Defective Myoblast Fusion Signaling in Rhabdomyosarcoma Pathogenesis

横纹肌肉瘤发病机制中的成肌细胞融合信号缺陷

基本信息

  • 批准号:
    9753132
  • 负责人:
  • 金额:
    $ 35.95万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-09-01 至 2022-08-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Rhabdomyosarcoma (RMS), the most common childhood soft tissue sarcoma, is a malignancy of muscle-lineage myoblasts that are blocked from differentiating into syncytial muscle. RMS is typically divided into two subgroups: Embryonal RMS (E-RMS), which is more common, and Alveolar RMS (A-RMS), which is more aggressive. Despite intensive therapy, children with high-risk RMS suffer from a 3-year event-free survival of only 20%. Treatments for high-risk RMS have not improved for three decades, underscoring the need to elucidate the molecular underpinnings of the disease and design new precision drug therapies. Using an innovative Drosophila RMS-related model, the lab conducted an unbiased genetic modifier screen to uncover new genetic drives of RMS. Extending these findings to mammalian systems, we recently reported that misexpression of TANC1, which encodes an adaptor molecule that regulates myoblast cell-cell fusion, dysregulates fusion signaling and promotes RMS. As the machinery necessary for mammalian myoblast fusion is largely unexplored, the notion that dysregulated myoblast fusion drives RMS was novel. Since our the discovery of dysregulated myoblast fusion in RMS, we have explored/learned the following: 1) The Immunoglobulin Superfamily (Ig-S) transmembrane Receptor (Ig-S-R) family members Kirrel and Nephrin are putative fusion regulators, expression of which appears altered in RMS. Roles for Kirrel or Nephrin in RMS have not been explored. 2) EGFR signaling is critical in flies for myoblast differentiation and fusion, yet a role for EGFR in mammalian myoblast fusion/maturation or RMS has not been functionally explored. We preliminary data now argue that EGFR overexpression misregulated the myoblast fusion machinery, which drives RMS. We have also shown the silencing or pharmacologic inhibition of EGFR antagonizes RMS tumorigenesis in vivo. The findings argue that EGFR overexpression is a provocative and targetable RMS pathogenesis mechanism. In this proposal, we aim to: 1) Identify the key transmembrane receptors that incite defective myoblast fusion potential in RMS; 2) Test whether EGFR signaling underlies RMS differentiation-arrest; & 3) Interrogate expression of TANC1, KIRREL and NEPHRIN, and EGFR in human tumors. Our overall objective is to use our informative and complementary model systems to uncover new mechanisms underlying RMS. Our long-term goal is to translate these insights into new directed RMS therapies. We postulate that our innovative strategies will reveal new molecular targets for RMS precision therapy and therein have a positive clinical impact on RMS morbidity and mortality.


项目成果

期刊论文数量(0)
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RENE L GALINDO其他文献

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{{ truncateString('RENE L GALINDO', 18)}}的其他基金

T35 NEI Medical Student Summer Research Training
T35 NEI 医学生暑期研究培训
  • 批准号:
    10376283
  • 财政年份:
    2018
  • 资助金额:
    $ 35.95万
  • 项目类别:
T35 NEI Medical Student Summer Research Training
T35 NEI 医学生暑期研究培训
  • 批准号:
    9904700
  • 财政年份:
    2018
  • 资助金额:
    $ 35.95万
  • 项目类别:
T35 NHLBI Medical Student Research Training Program
T35 NHLBI 医学生研究培训计划
  • 批准号:
    10112288
  • 财政年份:
    2017
  • 资助金额:
    $ 35.95万
  • 项目类别:
T35 NHLBI Medical Student Research Training Program
T35 NHLBI 医学生研究培训计划
  • 批准号:
    9209071
  • 财政年份:
    2017
  • 资助金额:
    $ 35.95万
  • 项目类别:
Defective Myoblast Fusion Signaling in Rhabdomyosarcoma Pathogenesis
横纹肌肉瘤发病机制中的成肌细胞融合信号缺陷
  • 批准号:
    9999474
  • 财政年份:
    2016
  • 资助金额:
    $ 35.95万
  • 项目类别:
Defective Myoblast Fusion Signaling in Rhabdomyosarcoma Pathogenesis
横纹肌肉瘤发病机制中的成肌细胞融合信号缺陷
  • 批准号:
    9283441
  • 财政年份:
    2016
  • 资助金额:
    $ 35.95万
  • 项目类别:
Minority Predoctoral NHLBI Research Training at UT Southwestern
UT 西南大学少数族裔博士前 NHLBI 研究培训
  • 批准号:
    8465254
  • 财政年份:
    2009
  • 资助金额:
    $ 35.95万
  • 项目类别:
R.L. Kirschstein T-35 to Support NHLBI-focused Short-term Predoctoral Training
R.L. Kirschstein T-35 支持以 NHLBI 为重点的短期博士前培训
  • 批准号:
    8231330
  • 财政年份:
    2008
  • 资助金额:
    $ 35.95万
  • 项目类别:
Clinical & Basic NIDDK Research Training for Medical Students
临床
  • 批准号:
    8447078
  • 财政年份:
    2003
  • 资助金额:
    $ 35.95万
  • 项目类别:
Clinical & Basic NIDDK Research Training for Medical Students
临床
  • 批准号:
    8253730
  • 财政年份:
    2003
  • 资助金额:
    $ 35.95万
  • 项目类别:

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