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IMMUNOLOGICAL ASPECTS OF HEMORRHAGE

IMMUNOLOGICAL ASPECTS OF HEMORRHAGE
出血的免疫学方面
批准号:
2857116
负责人:
IRSHAD H CHAUDRY
金额:
$38.07万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
1988
资助国家:
美国
项目状态:
已结题
起止时间:
1988-04-01 至 2003-03-31

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中文摘要
翻译
我们最近的研究表明,发情前雌性小鼠[与周期-
英文摘要
Our recent studies indicate that proestrus female mice [with cycle- increased levels of estrogen and prolactin (PRL)] have improved immune responses after trauma-hemorrhage as opposed to markedly depressed responses in males. Moreover, the survival rate of proestrus females following sepsis after trauma-hemorrhage was significantly higher than age-matched males. In contrast to young proestrus mice, aged females (defined by lowered estradiol levels) show marked immunosuppression after trauma. Our hypothesis, therefore, is that it is the high estradiol or a high estradiol: androgen ratio which directly (receptor- mediated) or indirectly (receptor-independent) enhance immune functions in proestrus females, and the loss of these estrogenic effects may contribute to the failure to maintain immune responses in aged females after trauma-hemorrhage. Studies are proposed to determine the mechanism of regulation of estradiol and estrone by hypothalamic/pituitary factors adrenals and aromatase activity and determine how differences in estradiol levels or the estradiol: androgen ratio due to the estrus cycle, ovariectomy (OVX, in middle aged mice to reduce estrogen), and age affect immune responses after trauma. Sex steroids (SS) receptor- mediated and receptor-independent gene activation mechanisms will be studied in T-cells and macrophages (Mphi). Since activation of AF-1 and AF-2 regions of estrogen receptor (ER) is critical for agonist and antagonist effects, activation of the ER agonist regions by estrogens in T-lymphocytes will be evaluated by transfection studies. Moreover, since SS non-ligand response also involve [Ca2+]i mobilization, T cells and Mphi will be examined for Ca2+ signal transduction and the expression and translocation of PKC isoforms. The release of TH1 and TH2 cytokines and IL-6 and the effects of PRL on their release in proestrus, OVX, aged, ER-, and PRL-knockout mice will also be evaluated. Additionally, the effect of SS on PRL and TH1 and TH2 cytokine-induced JAK-STAT expressions will be evaluated. Analysis of bone marrow for lymphoblastoid/myeloblastoid cell composition, and the effect of SS on the population of these cells will be determined. We will evaluate if administration of beta-estradiol, Raloxifene or PRL in vivo after trauma-hemorrhage improves the depressed immune responses in estrogen deficient mice. If a single dose is ineffective, multiple doses of these drugs with or without gonadotropin releasing hormone (GnRH) or flutamide (androgen receptor antagonist) will be administered to determine whether synergistic beneficial effects on immune responses are produced and whether the susceptibility to sepsis after trauma is decreased. Detailed mechanistic studies of T cell and Mphi functions using molecular biological techniques to determine why low estradiol fails to maintain immune functions in aged females after trauma and the use of estradiol, Raloxifene, PRL, GnRH or flutamide to restore immune functions should yield novel information and provide an innovative approach for improving the immune responses and reducing mortality from sepsis following trauma-hemorrhage in postmenopausal as well as in surgically OVX patients with low estrogen activity.
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会议论文
TRAUMA AND INFLAMMATION RESEARCH TRAINING
Trauma and Inflammation Research Training
TRAUMA AND IMFLAMMATION RESEARCH TRAINING
TRAUMA AND INFLAMMATION RESEARCH TRAINING
国内基金
海外基金
运动对骨骼肌 Aromatase/17β-estradiol 通路的影响及功能研究
  • 批准号:
    19ZR1452900
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2019
  • 负责人:
    史仍飞
  • 依托单位: