Targeting the dependency of cancer cells on the sirtuin SIRT5

靶向癌细胞对 Sirtuin SIRT5 的依赖性

基本信息

  • 批准号:
    10261077
  • 负责人:
  • 金额:
    $ 23.52万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-04-01 至 2024-03-31
  • 项目状态:
    已结题

项目摘要

SUMMARY (from parent grant RO1 CA223534) New anticancer agents are still in great demand due to the heterogeneous nature of cancer and the development of resistance to existing drugs. This collaborative proposal by three PIs (Richard Cerione, Hening Lin, and Robert Weiss) aims to establish SIRT5 inhibition as new strategy to treat cancers. SIRT5 is a member of the sirtuin family of enzymes that are known to have NAD+-dependent protein lysine deacylation activities. They play important roles in physiology, including the regulation of transcription, metabolism, and lifespan. We were the first to discover that SIRT5, a mitochondrial sirtuin with very weak deacetylation activity, prefers to hydrolyze negatively charged acyl lysine modifications, such as succinyl and malonyl lysine, from proteins. We and others have established lysine succinylation as an abundant post-translational modification that affects many metabolic enzymes. Moreover, we have recently obtained exciting preliminary data showing that SIRT5 deletion impairs tumorigenesis and metastasis in mice. At the cellular level, we found that inactivating SIRT5 inhibits the anchorage-independent growth of cancer cells, but in some cases has little effect on proliferation in conventional monolayer cultures. We hypothesize that SIRT5-mediated regulation of metabolism is required for malignant transformation and the acquisition of properties like anchorage- independent growth and invasiveness. One objective of the proposed studies is to understand the detailed molecular functions of SIRT5 in cancer cells, as well as in the tumor microenvironment. Successful completion of this goal is likely to shed light on the unique dependencies of cancers on metabolic alterations, knowledge that can help the development of novel therapeutics for treating cancer. Based on the discovery of the novel enzymatic activity of SIRT5, we have developed small molecule inhibitors of SIRT5 that are very selective and do not inhibit other sirtuins. Some of the inhibitors have shown promising anticancer activity in cell culture and mouse models. Another goal of this proposal is to develop additional SIRT5 inhibitors with improved in vivo efficacies against cancer in mouse models. We are very excited about the robust translational potential of the project, which is based on strong fundamental understanding of the enzymatic activity and biochemistry of SIRT5, coupled with rigorous biological analyses in cultured cells and mice.
总结(来自母公司授权RO 1 CA 223534) 由于癌症的异质性和肿瘤的免疫原性,新的抗癌剂仍然有很大的需求。 对现有药物产生耐药性。这项由三位PI(Richard Cerione, Hening Lin和Robert韦斯)旨在建立SIRT 5抑制作为治疗癌症的新策略。SIRT 5是一个 已知具有NAD+依赖性蛋白质赖氨酸脱酰作用的酶的沉默调节蛋白家族成员 活动它们在生理学中起着重要作用,包括转录、代谢和 寿命我们是第一个发现SIRT 5,一种具有非常弱的脱乙酰化活性的线粒体sirtuin, 优选水解带负电荷的酰基赖氨酸修饰,如琥珀酰和丙二酰赖氨酸, proteins.我们和其他人已经建立了赖氨酸琥珀酰化作为一种丰富的翻译后修饰 影响许多代谢酶。此外,我们最近获得了令人兴奋的初步数据, SIRT 5缺失会损害小鼠的肿瘤发生和转移。在细胞水平上,我们发现, SIRT 5的失活抑制了癌细胞的锚定非依赖性生长,但在某些情况下, 对常规单层培养物中增殖的影响。我们假设SIRT 5介导的调节 代谢是恶性转化和获得诸如锚定的性质所必需的- 独立生长和入侵性。拟议研究的一个目标是了解 SIRT 5在癌细胞以及肿瘤微环境中的分子功能。成功完成 这一目标的实现可能会揭示癌症对代谢改变的独特依赖性, 可以帮助开发治疗癌症的新疗法。基于小说的发现 由于SIRT 5的酶活性,我们已经开发了SIRT 5的小分子抑制剂,其具有非常高的选择性, 不抑制其他sirtuins。一些抑制剂在细胞培养中显示出有希望的抗癌活性, 小鼠模型。该提议的另一个目标是开发另外的SIRT 5抑制剂,其具有改善的体内活性。 在小鼠模型中对抗癌症的功效。我们非常兴奋的是, 该项目是基于对酶活性和生物化学的深刻理解, SIRT 5,再加上培养细胞和小鼠的严格生物学分析。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

RICHARD A. CERIONE其他文献

RICHARD A. CERIONE的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('RICHARD A. CERIONE', 18)}}的其他基金

