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，是导致与衰老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主要原因是胸腺随年龄的出生后退化，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尚不清楚。这些机制的鉴定具有明确的临床意义，因为它们代表了诱导胸腺反弹和免疫系统再生的潜在治疗靶点，并且对细胞替代策略也具有重要意义。一种已被充分证明的机制是雄激素耗竭在诱导反弹中的作用-人或小鼠中的手术或化学去势至少诱导短暂的胸腺恢复和增加的T细胞产生，并且细胞内雄激素受体（AR）的缺失导致胸腺大小增加。由于雄激素主要通过AR影响受体细胞内的基因表达来起作用，因此确定哪些细胞接收与退化相关的雄激素信号对于理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缺失小鼠的数据由于整体雄激素耗竭或不敏感的全身效应而变得复杂，因此在这些模型中发生反弹的细胞靶点和机制都是未知的。此外，还没有关于自然老化过程中Ar空胸腺的深入研究。因此，雄激素在胸腺寿命中的正常作用和雄激素耗竭影响胸腺功能的机制都不确定。现有的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（TEC）是介导雄激素信号传导作用的主要候选细胞。在目前的合作提案中，我们将测试雄激素对胸腺的影响是通过对胸腺基质，特别是TEC的直接影响介导的假设。此外，我们提出，这些影响是，部分，直接或间接介导的TEC特异性转录因子FoxN 1。为此，我们提出了两个具体的目标：1）通过比较全身性和组织特异性雄激素受体缺失的影响来检验雄激素是胸腺退化和反弹的主要调节因子的假设; 2）检验雄激素信号传导在出生后胸腺中起作用的分子机制。在拟议的实验中，我们将使用分子和遗传学的方法来研究雄激素影响出生后胸腺的机制，胸腺反弹介导。这些研究可能会确定新的目标，在治疗免疫衰老和胸腺退化的治疗干预。 公共卫生相关性：免疫衰老是导致疾病发病率增加和生活质量下降的重要因素。胸腺退化是免疫衰老的一个关键组成部分，但这一过程的机制知之甚少。类固醇激素，特别是雄激素，被认为是退化的主要贡献者，雄激素阻断可导致胸腺再生。目前的建议旨在确定在出生后胸腺和胸腺反弹期间雄激素信号传导的细胞和分子靶点。

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.