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Intracellular trafficking of Bisphosphonates in bone mesenchymal Stem Cells

骨髓间充质干细胞中双磷酸盐的细胞内运输

基本信息

批准号：
8356486
负责人：
Sunday O Akintoye
金额：
$ 24万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8356486
关键词：
AKT inhibition Accounting Acute Animal Disease Models Animal Model Apoptosis Attenuated Bone Marrow Bone Matrix Bone Resorption Bone Transplantation Bone necrosis Calcium Channel Cell Differentiation process Cell Survival Cell Therapy Cells Chronic Complication Cytosol Dental Deposition Endocytic Vesicle Endocytosis Enzymes Extracellular Space Goals Healed Human In Vitro Inflammation Ions Jaw Label Life Link Lipids Liquid substance Location Lytic Metastatic Lesion Malignant neoplasm of prostate Measures Mesenchymal Stem Cells Mesoderm Metastatic Neoplasm to the Bone Modeling Monomeric GTP-Binding Proteins Multiple Myeloma Necrosis Neoplasm Metastasis Neural Crest Nitrogen Operative Surgical Procedures Oral Osteoclasts Osteoporosis Outcome Paget&apos s Disease Pathway interactions Phase Phosphorylation Population Preventive Process Production Protein Isoprenylation Proteins Rattus Relative (related person)Signal Pathway Signaling Protein Site Specificity Stem cells Stromal Cells Surrogate Markers Transplantation base bisphosphonate bone bone turnover cancer cell cellular imaging cofactor cytotoxic design effective therapy farnesyl pyrophosphate geranylgeranyl pyrophosphate healing improved in vivo insight isoprenoid long bone malignant breast neoplasm mandible/maxilla mevalonate microbial orofacial osteogenic osteoprogenitor cell prenylation prevent rho senescence trafficking tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Nitrogen-containing bisphosphonates (n-BP) effectively control dysregulated bone turnover, osteolytic lesions of cancer metastasis and have anti-tumor activities. Unfortunately, osteonecrosis of the jaw (ONJ) is a major complication of n-BP therapy. Reasons for jaw-specific location of n-BP related osteonecrosis are unclear making it challenging to design targeted therapies. n-BPs act on osteoclasts and cancer cells by blocking the farnesyl pyrophosphate (FPP) synthase in the mevalonate signaling pathway; the outcome is loss of prenylation of small GTPase signaling proteins and dysregulation of cell survival and differentiation. We have shown that orofacial bone marrow stromal cells or bone mesenchymal stem cells (BMSCs) from neural crest-derived maxilla/mandible (OFMSCs) are highly proliferative with long population doublings relative to those of mesoderm-derived iliac bone (ICMSCs) and long bones (LBMSCs). Therefore, they may readily succumb to n-BP similar to rapidly proliferative cancer cells. Our preliminary studies showed that OFMSCs are indeed more sensitive to n-BP than ICMSCs based on enhanced n-BP uptake, slow elimination from the cytosol, decreased survival and decreased osteogenic differentiation. We hypothesize that sensitivity of OFMSCs to n-BP contributes in part to initiation of ONJ based on site-dependent n-BP uptake, intracellular processing, inhibition of FPP synthase in the mevalonate pathway and consequent loss of prenylation of small GTPase signaling proteins. In aim 1 we will determine how uptake and intracellular trafficking of n-BP in OFMSCs modulates survival and aim 2 will explore BMSC-based therapy to prevent ONJ in a small animal model. The goal is to formulate preventive measures for ONJ. PUBLIC HEALTH RELEVANCE: Bisphosphonate is an effective therapy for bone complications associated with cancer metastasis but a major complication is jaw bone necrosis. We want to understand how jaw bone stem cells readily succumb to effects of bisphosphonate so the complication of jaw necrosis can be prevented.

描述（申请人提供）：含氮双膦酸盐（n-BP）可有效控制骨转换失调、癌症转移的溶骨性病变，并具有抗肿瘤活性。不幸的是，颌骨坏死 (ONJ) 是 n-BP 治疗的主要并发症。 n-BP 相关骨坏死的颌特异性位置的原因尚不清楚，这使得设计靶向治疗具有挑战性。 n-BP 通过阻断甲羟戊酸信号通路中的法尼基焦磷酸 (FPP) 合酶来作用于破骨细胞和癌细胞；结果是小 GTP 酶信号蛋白的异戊二烯化丧失以及细胞存活和分化的失调。我们已经证明，相对于中胚层来源的髂骨（ICMSCs）和长骨（LBMSCs），来自神经嵴来源的上颌骨/下颌骨（OFMSCs）的口面部骨髓基质细胞或骨间充质干细胞（BMSCs）具有高度增殖性，并且群体倍增时间较长。因此，它们可能很容易屈服于 n-BP，类似于快速增殖的癌细胞。我们的初步研究表明，OFMSC 确实比 ICMSC 对 n-BP 更敏感，因为 n-BP 摄取增强、细胞质消除缓慢、存活率降低和成骨分化减少。我们假设 OFMSC 对 n-BP 的敏感性部分有助于基于位点依赖性 n-BP 摄取、细胞内加工、甲羟戊酸途径中 FPP 合酶的抑制以及随后小 GTPase 信号蛋白异戊二烯化的 ONJ 启动。在目标 1 中，我们将确定 OFMSC 中 n-BP 的摄取和细胞内运输如何调节存活，目标 2 将探索基于 BMSC 的疗法，以在小动物模型中预防 ONJ。目标是制定 ONJ 的预防措施。公众健康相关性：双磷酸盐是治疗与癌症转移相关的骨并发症的有效疗法，但主要并发症是颌骨坏死。我们想了解颌骨干细胞如何容易屈服于双磷酸盐的作用，从而可以预防颌骨坏死的并发症。