Regulation of hemopoietic stem cell expansion by calciotrophic hormones

钙营养激素对造血干细胞扩增的调节

• 批准号: 8097069
• 负责人: ROBERTO PACIFICI
• 金额: $ 40.11万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8097069
• 关键词: Accounting; Acute; Affect; Apoptosis; Binding; Biology; Bone Marrow; Bone Marrow Cells; Bone Marrow Stem Cell Transplantation; CD40 Antigens; CD8B1 gene; Cells; Data; Distal; Estrogen Antagonists; Estrogens; Figs - dietary; Future; Goals; Hormones; Human; Hyperparathyroidism; Interdisciplinary Study; Interleukin-6; Laboratories; Lead; Ligands; Mediating; Menopause; Modeling; Mus; Osteoblasts; Outcome; Ovariectomy; Parathyroid Hormone Receptor; Parathyroid gland; Pathway interactions; Play; Premenopause; Production; Proteins; Public Health; Publishing; Regulation; Reporting; Research Personnel; Role; Signal Transduction; Source; Stem cell transplant; Stem cells; Stromal Cells; T-Cell Receptor; T-Lymphocyte; TNFSF5 gene; Transplantation; Woman; base; bone; bone cell; cytokine; deprivation; design; improved; in vivo; jagged1 protein; notch protein; novel; novel strategies; osteogenic; parathyroid hormone-related protein; prevent; receptor; self-renewal; stem cell biology; stem cell population

DESCRIPTION (provided by applicant): The goal of this application is to determine how T lymphocytes increase the capacity of ovariectomy (ovx) and parathyroid hormone (PTH) to expand hemopoietic stem cells (HSCs). Ovx is known to increase the number of hemopoietic cells in the bone marrow (BM) and our preliminary data show that ovx increase the number of HSCs in T lymphocyte replete but not T lymphocyte deficient mice. Preliminary data show that T lymphocytes contribute to the HSC expansion induced by ovx by expressing the costimulatory molecule CD40L and by secreting soluble IL-6 receptor (sIL-6R), a receptor subunit required for HSCs to respond to the hemopoietic cytokine IL-6. Data also show that blockade of the T lymphocytes costimulatory molecule CD40L prevents T lymphocytes from upregulating stromal cells (SCs) Jagged1 and IL-6 expression. Jagged1 is a Notch ligand which activates Notch signaling in HSCs. IL-6 is a hemopoietic cytokine. Based on these data we hypothesize that ovx expands HSCs through T cell CD40L mediated stimulation of SC Jagged1 and IL-6 production. PTH has been shown to expand HSCs by upregulating the SC expression of Jagged1 and IL-6. Our preliminary data show that PTH fails to increase the number of HSCs in T cell deficient mice and in mice lacking the T cell costimulatory molecule CD40L. Additional data show that PTH does not increase the number of HSCs in mice expressing a silent PTH receptor in T cells, implying a role for direct targeting of T cells by PTH. We also hypothesize that T cell contribute to the HSC expansion induced by PTH by inducing the activation of Wnt signaling in SCs. In Specific Aim 1 we will determine the mechanism by which T cells contribute to expansion of HSCs induced by PTH. Specifically we will investigate the role of T cell produced factors including Wnt ligands, sIL-6R, and CD40L in activating Wnt signaling in SCs and Notch signaling in HSCs. In Specific Aim 2 we will determine whether direct targeting of T cells by PTH is required for the hormone to induce the expansion of HSCs. This will be accomplished by utilizing a mouse generated in our laboratory which expresses a silent PTH receptor in T cells. In Specific Aim 3 we will investigate the role the role of T lymphocytes produced Wnt ligands, sIL-6R, and CD40L in activating Wnt signaling in SCs and Notch signaling in HSCs in ovx mice. Lack of information about the mechanisms by which ovx and PTH expand HSCs through T cells is a critical barrier to progress of the understanding the cross-talk between hemopoietic cells and bone cells. Our proposal has the potential to decrease this barrier. If the aims of the projects are achieved our understanding of the mechanism of action of two key calciotrophic hormones, estrogen and parathyroid hormone, will be increased. New data about the role of T lymphocytes in the mechanism by which estrogen and PTH regulate HSCs will increase the scope and the depth of osteoimmunology, a novel field of multidisciplinary research. PUBLIC HEALTH RELEVANCE: New discoveries about the mechanism of action of estrogen and parathyroid hormone are relevant to public health as it may lead to the identification of novel strategies for improving the outcome of HSC transplantation in humans and for understanding the impact of menopause and hyperparathyroidism on hemopoiesis.

