Regulation Of Metabolism And Gene Expression By Iron-Sulfur Clusters - Resubmission - 1

铁硫簇对代谢和基因表达的调节 - 重新提交 - 1

基本信息

项目摘要

Iron-sulfur clusters (ISCs) are essential protein cofactors whose dysregulation is linked to a wide range of debilitating diseases including Friedrch’s ataxia. This pathology is due in part to the use of ISCs in iron-responsive proteins (IRPs), which control the translation of mRNAs in the iron-starvation response. We recently found that by suppressing ISC biosynthesis we can robustly activate this IRP-mediated iron-starvation response, sensitizing cancer cells to cell death by ferroptosis. Our preliminary data, which form the premise of our application, point to an unexpected mode of IRP2 regulation by ISCs and demonstrate that the mechanism by which ISCs modulate the iron-starvation response, and therefore impact human disease, remains unclear. Our long-term goal is to dissect the mechanisms by which ISCs regulates cellular responses to changing iron and oxygen availability and how this response is mediated by IRPs. We anticipate that these discoveries will lead to the identification of pathologies for diseases where prior ISC involvement was unclear, to new treatments for diseases of ISC dysregulation, and will facilitate novel methods to sensitize cancer cells to ferroptosis. The objective of this grant is to dissect how ISCs control IRP2 activation and to comprehensively define the targets of IRP1 and IRP2 and the conditions under which they are activated. Our overarching hypothesis is that ISCs integrate iron and oxygen level inputs to effect specific translational responses via differential regulation of IRPs. Our rationale is that identification of the specific mechanisms by which IRPs are activated and the targets that they activate will enable the discovery of novel strategies to treat cancer and disorders of ISC metabolism. Our specific aims will test the following hypotheses: (Aim 1) ISCs can activate the iron-starvation response through an IRP2-mediated mechanism; (Aim 2) IRPs exhibit differential IRE binding in response to iron and oxygen level modulation. Upon completion of these aims we will (1) gain an understanding of how cells sense iron and oxygen levels and integrate these inputs using ISC sensors and (2) identify IRP regulated target genes and the conditions in which they are regulated. This contribution is significant because dysregulation of IRPs occurs frequently in human pathologies and inducing activation of the iron starvation response sensitizes cancer cells to ferroptotic cell death. This research is innovative because we challenge paradigms in cellular iron-sensing to arrive at a comprehensive mechanism by which cells respond to changes in the level of this important nutrient, and because we utilize heretofore unique approaches to identify RNAs regulated by the iron starvation response and define their activation by upstream stimuli. The outcomes of this study promise disrupt our understanding of iron sensing and have broad implications for the treatment of cancer as well as human diseases related to defects in iron metabolism and storage.
铁-硫簇(ISCs)是一种重要的蛋白质辅因子,其失调与包括Friedrch‘s共济失调在内的多种衰弱疾病有关。这种病理在一定程度上是由于ISCs在铁反应蛋白(IRPS)中的使用,它控制着铁饥饿反应中mRNAs的翻译。我们最近发现,通过抑制ISC的生物合成,我们可以强有力地激活IRP介导的铁饥饿反应,通过铁下垂使癌细胞对细胞死亡敏感。我们的初步数据是我们应用的前提,它指出了ISCs对IRP2的一种意想不到的调控模式,并表明ISCs调节铁饥饿反应从而影响人类疾病的机制尚不清楚。我们的长期目标是剖析ISCs调节细胞对铁和氧气供应变化的反应的机制,以及这种反应是如何由IRPS介导的。我们预计,这些发现将导致对先前不清楚ISC参与的疾病的病理识别,对ISC调节失调疾病的新治疗,并将促进使癌细胞对铁下垂敏感的新方法。这笔赠款的目的是剖析ISCs如何控制IRP2的激活,并全面定义IRP1和IRP2的靶标以及它们被激活的条件。我们的主要假设是,ISCs整合了铁和氧水平的输入,通过对IRPS的不同调控来影响特定的翻译反应。我们的基本原理是确定IRPS被激活的特定机制及其激活的靶点,这将使我们能够发现治疗癌症和ISC代谢障碍的新策略。我们的特定目标将检验以下假设:(目标1)ISCs可以通过IRP2介导的机制激活铁饥饿反应;(目标2)IRPS对铁和氧水平的调节表现出不同的IRE结合。在完成这些目标后,我们将(1)了解细胞如何感知铁和氧水平,并使用ISC传感器整合这些输入,以及(2)识别IRP受调控的靶基因和它们被调控的条件。这一贡献是重要的,因为IRPS的失调在人类病理中经常发生,诱导铁饥饿反应的激活使癌细胞对铁链细胞死亡敏感。这项研究具有创新性,因为我们挑战了细胞铁感应的范式,以得出细胞对这种重要营养物质水平的变化做出反应的综合机制,而且因为我们利用迄今唯一的方法来识别受铁饥饿反应调节的RNA,并通过上游刺激来定义它们的激活。这项研究的结果有望打乱我们对铁感应的理解,并对癌症以及与铁代谢和储存缺陷有关的人类疾病的治疗具有广泛的意义。

