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: 7849241
• 负责人: ROBERTO PACIFICI
• 金额: $ 1.86万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849241
• 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 memory cell; T-Lymphocyte; TNF gene; Testing; Up-Regulation; Woman; bone; bone loss; cytokine; design; disease characteristic; in vivo; new therapeutic target; prevent; reconstitution; response; 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（申请人提供）：绝经后骨质疏松症（PMO）是老年女性的常见疾病，源于更年期卵巢功能的停止。对卵巢切除 (ovx) 小鼠（一种已建立的 PMO 模型）的研究表明，通过扩大活化 T 细胞库来增强 TNF 的产生，在 ovx 诱导的骨质流失机制中发挥着关键作用。然而，目前尚不清楚 ovx 是否仅通过刺激 BM 中的 T 细胞 TNF 产生（而不是增强所有淋巴器官中的 T 细胞 TNF 产生）而导致骨质流失。因此，在目标 1 中，我们将确定：a) ovx 是否改变表型和归巢到骨的 T 细胞数量，b) 抑制 T 细胞归巢到 BM（通过抗 LFA-1a 和抗整合素 a4 亚基治疗）是否可以防止 ovx 诱导的骨质流失，以及 c) ovx 是否会导致缺乏次级淋巴器官的小鼠骨质流失。 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，从而导致年轻成年小鼠 T 细胞库扩张和 ovx 引起的骨质流失。 E 缺乏引起的胸腺活性的复苏在老年小鼠中减弱，我们假设胸腺 T 细胞输出反弹的减弱减弱了 ovx 诱导老年小鼠骨质流失的能力。因此，在目标 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 诱导的衰老小鼠骨质流失的贡献。 衰老和阉割都会降低免疫耐受性。因此，我们的数据显示 ovx 增加 MHC 表达和抗原呈递，表明 ovx 诱导更高的 MHC 介导的自身肽呈递。我们假设这种增强的 T 细胞对自身肽/MHC 的反应对于 ovx 诱导的骨质流失至关重要。我们将通过以下方式检验这一假设：a) 确定 MHC 表达对 ovx 诱导的骨质流失的贡献，b) 测试 ovx 后 T 细胞对自身肽/MHC 的反应是否发生变化，c) 确定 ovx 后 T 细胞库是否因自身反应性 T 细胞的寡克隆扩增而发生变化，以及 d) 调查 ovx 是否会破坏对特定抗原的耐受性。 该项目实现了本次 RFA 的目标，即征集旨在确定衰老引起的炎症介质变化的原因（包括对细胞因子产生改变的来源的研究）或衰老特征的条件和疾病变化的后果的申请。 该项目还与公共健康相关，因为可能会更好地表征不同年龄骨骼中 E 的作用机制，证明免疫系统与骨骼之间的联系，并确定骨质疏松症的新治疗靶点。