Selective mRNA translation in developmental disorders

发育障碍中的选择性 mRNA 翻译

基本信息

  • 批准号:
    10652419
  • 负责人:
  • 金额:
    $ 52.8万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-06-18 至 2024-05-31
  • 项目状态:
    已结题

项目摘要

Abstract RASopathies cause the majority of congenital disorders affecting nearly 1 in 1000 individuals. In particular, mutations in RAS-MAPK pathway genes lead to distinct pathologies including craniofacial dysmorphology, mental impairment, musculoskeletal defects, and a predisposition to cancer. Although presentations may vary between different mutations, nearly all RASopathies share common skin growth abnormalities. At a genetic level, germline mutations to RAS pathway members including Hras and Kras are known to cause these defects which are best exemplified by Costello, Noonan, and Cardiofaciocutaneous syndromes. For years, comprehensive interrogation of RAS in development has been limited to genome-wide studies of DNA and RNA. While important, these investigations have left translation-based mechanisms largely untouched. This is remarkable in light of emerging evidence that developmental disorders, such as Diamond-Blackfan Anemia and Schwachman-Diamond and Treacher Collins syndromes (reviewed in Tahmasebi et al., 2018), are causally linked to impairments in the translation apparatus. Thus, our current knowledge of the mechanistic basis of RASopathies is incomplete, which is a barrier to therapeutic innovation. Our long-term goal is to uncover the mechanism of Ras-mediated tissue growth, which will ultimately yield innovative therapies to restore normal tissue homeostasis without compromising housekeeping functions during development. Using skin as a defined model of tissue development we have discovered that hyperactive Hras simultaneously drives specialized proliferation and differentiation programs by rewiring the translation initiation machinery through eIF2B5. Utilizing state-of-the-art in vivo genetic screens pioneered in our laboratory, we have determined the regulon of genes that eIF2B5 governs to impact self-renewal and cell fate choice. Remarkably, these mRNA networks are clearly demarcated by their function with ubiquitination emerging as a key regulator of cellular differentiation. As such, we hypothesize that activation of Ras promotes translation of a subset of mRNAs that support non-physiological tissue growth during development, where increased stem cell proliferation is balanced by their loss through differentiation into post-mitotic progeny. In this proposal we will use a confluence of in vivo models, intra-vital microscopy, and newly developed cellular and molecular assays to delineate how the interplay between RAS and eIF2B5 influences tissue dynamics. We will accomplish the following Aims: 1) Uncover how eIF2B5-dependent ubiquitin ligases directs progenitor renewal and fate choice; and 2) Elucidate how activated Hras and eIF2B5 direct mRNA specific translation to regulate progenitor renewal. Collectively, the successful completion of our Aims will provide a new understanding of cellular and molecular principles that support Ras-driven non-physiological growth during development. Ultimately, these new insights will inform the development of novel therapeutics, which can differentially inhibit the pathologic impact of Ras mediated tissue imbalance while maintain homeostasis which is essential for life.
摘要

项目成果

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Slobodan Beronja其他文献

Slobodan Beronja的其他文献

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{{ truncateString('Slobodan Beronja', 18)}}的其他基金

Fred Hutch Preclinical Ultrasound
Fred Hutch 临床前超声
  • 批准号:
    10414698
  • 财政年份:
    2022
  • 资助金额:
    $ 52.8万
  • 项目类别:
Selective mRNA translation in developmental disorders
发育障碍中的选择性 mRNA 翻译
  • 批准号:
    10413944
  • 财政年份:
    2020
  • 资助金额:
    $ 52.8万
  • 项目类别:
Selective mRNA translation in developmental disorders
发育障碍中的选择性 mRNA 翻译
  • 批准号:
    10197974
  • 财政年份:
    2020
  • 资助金额:
    $ 52.8万
  • 项目类别:
Selective mRNA translation in developmental disorders
发育障碍中的选择性 mRNA 翻译
  • 批准号:
    10700960
  • 财政年份:
    2020
  • 资助金额:
    $ 52.8万
  • 项目类别:
Differentiation balances oncogene-driven proliferation to maintain epidermal homeostasis
分化平衡癌基因驱动的增殖以维持表皮稳态
  • 批准号:
    10656102
  • 财政年份:
    2017
  • 资助金额:
    $ 52.8万
  • 项目类别:
Differentiation balances oncogene-driven proliferation to maintain epidermal homeostasis
分化平衡癌基因驱动的增殖以维持表皮稳态
  • 批准号:
    10210188
  • 财政年份:
    2017
  • 资助金额:
    $ 52.8万
  • 项目类别:
Differentiation balances oncogene-driven proliferation to maintain epidermal homeostasis
分化平衡癌基因驱动的增殖以维持表皮稳态
  • 批准号:
    10736269
  • 财政年份:
    2017
  • 资助金额:
    $ 52.8万
  • 项目类别:
Differentiation balances oncogene-driven proliferation to maintain epidermal homeostasis
分化平衡癌基因驱动的增殖以维持表皮稳态
  • 批准号:
    9384220
  • 财政年份:
    2017
  • 资助金额:
    $ 52.8万
  • 项目类别:
Mechanisms of epidermal growth during development, homeostasis, and tumorigenesis
发育、稳态和肿瘤发生过程中表皮生长的机制
  • 批准号:
    8726283
  • 财政年份:
    2013
  • 资助金额:
    $ 52.8万
  • 项目类别:
Mechanisms of epidermal growth during development, homeostasis, and tumorigenesis
发育、稳态和肿瘤发生过程中表皮生长的机制
  • 批准号:
    8714189
  • 财政年份:
    2013
  • 资助金额:
    $ 52.8万
  • 项目类别:

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