项目成果

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Richard Lewis Possemato其他文献

Richard Lewis Possemato的其他文献

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{{ truncateString('Richard Lewis Possemato', 18)}}的其他基金

Regulation Of Metabolism And Gene Expression By Iron-Sulfur Clusters - Resubmission - 1
铁硫簇对代谢和基因表达的调节 - 重新提交 - 1
  • 批准号:
    9885268
  • 财政年份:
    2020
  • 资助金额:
    $ 38.59万
  • 项目类别:
Regulation Of Metabolism And Gene Expression By Iron-Sulfur Clusters - Resubmission - 1
铁硫簇对代谢和基因表达的调节 - 重新提交 - 1
  • 批准号:
    10227441
  • 财政年份:
    2020
  • 资助金额:
    $ 38.59万
  • 项目类别:
Regulation Of Metabolism And Gene Expression By Iron-Sulfur Clusters - Supplement
铁硫簇对代谢和基因表达的调节 - 补充
  • 批准号:
    10669888
  • 财政年份:
    2020
  • 资助金额:
    $ 38.59万
  • 项目类别:
Regulation Of Metabolism And Gene Expression By Iron-Sulfur Clusters - Resubmission - 1
铁硫簇对代谢和基因表达的调节 - 重新提交 - 1
  • 批准号:
    10534796
  • 财政年份:
    2020
  • 资助金额:
    $ 38.59万
  • 项目类别:
Regulation Of Metabolism And Gene Expression By Iron-Sulfur Clusters - Supplement
铁硫簇对代谢和基因表达的调节 - 补充
  • 批准号:
    10738651
  • 财政年份:
    2020
  • 资助金额:
    $ 38.59万
  • 项目类别:
Targeting Metabolic Liabilities in Cancer
针对癌症的代谢负担
  • 批准号:
    10079472
  • 财政年份:
    2018
  • 资助金额:
    $ 38.59万
  • 项目类别:
Targeting Metabolic Liabilities in Cancer
针对癌症的代谢负担
  • 批准号:
    10328918
  • 财政年份:
    2018
  • 资助金额:
    $ 38.59万
  • 项目类别:
Rapid Determination of Phenotypic Responses Across Cancer Cell Lines
快速测定癌细胞系的表型反应
  • 批准号:
    8959212
  • 财政年份:
    2015
  • 资助金额:
    $ 38.59万
  • 项目类别:
Identification of Metabolic Liabilities in Breast Cancer
乳腺癌代谢负担的识别
  • 批准号:
    8920191
  • 财政年份:
    2014
  • 资助金额:
    $ 38.59万
  • 项目类别:
Identification of Metabolic Liabilities in Breast Cancer
乳腺癌代谢负担的识别
  • 批准号:
    8352910
  • 财政年份:
    2012
  • 资助金额:
    $ 38.59万
  • 项目类别:

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Bone-Adipose Interactions During Skeletal Anabolism
骨骼合成代谢过程中骨-脂肪相互作用
  • 批准号:
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  • 财政年份:
    2022
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Bone-Adipose Interactions During Skeletal Anabolism
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BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): Combined long-acting PTH and calcimimetics actions on skeletal anabolism
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    10365254
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剖析与年龄和骨关节炎相关的关节软骨合成代谢下降有关的分子机制
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促进NAD合成代谢以延长寿命
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