Estrogen-T cell Interactions

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。绝经后妇女用雌激素替代疗法治疗以减轻她们的绝经症状。在1940年至1975年期间，估计有500万至1000万美国人在怀孕期间或在子宫内接受了乙烯雌酚（DES），一种合成雌激素。暴露于DES与“DES母亲”乳腺癌风险增加和“DES女儿”宫颈阴道癌终身风险增加有关。暴露于DES也与“DES儿子和女儿”的广泛异常有关，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，已经鉴定了许多异种雌激素，包括环境雌激素和植物雌激素，其结合雌激素受体（ER）并介导类似于生理雌激素的活性。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。本实验室的研究首次证实，出生前后暴露于雌二醇（E2）和DES可诱导胸腺细胞凋亡，改变T细胞受体和CD分子的表达，调节T细胞的正向和负向选择。在目前的研究中，我们将测试的中心假设，产前暴露于DES改变了阳性和/或阴性选择的T细胞在胸腺中，导致产生倾斜的T细胞库与增强对自身抗原的反应性和降低对非自身抗原的反应。目的1：研究雌激素反应元件（ERE）和其他转录因子对Fas和Fas配体基因的调控作用。目标2将测试产前暴露于DES是否改变胸腺中T细胞的阳性和阴性选择，从而使成熟T细胞对自身抗原而不是非自身抗原的免疫应答性发生偏移。目的3研究ER α在DES诱导的细胞凋亡和自身免疫发生中的作用.此外，在DES诱导的胸腺细胞凋亡的T细胞间质细胞相互作用的作用将进行研究。在目标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，提出的研究应提供新的信息机制，产前暴露于DES导致产后增加自身免疫和癌症的易感性，并开发潜在的方法，以防止这种免疫毒性。 公共卫生相关性：在怀孕期间服用一种称为己烯雌酚的合成雌激素的妇女及其子女中观察到癌症和自身免疫性疾病的发病率很高。绝经后妇女在激素替代疗法中给予雌激素，以及在环境和食物中发现的几种化学物质作为雌激素引起严重的健康问题。因此，我们的研究旨在深入了解雌激素介导其对免疫系统的毒性作用的机制，从而制定预防和治疗策略。

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.