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Development of Pharmacological Treatment of Osteochondromas

Development of Pharmacological Treatment of Osteochondromas
骨软骨瘤药物治疗研究进展
批准号:
10460410
负责人:
MOTOMI ENOMOTO-IWAMOTO
金额:
$30.29万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-02-01 至 2024-01-31

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中文摘要
翻译
摘要 骨软骨瘤是儿童或青春期最常见的骨骼肿瘤。肿瘤 随着时间的推移而增长,并导致骨骼畸形、神经压迫、疼痛和其他健康问题。 骨软骨瘤主要通过手术治疗,因此多发性骨软骨瘤的治疗可能 需要重复手术。位于手术高危部位的骨软骨瘤可以进行非手术治疗 然而,在外科手术中,这增加了向恶性软骨肉瘤发展的可能性。最终目标 该项目的核心是开发非手术疗法,以阻止骨软骨瘤的形成和生长。 举止得力。多发性骨软骨瘤可由硫酸乙酰肝素合成酶突变引起 EXT1或EXT2。我们实验室和其他研究小组的研究表明,硫酸肝素的减少 诱导多种信号通路的改变,导致骨软骨瘤。我们对此的长期研究 核维甲酸受体γ揭示:(1)药理激活视黄酸受体γ强烈抑制 异位软骨形成;(2)RARγ在小鼠和人软骨细胞中表达 骨软骨瘤;(3)RARγ激动剂抑制异位软骨形成和诱导退缩。 存在软骨瘤肿块的小鼠骨软骨瘤模型。我们假设RARγ可以 是一种新型的抗软骨生成和促进骨软骨瘤的药物治疗靶点。 肥大作用。骨软骨瘤的细胞起源尚不清楚。我们最近发现了一种 新的软骨前体细胞群有助于生长板的对位宽度生长。这些 细胞是Wnt反应的骨骼祖细胞,存在于生长板和邻近的软骨膜中。 我们假设这些前体细胞的异常调节诱导骨软骨瘤和RARγ信号转导 改善他们改变的本性。为了验证这些假设,我们提出了三个目标:目标1,建立 RARγ激动剂对小鼠骨软骨瘤的治疗作用及其分子作用研究 模型;目标2,确定促进骨软骨瘤形成和生长的细胞及其 以及Aim3,以研究RARγ激动剂对人类的作用 骨软骨瘤细胞。这项研究涉及多种实验程序,包括药物治疗和 小鼠,组织学和分子生物学评价小鼠疾病模型,高通量基因 人肿瘤细胞的表达分析与研究。该项目将测试创新想法在 骨软骨瘤的发病机制,以及如何从治疗上对抗它们的同样创新的想法。
英文摘要
Abstract Osteochondromas are the most common skeletal tumors during childhood or adolescence. The tumors grow over time and cause skeletal deformities, nerve compression, pain and other health problems. Osteochondromas are primarily treated surgically and thereby treatment for multiple osteochondromas may require repetitive surgery. Osteochondromas located at a high-risk site for surgery may be managed non- surgically, however, this increases the potential for progression to malignant chondrosarcomas. The final goal of this project is to develop non-surgical therapies that would stop osteochondroma formation and growth in an effective manner. Multiple osteochondromas can be caused by mutations in the heparan sulfate synthases EXT1 or EXT2. Research from our lab and other groups have indicated that reduction in heparan sulfate induce alterations of multiple signaling pathways, leading to osteochondromas. Our long-term studies on nuclear retinoic acid receptor gamma (RARγ) reveal that (1) pharmacologic activation of RARγ strongly inhibits ectopic cartilage formation; (2) RARγ is expressed in cartilage elements in mouse and human osteochondromas; and (3) RARγ agonists inhibited ectopic cartilage formation and induced involution of existing cartilaginous tumor masses in the osteochondroma mouse model. We hypothesize that RARγ could be a novel pharmaco-therapeutic target for osteochondromas by an anti-chondrogenic action and pro- hypertrophic action. The cell origin of osteochondromas remains to be clarified. We have recently discovered a novel cell population of chondroprogenitors contributing to appositional width growth of growth plate. These cells are Wnt-responsive skeletal progenitors and reside in growth plate and the neighboring perichondrium. We hypothesize that aberrant regulation of these progenitors induce osteochondromas and RARγ signaling ameliorates their altered nature. To test these hypotheses, we propose three aims: Aim 1, To establish therapeutic efficacy of RARγ agonists and examine their molecular actions in the mouse osteochondroma model; Aim 2, To determine the cells that contribute to osteochondroma formation and growth and their response to RARγ signaling; and Aim3, To investigate the actions of RARγ agonists on human osteochondroma cells. The study involves diverse experimental procedures encompassing drug treatment with mice, histological and molecular biological assessments of the mouse disease models, high throughput gene expression analysis and study on human tumor cells. The Project will test innovative ideas on the pathogenesis of osteochondroma and equally innovative ideas on how to combat them therapeutically.
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The role of myosin II in tendon repair under glucose control
  • 批准号:
    10649584
  • 项目类别:
  • 资助金额:
    $16.1万
  • 财政年份:
    2022
  • 负责人:
    MOTOMI ENOMOTO-IWAMOTO
  • 依托单位:
The role of myosin II in tendon repair under glucose control
  • 批准号:
    10440751
  • 项目类别:
  • 资助金额:
    $20.12万
  • 财政年份:
    2022
  • 负责人:
    MOTOMI ENOMOTO-IWAMOTO
  • 依托单位:
Development of Pharmacological Treatment of Osteochondromas
  • 批准号:
    10571866
  • 项目类别:
  • 资助金额:
    $30.59万
  • 财政年份:
    2019
  • 负责人:
    MOTOMI ENOMOTO-IWAMOTO
  • 依托单位:
Stimulation of tendon repair by retinoid nuclear receptor agonists
  • 批准号:
    8582078
  • 项目类别:
  • 资助金额:
    $22.19万
  • 财政年份:
    2013
  • 负责人:
    MOTOMI ENOMOTO-IWAMOTO
  • 依托单位:
国内基金
海外基金
Agonist-GPR119-Gs复合物的结构生物学研究
  • 批准号:
    32000851
  • 项目类别:
    青年科学基金项目
  • 资助金额:
    24.0万元
  • 批准年份:
    2020
  • 负责人:
    乔安娜
  • 依托单位: