Steroid Receptors and Transcriptional Control of Thymic Rebound

类固醇受体和胸腺反弹的转录控制

• 批准号: 7939727
• 负责人: Clare Blackburn
• 金额: $ 29.4万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939727
• 关键词: Ablation; Affect; Age; Aging; Androgen Receptor; Androgens; Biological Assay; CCL25 gene; Castration; Cells; Characteristics; Chemicals; Data; Development; Disease; Down-Regulation; Epithelial; Epithelial Cell Proliferation; Gene Expression; Growth; Health; Hematopoietic; Homeostasis; Human; Immune system; Immunologic Deficiency Syndromes; Incidence; Knockout Mice; LacZ Genes; Link; Longevity; Lymphoid Cell; Mediating; Mediator of activation protein; Mesenchymal; Mesenchyme; Modeling; Molecular; Molecular Genetics; Molecular Profiling; Molecular Target; Mus; Natural regeneration; Neural Crest; Operative Surgical Procedures; Population; Process; Production; Publishing; Quality of life; Receptor Signaling; Recovery; Role; Signal Transduction; Site; Steroid Receptors; Stromal Cells; T-Cell Development; T-Lymphocyte; Testing; Therapeutic Intervention; Thymic epithelial cell; Thymus Gland; Tissues; Transcriptional Regulation; Validation; age related; cell type; cellular targeting; clinically relevant; immunosenescence; in vitro Model; in vivo; mouse model; mutant; novel; postnatal; premature; prevent; public health relevance; research study; response; steroid hormone; therapeutic target; thymocyte; transcription factor

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.

描述（由申请人提供）：免疫衰老，或免疫系统功能随着年龄的增长而下降，是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出生后胸腺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中心重要性是公认的；然而，这一过程发生的细胞和分子机制尚不清楚。确定这些机制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。一个已被充分证明的机制是雄激素消耗在诱导反弹中的作用——手术或化学阉割在人类或小鼠中诱导至少短暂的胸腺恢复和增加T细胞的产生，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影响接收细胞内的基因表达，因此确定哪些细胞接收到与内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，由于阉割和Ar缺失小鼠的数据被全局雄激素消耗或不敏感的系统性影响所复杂化，因此在这些模型中，细胞靶点和反弹发生的机制都不清楚。此外，还没有关于胸腺自然衰老过程的深入研究。因此，雄激素在胸腺寿命中的正常作用和雄激素消耗影响胸腺功能的机制都是不确定的。现有资料一致指出胸腺基质靶点是胸腺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）是介导雄激素信号传导作用的主要候选细胞。在目前的合作建议中，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的直接影响来介导的假设。此外，我们认为这些影响部分是由tec特异性转录因子FoxN1直接或间接介导的。为此，我们提出了两个具体目标：1)通过比较系统性和组织特异性雄激素受体缺失的影响来验证雄激素是胸腺复旧和反弹的主要调节因子的假设；2)测试雄性激素信号在出生后胸腺中的分子机制。在我们提出的实验中，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，以及通过雄激素介导胸腺反弹。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。