Biological Indicators of Racial Disparity in Ameloblastoma Recurrence

成釉细胞瘤复发的种族差异的生物学指标

基本信息

  • 批准号:
    10540745
  • 负责人:
  • 金额:
    $ 36.43万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-12-14 至 2026-11-30
  • 项目状态:
    未结题

项目摘要

Project Summary Ameloblastoma accounts for 14% of all odontogenic tumors and African-Americans are five times more likely to develop ameloblastoma compared to Caucasians. Despite radical surgery, 10% of ameloblastomas recur and 25% of recurrent ameloblastomas occur in the black racial group. The biological determinants of ameloblastoma racial disparity are unclear and there are no specific biological markers to predict recurrence. Most ameloblastomas display genetic mutations of BRAF that encodes the serine/threonine protein kinase B-Raf, an activator of MAPK/ERK-signaling pathway. BRAF oncogenes induce the expression of key autophagic markers that include LC3, p62 and BECLIN1. High expressions of p62, ATG7 and LC3 have been identified in all variants of ameloblastoma and our in vivo mouse ameloblastoma tumor model displayed elevated LC3 and p62 levels. These suggest ameloblastoma recurrence can be attributed to autophagic cell survival mechanisms of residual invasive neoplastic odontogenic epithelium. Interplay of autophagic regulator BECNLIN1 with RUBICON [Run domain Beclin-1-interacting and cysteine-rich domain-containing protein], a component of LC3-associated phagocytosis (LAP) dysregulates autophagosomal maturation and endocytic trafficking to promote tumor migration and invasiveness. Our hypothesis is that autophagy reactivates residual invasive odontogenic epithelium by LAP-mediated entosis and recycling of bioenergetic cellular components. Our collaborative group has a relatively large cohort of ameloblastoma tissues and have generated epithelial-derived (EP-AMCs) and mesenchymal-derived (MS-AMCs) ameloblastoma cell lines from BRAF V600E+ multicystic/follicular ameloblastomas. To elucidate biological mechanisms contributing to racial disparity in Black versus White racial groups, we will determine prognostic biomarkers of ameloblastoma recurrence and assess how LC3-mediated autophagic ‘cargo’ processing orchestrate recurrence disparity. In Aim 1 we will determine whether autophagic proteins are pro-oncogenic adaptors associated with ameloblastoma racial disparity, aggressive phenotype and propensity for recurrence. In Aim 2, we will assess whether residual invasive ameloblastic epithelium survive using LAP-mediated entosis and recycling of bioenergetic cellular components. While ameloblastoma is relatively rare, understanding the interplay of two converging cytoprotective pathways in ameloblastoma growth pattern and recurrence has the potential to lead to new prognostic biomarkers and precision-guided therapies to alleviate racial disparities in BRAF+ tumors like ameloblastoma.
项目摘要 成釉细胞瘤占所有牙源性肿瘤的14%,非洲裔美国人患成釉细胞瘤的可能性是其他人的五倍。 与白种人相比,会发生成釉细胞瘤。尽管进行了根治性手术,10%的成釉细胞瘤会复发, 25%的复发性成釉细胞瘤发生在黑人种族群体中。成釉细胞瘤的生物学决定因素 种族差异尚不清楚,也没有特定的生物标志物来预测复发。最 成釉细胞瘤显示编码丝氨酸/苏氨酸蛋白激酶B-Raf的BRAF基因突变, MAPK/ERK信号通路的激活剂。BRAF癌基因诱导关键自噬标志物的表达 包括LC 3、p62和BECLIN 1。p62、ATG 7和LC 3的高表达已在所有变体中鉴定 的成釉细胞瘤和我们的体内小鼠成釉细胞瘤肿瘤模型显示升高的LC 3和p62水平。 这些提示成釉细胞瘤复发可归因于自噬细胞存活机制, 侵袭性肿瘤性牙源性上皮。自噬调节因子BECNLIN 1与RUBICON的相互作用[运行 结构域Beclin-1相互作用和富含半胱氨酸的结构域蛋白],LC 3相关的 吞噬作用(phagocytosis,简称EGA)调节自噬体成熟和内吞运输,促进肿瘤细胞的增殖, 迁移和入侵。我们的假设是,自噬重新激活残留的侵袭性牙源性 上皮细胞通过LAP介导的内陷和生物能细胞成分的再循环。我们的合作小组 具有相对较大的成釉细胞瘤组织群,并产生上皮源性(EP-AMC), 来自BRAF V600 E+多囊/滤泡的间充质源性(MS-AMC)成釉细胞瘤细胞系 成釉细胞瘤阐明导致黑人与白色种族差异的生物学机制。 我们将确定成釉细胞瘤复发的预后生物标志物,并评估LC 3介导的 自噬“货物”加工协调复发差异。在目标1中,我们将确定自噬是否 蛋白质是与成釉细胞瘤种族差异、侵袭性表型和 复发倾向在目标2中,我们将评估残余的浸润性成釉细胞上皮是否存活, LAP介导的生物能量细胞成分的内陷和再循环。虽然成釉细胞瘤相对罕见, 了解成釉细胞瘤生长模式中两种会聚细胞保护途径的相互作用, 复发有可能导致新的预后生物标志物和精确指导的治疗,以减轻 BRAF+肿瘤如成釉细胞瘤的种族差异。

