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)是老年妇女的一种常见疾病，源于绝经时卵巢功能的停止。在卵巢切除(OVX)小鼠上的研究表明，通过扩大活化的T细胞池来促进肿瘤坏死因子的产生在OVX诱导的骨丢失机制中起着关键作用。然而，目前尚不清楚去卵巢是否通过刺激骨髓中的T细胞肿瘤坏死因子的产生(而不是促进所有淋巴器官中的T细胞肿瘤坏死因子的产生)而导致骨丢失。因此，在目标1中，我们将确定：a)OVX是否改变了归巢于骨的T细胞的表型和数量，b)抑制归巢于BM的T细胞(通过抗LFA-1a和抗整合素A4亚单位治疗)是否防止了OVX导致的骨丢失，以及c)OVX是否导致缺乏次级淋巴器官的小鼠的骨丢失。 我们的数据表明，雌激素(E)缺乏导致胸腺T细胞输出的反弹，这有助于T细胞库的扩大和OVX导致的幼年小鼠的骨丢失。在老年小鼠中，E缺乏诱导的胸腺活动的恢复是减弱的，我们假设这种胸腺T细胞输出的减少反弹减轻了OVX诱导老年小鼠骨质丢失的能力。因此，在目标2中，我们将利用去胸腺/去卵巢小鼠来确定胸腺T细胞输出在去卵巢诱导的衰老小鼠骨丢失中的作用。 衰老和阉割都会降低免疫耐受性。因此，我们的数据显示，OVX增加了MHC的表达和抗原递呈，这表明OVX诱导更高的MHC介导的自体肽递呈。我们推测，这种增强的T细胞对自体多肽/MHC的反应是OVX诱导的骨丢失的关键。我们将通过以下方法验证这一假设：a)确定MHC表达在OVX诱导的骨丢失中的作用；b)测试OVX后T细胞对自体多肽/MHC的反应是否发生变化；c)确定OVX后T细胞是否由于自身反应性T细胞的寡克隆扩增而发生变化；以及d)研究OVX是否打破了对特定抗原的耐受性。 该项目实现了这一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(包括对改变的细胞因子产生的来源的研究)的申请，或这种衰老条件和疾病的变化的后果。 该项目也与公众健康有关，可能导致更好地描述E在不同年龄的骨骼中的作用机制，展示免疫系统与骨骼之间的联系，并确定治疗骨质疏松症的新靶点。