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: 8703679
• 负责人: ROBERTO PACIFICI
• 金额: $ 43.78万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703679
• 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.

描述(申请人提供)：本申请的目标是确定T淋巴细胞如何增加卵巢切除(OVX)和甲状旁腺激素(PTH)的能力以扩大造血干细胞(HSCs)。OVX可以增加骨髓(BM)中的造血细胞数量，我们的初步数据表明，OVX可以增加T淋巴细胞充盈小鼠的HSCs数量，但不能增加T淋巴细胞缺陷小鼠的HSCs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)参与OVX诱导的HSC扩增，sIL-6R是HSC反应造血细胞因子IL-6所需的受体亚单位。数据还显示，阻断T淋巴细胞共刺激分子CD40L可阻止T淋巴细胞上调基质细胞(SCs)Jagged1和IL-6的表达。Jagged1是一种Notch配体，可以激活HSC中的Notch信号。IL-6是一种造血细胞因子。根据这些数据，我们假设OVX通过T细胞CD40L介导的刺激SC Jagged1和IL-6的产生来扩增HSC。甲状旁腺激素通过上调Jagged1和IL-6的SC表达来扩增HSCs。我们的初步数据显示，甲状旁腺素不能增加T细胞缺陷小鼠和缺乏T细胞共刺激分子CD40L的小鼠的HSCs数量。其他数据显示，甲状旁腺素不会增加T细胞中表达沉默的甲状旁腺素受体的小鼠的HSC数量，这意味着甲状旁腺激素直接靶向T细胞的作用。我们还假设，T细胞通过诱导SCs中Wnt信号的激活而参与PTH诱导的HSC的扩增。在特定的目标1中，我们将确定T细胞促进甲状旁腺素诱导的HSCs增殖的机制。具体地说，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SCs中的Wnt信号和HSC中的Notch信号中的作用。在特定的目标2中，我们将确定甲状旁腺素是否需要直接靶向T细胞，以诱导HSCs的扩张。这将通过利用我们实验室培育的一只小鼠来实现，该小鼠在T细胞中表达沉默的PTH受体。在具体目标3中，我们将研究产生Wnt配体、sIL-6R和CD40L的T淋巴细胞在激活去卵巢小鼠SCs中的Wnt信号和激活HSC中的Notch信号中的作用。缺乏关于OVX和PTH通过T细胞扩增HSCs的机制的信息是了解造血细胞和骨细胞之间相互作用的关键障碍。我们的建议有可能降低这一障碍。如果这些项目的目标得以实现，我们对雌激素和甲状旁腺激素这两种关键的钙营养激素的作用机制的了解将会增加。有关T淋巴细胞在雌激素和甲状旁腺素调节HSCs机制中作用的新数据将扩大骨免疫学的范围和深度，这是一个多学科研究的新领域。