Probing the molecular mechanisms that regulate key steps in the GPCR-sensory response pathway responsible for vision in dim light
探索调节负责弱光视觉的 GPCR 感觉反应通路关键步骤的分子机制
  • 批准号:
    10635707
  • 财政年份:
    2023
  • 资助金额:
    $ 23.52万
  • 项目类别:
Administrative-Core
行政核心
  • 批准号:
    10231134
  • 财政年份:
    2019
  • 资助金额:
    $ 23.52万
  • 项目类别:
Administrative-Core
行政核心
  • 批准号:
    10443673
  • 财政年份:
    2019
  • 资助金额:
    $ 23.52万
  • 项目类别:
MacCHESS Synchrotron Source for Structural Biology
MacCHESS 结构生物学同步加速器源
  • 批准号:
    9805369
  • 财政年份:
    2019
  • 资助金额:
    $ 23.52万
  • 项目类别:
Targeting the dependency of cancer cells on the sirtuin SIRT5
靶向癌细胞对 Sirtuin SIRT5 的依赖性
  • 批准号:
    9895673
  • 财政年份:
    2019
  • 资助金额:
    $ 23.52万
  • 项目类别:
MacCHESS Synchrotron Source for Structural Biology
MacCHESS 结构生物学同步加速器源
  • 批准号:
    10231133
  • 财政年份:
    2019
  • 资助金额:
    $ 23.52万
  • 项目类别:
MacCHESS Synchrotron Source for Structural Biology
MacCHESS 结构生物学同步加速器源
  • 批准号:
    10582108
  • 财政年份:
    2019
  • 资助金额:
    $ 23.52万
  • 项目类别:
Targeting the dependency of cancer cells on the sirtuin SIRT5
靶向癌细胞对 Sirtuin SIRT5 的依赖性
  • 批准号:
    10369635
  • 财政年份:
    2019
  • 资助金额:
    $ 23.52万
  • 项目类别:
Administrative-Core
行政核心
  • 批准号:
    10693127
  • 财政年份:
    2019
  • 资助金额:
    $ 23.52万
  • 项目类别:
MacCHESS Synchrotron Source for Structural Biology
MacCHESS 结构生物学同步加速器源
  • 批准号:
    10443671
  • 财政年份:
    2019
  • 资助金额:
    $ 23.52万
  • 项目类别:

相似国自然基金

相似海外基金

New development of cellular regeneration therapy in jaw bone using stem cells derived from adipocytes jaw bone
利用颌骨脂肪细胞来源的干细胞进行颌骨细胞再生治疗的新进展
  • 批准号:
    23K16058
  • 财政年份:
    2023
  • 资助金额:
    $ 23.52万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
A novel mechanism of insulin resistance mediated by uric acid metabolism in adipocytes
脂肪细胞尿酸代谢介导胰岛素抵抗的新机制
  • 批准号:
    23K10969
  • 财政年份:
    2023
  • 资助金额:
    $ 23.52万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Hypertrophic adipocytes as biophysical mediators of breast cancer progression
肥大脂肪细胞作为乳腺癌进展的生物物理介质
  • 批准号:
    10751284
  • 财政年份:
    2023
  • 资助金额:
    $ 23.52万
  • 项目类别:
Development of adipocytes for gene therapy that avoids cellular stress due to overexpression of therapeutic proteins
开发用于基因治疗的脂肪细胞,避免因治疗蛋白过度表达而造成的细胞应激
  • 批准号:
    23H03065
  • 财政年份:
    2023
  • 资助金额:
    $ 23.52万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Functional analysis of bitter taste receptors in adipocytes and hepatocytes
脂肪细胞和肝细胞中苦味受体的功能分析
  • 批准号:
    23K05107
  • 财政年份:
    2023
  • 资助金额:
    $ 23.52万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Elucidation of mechanisms for conversion of adipocytes to cancer-associated fibroblasts in osteosarcoma microenvironment
阐明骨肉瘤微环境中脂肪细胞转化为癌症相关成纤维细胞的机制
  • 批准号:
    23K19518
  • 财政年份:
    2023
  • 资助金额:
    $ 23.52万
  • 项目类别:
    Grant-in-Aid for Research Activity Start-up
Study on UCP-1 independent metabolic regulation by brown adipocytes
棕色脂肪细胞对UCP-1独立代谢调节的研究
  • 批准号:
    23K18303
  • 财政年份:
    2023
  • 资助金额:
    $ 23.52万
  • 项目类别:
    Grant-in-Aid for Challenging Research (Exploratory)
NKA/CD36 signaling in adipocytes promotes oxidative stress and drives chronic inflammation in atherosclerosis
脂肪细胞中的 NKA/CD36 信号传导促进氧化应激并驱动动脉粥样硬化的慢性炎症
  • 批准号:
    10655793
  • 财政年份:
    2023
  • 资助金额:
    $ 23.52万
  • 项目类别:
The mechanisms of the signal transduction from brown adipocytes to afferent neurons and its significance.
棕色脂肪细胞向传入神经元的信号转导机制及其意义。
  • 批准号:
    23K05594
  • 财政年份:
    2023
  • 资助金额:
    $ 23.52万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Characterizing breast cancer invasion and proliferation when co-aggregated with adipocytes in multicellular spheroids created with a custom bioreactor to augment cell-cell connectivity.
当与多细胞球体中的脂肪细胞共聚集时,表征乳腺癌的侵袭和增殖,该多细胞球体是用定制生物反应器创建的,以增强细胞间的连接。
  • 批准号:
    10334113
  • 财政年份:
    2022
  • 资助金额:
    $ 23.52万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了