描述（由申请人提供）：本申请的目的是确定 T 淋巴细胞如何提高卵巢切除术 (ovx) 和甲状旁腺激素 (PTH) 扩增造血干细胞 (HSC) 的能力。已知 ovx 可以增加骨髓 (BM) 中造血细胞的数量，我们的初步数据表明，ovx 可以增加 T 淋巴细胞充足的小鼠中的 HSC 数量，但不会增加 T 淋巴细胞缺乏的小鼠中的 HSC 数量。初步数据显示，T淋巴细胞通过表达共刺激分子CD40L和分泌可溶性IL-6受体（sIL-6R）来促进ovx诱导的HSC扩张，sIL-6R是HSC响应造血细胞因子IL-6所需的受体亚基。数据还表明，阻断 T 淋巴细胞共刺激分子 CD40L 可防止 T 淋巴细胞上调基质细胞 (SC) Jagged1 和 IL-6 的表达。 Jagged1 是一种 Notch 配体，可激活 HSC 中的 Notch 信号传导。 IL-6是一种造血细胞因子。基于这些数据，我们假设 ovx 通过 T 细胞 CD40L 介导的 SC Jagged1 和 IL-6 产生刺激来扩增 HSC。 PTH 已被证明可以通过上调 Jagged1 和 IL-6 的 SC 表达来扩增 HSC。我们的初步数据表明，PTH 无法增加 T 细胞缺陷小鼠和缺乏 T 细胞共刺激分子 CD40L 的小鼠中 HSC 的数量。其他数据表明，PTH 不会增加 T 细胞中表达沉默 PTH 受体的小鼠中 HSC 的数量，这意味着 PTH 具有直接靶向 T 细胞的作用。我们还假设 T 细胞通过诱导 SC 中 Wnt 信号的激活来促进 PTH 诱导的 HSC 扩增。在具体目标 1 中，我们将确定 T 细胞促进 PTH 诱导的 HSC 扩增的机制。具体来说，我们将研究 T 细胞产生的因子（包括 Wnt 配体、sIL-6R 和 CD40L）在激活 SC 中的 Wnt 信号传导和 HSC 中的 Notch 信号传导中的作用。在具体目标 2 中，我们将确定激素诱导 HSC 扩增是否需要 PTH 直接靶向 T 细胞。这将通过利用我们实验室培育的小鼠来实现，该小鼠在 T 细胞中表达沉默的 PTH 受体。在具体目标 3 中，我们将研究 T 淋巴细胞产生的 Wnt 配体、sIL-6R 和 CD40L 在激活 ovx 小鼠 SC 中的 Wnt 信号传导和 HSC 中的 Notch 信号传导中的作用。缺乏关于 ovx 和 PTH 通过 T 细胞扩增 HSC 的机制的信息，是理解造血细胞和骨细胞之间相互作用的一个关键障碍。我们的建议有可能减少这一障碍。如果这些项目的目标得以实现，我们对两种关键的促钙激素（雌激素和甲状旁腺激素）作用机制的了解将会加深。关于 T 淋巴细胞在雌激素和 PTH 调节 HSC 机制中的作用的新数据将扩大骨免疫学这一多学科研究的新领域的范围和深度。 公共健康相关性：关于雌激素和甲状旁腺激素作用机制的新发现与公共健康相关，因为它可能导致确定新策略，以改善人类 HSC 移植的结果，并了解更年期和甲状旁腺功能亢进症对健康的影响。造血作用。