Steroid Receptors and Transcriptional Control of Thymic Rebound

描述(由申请人提供)：免疫衰老，或免疫系统功能随年龄增长而下降，是与老龄化相关的人类健康质量普遍下降的主要原因。衰老相关免疫缺陷的一个主要原因是胸腺出生后随着年龄的增长而退化，这导致幼稚T细胞的产生减少。胸腺退化在免疫衰老发展中的核心重要性已经得到了很好的证实；然而，这一过程发生的细胞和分子机制还不是很清楚。识别这些机制具有明显的临床意义，因为它们是诱导胸腺反弹和免疫系统再生的潜在治疗靶点，也对细胞替代策略具有重要意义。已有文献记载的一种机制是雄激素耗竭在诱导反弹中的作用--在人类或小鼠中，手术或化学去势至少可以诱导短暂的胸腺恢复和T细胞产生增加，而细胞内雄激素受体(AR)的缺失会导致胸腺大小增加。由于雄激素主要通过AR影响受体细胞内的基因表达，因此识别哪个细胞(S)接收与退缩相关的雄激素信号对于了解雄激素影响胸腺的机制至关重要。然而，由于来自去势和AR缺失小鼠的数据被全球雄激素耗尽或不敏感的全身效应复杂化，这些模型中发生反弹的细胞靶点和机制都不清楚。此外，还没有对自然衰老过程中AR零胸腺的彻底研究发表。因此，雄激素在胸腺寿命中的正常作用以及雄激素枯竭影响胸腺功能的机制都是不确定的。现有数据一致地指出，胸腺基质靶点是胸腺中雄激素作用的主要部位。在这些基质细胞类型中，胸腺上皮细胞(TECs)是介导雄激素信号转导效应的主要候选细胞。在目前的合作方案中，我们将测试这一假设，即雄激素对胸腺的影响是通过对胸腺基质，特别是TECs的直接影响来实现的。此外，我们认为这些效应在一定程度上是由TEC特异性转录因子FOXN1直接或间接介导的。为此，我们提出了两个特定的目标：1)通过比较全身和组织特异性雄激素受体缺失的影响，验证雄激素是胸腺退化和反弹的主要调节因素的假设；2)测试雄激素信号在出生后胸腺中作用的分子机制。在拟议的实验中，我们将使用分子和遗传学方法来研究雄激素影响出生后胸腺的机制，以及胸腺反弹的中介机制。这些研究可能为免疫衰老和胸腺退化的治疗干预确定新的靶点。 公共卫生相关性：随着年龄的增长，免疫衰老是增加疾病发病率和降低生活质量的重要因素。免疫衰老的一个关键成分是胸腺退化，但这一过程背后的机制尚不清楚。类固醇激素，特别是雄激素，被认为是导致退缩的主要因素，而雄激素阻断可以导致胸腺再生。目前的建议试图确定在出生后胸腺和胸腺反弹期间雄激素信号的细胞和分子靶点。

DESCRIPTION (provided by applicant): Immunosenescence, or the decrease in immune system function with aging, is a major contributor to the general decrease in the quality of human health associated with aging. A primary cause of aging-related immunodeficiency is the postnatal involution of the thymus with age, which results in decreased production of naive T cells. The central importance of thymic involution in the development of immunosenescence is well established; however, the cellular and molecular mechanisms by which this process occurs are less clear. Identification of these mechanisms is of clear clinical relevance, as they represent potential therapeutic targets for inducing thymic rebound and immune system regeneration, and also have significance for cell replacement strategies. One mechanism that has been well-documented is the role of androgen depletion in inducing rebound - surgical or chemical castration in humans or mice induces at least transient thymic recovery and increased T cell production, and deletion of the intracellular Androgen Receptor (AR) causes increased thymus size. Since androgens primarily act by affecting gene expression within a receiving cell via AR, identifying which cell(s) receive the androgen signal relevant to involution is critical to understanding the mechanism by which androgens affect the thymus. However, as data from castration and the Ar null mice are complicated by the systemic effects of global androgen depletion or insensitivity, neither the cellular target nor the mechanism by which rebound occurs in these models is known. Furthermore, no thorough study of the Ar null thymus during natural aging has been published. Thus, both the normal role of androgens in the lifespan of the thymus and the mechanism by which androgen depletion affects thymus function are uncertain. The available data consistently point to a thymic stromal target as the major site of androgen action in the thymus. Among these stromal cell types, thymic epithelial cells (TECs) are the leading candidates to mediate the effects of androgen signaling. In the current collaborative proposal, we will test the hypothesis that the effects of androgens on the thymus are mediated by direct effects on thymic stroma, in particular TECs. Furthermore, we propose that these effects are, in part, mediated directly or indirectly by the TEC-specific transcription factor FoxN1. To this end, we propose two specific aims: 1) to test the hypothesis that androgens are primary regulators of thymic involution and rebound by comparing the effects of systemic and tissue-specific androgen receptor deletion; and 2) to test the molecular mechanisms by which androgen signaling acts in the postnatal thymus. In the proposed experiments we will use molecular and genetic approaches to investigate the mechanisms by which androgens affect the postnatal thymus, and by which thymic rebound is mediated. These studies may identify novel targets for therapeutic intervention in the treatment of immunosenescence and thymic involution. PUBLIC HEALTH RELEVANCE: Immunosenescence is an important contributor to increased incidence of disease and reduced quality of life with aging. A key component of immunosenescence is thymic involution, but the mechanisms underlying this process are poorly understood. Steroid hormones, especially androgens, are thought to be major contributors to involution, and androgen blockade can result in thymic regeneration. The current proposal seeks to identify the cellular and molecular targets of androgen signaling in the postnatal thymus and during thymic rebound.