Ovariectomy Induced T Cell Inflammatory Cytokines/Bone Loss in Young & Old Mice

卵巢切除术诱导年轻人 T 细胞炎症细胞因子/骨质流失

• 批准号: 7906811
• 负责人: ROBERTO PACIFICI
• 金额: $ 29.55万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7906811
• 关键词: Age; Aging; Aging-Related Process; Antigen Presentation; Antigens; Attenuated; Bone Formation Stimulation; Bone Marrow; Bone Resorption; CD8B1 gene; Castration; Cells; Clinical; Data; Disease; Estrogens; Home environment; Homing; Immune Tolerance; Immune system; Inflammation Mediators; Inflammatory; Integrins; Knockout Mice; Lead; Link; Longevity; Lymphoid; Mediating; Mediator of activation protein; Menopause; Modeling; Mus; Nude Mice; Organ; Osteoclasts; Osteoporosis; Output; Ovarian; Ovariectomy; Peptide/MHC Complex; Peptides; Peripheral; Phenotype; Play; Postmenopausal Osteoporosis; Production; Public Health; Role; Source; T cell response; T memory cell; T-Lymphocyte; TNF gene; Testing; Up-Regulation; Woman; bone; bone loss; cytokine; design; disease characteristic; in vivo; new therapeutic target; prevent; reconstitution; senescence; stem; wasting; young adult

DESCRIPTION (provided by applicant): Postmenopausal osteoporosis (PMO) is a frequent disease of aging women stemming from the cessation of ovarian function at menopause. Studies in ovariectomized (ovx) mice, an established model of PMO, have disclosed that enhanced production of TNF by an expanded pool of activated T cells plays a key role in the mechanism of ovx induced bone loss. However, it is presently unknown if ovx causes bone loss by stimulating T cell TNF production exclusively in the BM (as opposed to enhancing T cell TNF production in all lymphoid organs). Thus, in aim 1 we will determine: a) if ovx alters the phenotype and the number of T cells which home to bone, b) whether the suppression of T cell homing to the BM (via treatment with anti- LFA-1a and anti-integrin a4 subunit) prevents ovx induced bone loss, and c) if ovx causes bone loss in mice lacking the secondary lymphoid organs. Our data show that estrogen (E) deficiency causes a rebound in thymic T cell output that contributes to the T cell pool expansion and the bone loss induced by ovx in young adult mice. The resurgence of thymic activity induced by E deficiency is attenuated in older mice and we hypothesize that such diminished rebound in thymic T cell export mitigates the capacity of ovx to induce bone loss in older mice. Thus, in Aim 2 we will utilize thymectomized/ovx mice to determine the contribution of thymic T cell output to ovx-induced bone loss in aging mice. Both aging and castration decrease immune tolerance. Accordingly, our data show that ovx increases MHC expression and antigen presentation, suggesting that ovx induces higher MHC mediated presentation of self peptides. We hypothesize that this enhanced T cell response to self-peptide/MHC is essential for ovx-induced bone loss. We will test this hypothesis by: a) determining the contribution of MHC expression to ovx induced bone loss, b) testing if the response of T cells to self-peptide/MHC changes after ovx, c) determining if there is a change in the T cell repertoire after ovx due to an oligoclonal expansion of self-reactive T cells, and d) investigating if ovx breaks tolerance to a defined antigen. The project fulfills the objective of this RFA, that is to solicits applications designed to determine either the causes of the changes in inflammatory mediators induced by aging (including studies on the source of the altered cytokine production), or the consequences of such changes in conditions and diseases characteristic of senescence. This project is also relevant for public health as may lead to a better characterization of the mechanism of action of E in bone at different ages, demonstrate a link between the immune system and bone, and identify novel therapeutic targets for osteoporosis.

描述（由申请人提供）：绝经后骨质疏松症（PMO）是一种经常出现衰老的妇女疾病，该疾病是由于更年期卵巢功能的停止而引起的。既定的PMO模型卵巢切除（OVX）小鼠的研究揭示了通过扩展的活化T细胞池增强TNF的产生，在OVX诱导的骨损失机理中起着关键作用。但是，目前尚不清楚OVX是否通过仅在BM中刺激T细胞TNF产生而导致骨质损失（而不是增强所有淋巴机器人的T细胞TNF产生）。因此，在目标1中，我们将确定：a）a）如果OVX改变了骨头家的表型和T细胞的数量，b）b）抑制T细胞向BM抑制（通过用抗LFA-1A进行处理和抗LFA-1A和抗融合蛋白A4亚基）是否会导致OVX会导致OVX诱导的骨骼损失，以及c）在小鼠中导致ovx造成骨骼损失，从而导致小鼠缺少overs ogg sect org or gynary or gry lym lym。 我们的数据表明，雌激素（E）缺乏会导致胸腺T细胞输出反弹，这有助于T细胞池的扩张和OVX在年轻小鼠中引起的骨质流失。 E型缺乏症引起的胸腺活性的复苏在老鼠中会减弱，我们假设胸腺T细胞中的这种反弹减弱可降低OVX诱导老鼠骨质流失的能力。因此，在AIM 2中，我们将利用胸腺切除/OVX小鼠来确定胸腺T细胞输出对OVX诱导的老化小鼠的骨质损失的贡献。 衰老和cast割都会降低免疫耐受性。因此，我们的数据表明OVX增加了MHC的表达和抗原表现，这表明OVX诱导了更高的MHC介导的自肽介绍。我们假设这种增强的T细胞对自肽/MHC的反应对于OVX诱导的骨质流失至关重要。 We will test this hypothesis by: a) determining the contribution of MHC expression to ovx induced bone loss, b) testing if the response of T cells to self-peptide/MHC changes after ovx, c) determining if there is a change in the T cell repertoire after ovx due to an oligoclonal expansion of self-reactive T cells, and d) investigating if ovx breaks tolerance to a defined antigen. 该项目实现了该RFA的目标，即旨在确定衰老引起的炎症介质变化的原因（包括对改变细胞因子产生改变的来源）的原因，或者是衰老典型和疾病的这种变化的后果。 该项目也与公共卫生有关，可能导致对E骨在不同年龄的骨骼作用机理的更好表征，展示免疫系统与骨骼之间的联系，并确定骨质疏松症的新型治疗靶标。