细胞移植产生新T细胞的能力下降也是造血干细胞移植的一大限制。因此，纠正和/或预防与年龄相关的胸腺退化（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（手术阉割）有些不切实际。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。该项目的目的是使用最近设计的，强大的物理方法（激光显微解剖，微阵列）和计算模型来生成胸腺基质基因的准确全局列表，无论是在未修饰的萎缩胸腺中，还是在阉割诱导的再生的各个阶段（起始期，对数期，终止期）。然后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节因子，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细胞免疫力下降是年龄相关性胸腺退行性变的直接后果，并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、疫苗接种反应降低、肿瘤监测下降、自身免疫增强等。因此，胸腺再生对人类健康具有重要意义。这一应用提出了一种新的方法来理解萎缩胸腺再生的生物学。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.