Estrogen-T cell Interactions

雌激素-T 细胞相互作用

• 批准号: 8197380
• 负责人: Mitzi Nagarkatti
• 金额: $ 30.52万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-08 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197380
• 关键词: Age; American; Antigens; Apoptosis; Atrophic; Autoantigens; Autoimmune Diseases; Autoimmunity; Benign; Binding; CD8B1 gene; Cell Communication; Chemicals; Child; Daughter; Development; Diethylstilbestrol; Disease; Elements; Endocrine Disruptors; Environment; Environmental Estrogen; Estradiol; Estrogen Receptors; Estrogen Replacement Therapy; Estrogens; Exposure to; Female; Fetal Thymic Organ Culture; Food; Generations; Genes; H-Y Antigen; Health; Hormone replacement therapy; Immune; Immune System Diseases; Immune system; In Vitro; Incidence; Induction of Apoptosis; Infection; Lead; Life; Link; Livestock; Lymphoma; MHC Class I Genes; Malignant Neoplasms; Mature T-Lymphocyte; Mediating; Menopausal Symptom; Mothers; Mus; Newborn Infant; Nuclear; Pesticides; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Phytoestrogens; Plants; Postmenopause; Predisposition; Pregnancy; Premature Birth; Prevention; Regulation; Reporting; Research; Risk; Role; Son; Spontaneous abortion; Stromal Cells; T cell differentiation; T-Cell Receptor; T-Lymphocyte; Testing; Thymus Gland; Time; Toxic effect; Transcriptional Regulation; Transgenic Mice; Transgenic Organisms; Tumor Necrosis Factor Ligand Superfamily Member 6; Uterine Cancer; Woman; cancer type; feeding; immunoregulation; immunotoxicity; in utero; in vivo; insight; lifetime risk; male; malignant breast neoplasm; men; novel; nuclear factors of activated T-cells; offspring; ovarian neoplasm; postnatal; prenatal; prenatal exposure; prevent; public health relevance; pup; reproductive; response; soy; surfactant; thymocyte; transcription factor; tumor; xenoestrogen

DESCRIPTION (provided by applicant): Estrogens have widespread applications in health and disease. Postmenopausal women are treated with estrogen replacement therapy to relieve them of the menopausal symptoms. Between 1940-1975, an estimated 5-10 million Americans received diethylstilbestrol (DES), a synthetic estrogen, during pregnancy or were exposed to the drug in utero. Exposure to DES has been associated with an increased risk for breast cancer in "DES mothers" and a lifetime risk of cervicovaginal cancers in "DES daughters". Exposure to DES has also been linked to a wide range of abnormalities in "DES sons and daughters" including immune system disorders such as increased incidence of autoimmunity, cancer and certain infections. Furthermore, a number of xenoestrogens which include environmental estrogens and phytoestrogens have been identified which bind estrogen receptors (ERs) and mediate activity similar to physiological estrogens. Thus, research on DES may serve as a template to study a growing list of endocrine disruptors. Studies from our lab demonstrated for the first time that prenatal and postnatal exposure to estradiol (E2) and DES can induce apoptosis in thymocytes, alter the expression of T cell receptor and CD molecules, and modulate positive and negative selection of T cells. In the current study, we will test the central hypothesis that prenatal exposure to DES alters the positive and/or negative selection of T cells in the thymus leading to generation of skewed T cell repertoire with enhanced reactivity towards self antigens and decreased response against non-self antigens. In aim# 1, we will investigate whether the regulation of Fas and Fas ligand genes involves estrogen responsive elements (ERE) and other transcription factors. Aim# 2 will test if prenatal exposure to DES alters positive and negative selection of T cells in the thymus and thereby skewing the immune responsiveness of mature T cells to self rather than non-self antigens. Aim# 3 will investigate the role of ERa in DES induced apoptosis and development of autoimmunity. Also, the role of T cell-stromal cell interactions in DES-induced thymocyte apoptosis will be studied. In Aim# 4, the mechanism by which prenatal DES exposure leads to increased susceptibility to autoimmune disease postnatally will be tested. Together, the studies proposed should provide novel information on the mechanism by which prenatal exposure to DES leads postnatally to increased susceptibility to autoimmunity and cancer and to development of potential approaches to prevent such immunotoxicity. PUBLIC HEALTH RELEVANCE: There has been a high incidence of cancers as well as autoimmune diseases observed in women who were prescribed during pregnancy, a synthetic estrogen known as diethylstilbestrol, as well as in their sons and daughters. Postmenopausal women administered estrogens in hormone replacement therapy, as well as, several chemicals found in the environment and foods act as estrogens causing significant health problems. Thus, our studies are aimed at providing insights into the mechanism by which estrogens mediate their toxic effects on the immune system, thereby leading to the development of strategies for their prevention and treatment.

描述（由申请人提供）：雌激素在健康和疾病方面有广泛的应用。绝经后妇女接受雌激素替代疗法，以缓解她们的更年期症状。在1940-1975年间，估计有5-10万美国人在怀孕期间或在子宫内接触过己烯雌酚（DES），这是一种合成雌激素。暴露于DES与“DES母亲”患乳腺癌的风险增加和“DES女儿”终生患宫颈癌的风险增加有关。暴露于DES也与“DES儿子和女儿”的各种异常有关，包括免疫系统疾病，如自身免疫、癌症和某些感染的发病率增加。此外，已经确定了一些异种雌激素，包括环境雌激素和植物雌激素，它们结合雌激素受体（er）并介导类似生理雌激素的活性。因此，对DES的研究可以作为一个模板来研究越来越多的内分泌干扰物。我们实验室的研究首次证明，产前和产后暴露于雌二醇（E2）和DES可以诱导胸腺细胞凋亡，改变T细胞受体和CD分子的表达，调节T细胞的阳性和阴性选择。在目前的研究中，我们将验证一个中心假设，即产前暴露于DES会改变胸腺中T细胞的阳性和/或阴性选择，导致T细胞库扭曲，对自身抗原的反应性增强，对非自身抗原的反应性降低。在目标# 1中，我们将研究Fas和Fas配体基因的调控是否涉及雌激素反应元件（ERE）和其他转录因子。目的2将测试产前暴露于DES是否会改变胸腺中T细胞的阳性和阴性选择，从而扭曲成熟T细胞对自身抗原而非非自身抗原的免疫反应。目的3将探讨ERa在DES诱导的细胞凋亡和自身免疫发展中的作用。此外，还将研究T细胞-基质细胞相互作用在des诱导胸腺细胞凋亡中的作用。在Aim# 4中，将测试产前DES暴露导致出生后自身免疫性疾病易感性增加的机制。总之，提出的研究应提供关于产前暴露于DES导致出生后对自身免疫和癌症易感性增加的机制的新信息，以及开发预防此类免疫毒性的潜在方法。