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: 8519417
• 负责人: ROBERTO PACIFICI
• 金额: $ 32.52万
• 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/8519417
• 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（由申请人提供）：本申请的目的是确定T淋巴细胞如何增加卵巢切除术（OVX）和甲状旁腺激素（PTH）的能力以扩大造血干细胞（HSC）。已知OVX会增加骨髓（BM）中血压细胞的数量，我们的初步数据表明，OVX会增加T淋巴细胞纤维中的HSC数量，但没有增加T淋巴细胞缺陷的小鼠。初步数据表明，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引起的HSC膨胀，这是HSC所需的受体亚基，该受体亚基需要HSC响应垂直性细胞因子IL-6。数据还表明，T淋巴细胞的封闭性分子CD40L可防止T淋巴细胞上调基质细胞（SCS）JAGGED1和IL-6表达。 JAGGED1是一种缺口配体，可激活HSC中的Notch信号。 IL-6是一种血有细胞因子。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产生的刺激扩展了HSC。已显示PTH通过上调JAGGED1和IL-6的SC表达来扩展HSC。我们的初步数据表明，PTH未能增加T细胞缺陷小鼠的HSC数量和缺乏T细胞共刺激分子CD40L的小鼠。其他数据表明，PTH不会增加表达T细胞中静音PTH受体的小鼠的HSC数量，这意味着通过PTH将T细胞直接靶向T细胞的作用。我们还假设T细胞通过诱导SC中Wnt信号的激活而导致PTH引起的HSC膨胀。在特定目标1中，我们将确定T细胞对PTH诱导的HSC膨胀的促进的机制。具体而言，我们将研究T细胞产生的因子的作用，包括Wnt配体，SIL-6R和CD40L在HSC中激活SCS和Notch信号传导中激活Wnt信号。在特定的目标2中，我们将确定是否需要通过PTH将T细胞直接靶向激素诱导HSC的膨胀。这将通过利用在我们的实验室中产生的小鼠来实现，该实验室在T细胞中表达无声的PTH受体。在特定目标3中，我们将研究产生Wnt配体，SIL-6R和CD40L的T淋巴细胞在OVX小鼠中激活Wnt信号的作用，SIL-6R和CD40L在HSC中激活Wnt信号。缺乏有关OVX和PTH通过T细胞扩展HSC的机制的信息，这是理解肢体细胞和骨细胞之间串扰的进展的关键障碍。我们的提议有可能减少这一障碍。如果实现了这些项目的目标，我们将了解两种关键的钙化激素，雌激素和甲状旁腺激素的作用机理。关于T淋巴细胞在雌激素和PTH调节HSC的机制中的作用的新数据将增加骨气免疫学的范围和深度，这是多学科研究的新领域。