项目成果

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{{ truncateString('Sunday O Akintoye', 18)}}的其他基金

Novel therapeutic approaches to remediate radiotherapy-induced bone necrosis
修复放射治疗引起的骨坏死的新治疗方法
  • 批准号:
    10912194
  • 财政年份:
    2023
  • 资助金额:
    $ 36.43万
  • 项目类别:
Biological Indicators of Racial Disparity in Ameloblastoma Recurrence
成釉细胞瘤复发的种族差异的生物学指标
  • 批准号:
    10347638
  • 财政年份:
    2021
  • 资助金额:
    $ 36.43万
  • 项目类别:
Dental outcomes in Fibrous Dysplasia/McCune Albright Syndrome
纤维性发育不良/麦库恩奥尔布赖特综合征的牙科结果
  • 批准号:
    8705613
  • 财政年份:
    2013
  • 资助金额:
    $ 36.43万
  • 项目类别:
Complications of Jaw Osteoradionecrosis in Cancer Management
颌骨放射性骨坏死在癌症治疗中的并发症
  • 批准号:
    8721197
  • 财政年份:
    2012
  • 资助金额:
    $ 36.43万
  • 项目类别:
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
  • 批准号:
    8537887
  • 财政年份:
    2012
  • 资助金额:
    $ 36.43万
  • 项目类别:
Complications of Jaw Osteoradionecrosis in Cancer Management
颌骨放射性骨坏死在癌症治疗中的并发症
  • 批准号:
    8546712
  • 财政年份:
    2012
  • 资助金额:
    $ 36.43万
  • 项目类别:
Complications of Jaw Osteoradionecrosis in Cancer Management
颌骨放射性骨坏死在癌症治疗中的并发症
  • 批准号:
    8353798
  • 财政年份:
    2012
  • 资助金额:
    $ 36.43万
  • 项目类别:
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
  • 批准号:
    8356486
  • 财政年份:
    2012
  • 资助金额:
    $ 36.43万
  • 项目类别:
Treatment of Osteoradionecrosis with Bone Marrow Stromal Cells
骨髓基质细胞治疗放射性骨坏死
  • 批准号:
    7668426
  • 财政年份:
    2006
  • 资助金额:
    $ 36.43万
  • 项目类别:
Treatment of Osteoradionecrosis with Bone Marrow Stromal Cells
骨髓基质细胞治疗放射性骨坏死
  • 批准号:
    7084879
  • 财政年份:
    2006
  • 资助金额:
    $ 36.43万
  • 项目类别:

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Development of a novel treatment for ameloblastoma by modifying tumor stroma based on CCN2
基于 CCN2 修饰肿瘤基质开发成釉细胞瘤新疗法
  • 批准号:
    23K09332
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    2023
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    $ 36.43万
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Biological Indicators of Racial Disparity in Ameloblastoma Recurrence
成釉细胞瘤复发的种族差异的生物学指标
  • 批准号:
    10347638
  • 财政年份:
    2021
  • 资助金额:
    $ 36.43万
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Investigation of inhibitory mechanisms of ameloblastoma proliferation by benzbromarone.
苯溴马隆抑制成釉细胞瘤增殖机制的研究。
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    2021
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Elucidating the mechanisms to induce ameloblastoma and its trial for the clinical setting
阐明成釉细胞瘤的诱发机制及其临床试验
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    20K09906
  • 财政年份:
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通过有意的细胞分化开发成釉细胞瘤新疗法的探索
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  • 财政年份:
    2018
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Treatment strategy using the molecular target medicine and elucidation of the growth mechanism of ameloblastoma
成釉细胞瘤的分子靶向药物治疗策略及生长机制的阐明
  • 批准号:
    17K17256
  • 财政年份:
    2017
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成釉细胞瘤恶化因素的分子分析,用于开发新的治疗药物
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  • 财政年份:
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成釉细胞瘤行为的遗传预测因子
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  • 财政年份:
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成釉细胞瘤多种形式集体细胞侵袭机制的阐明
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高分辨率阵列比较基因组杂交对成釉细胞瘤进行基因组诊断及分子靶点药物开发
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