Interfering with Protein-Protein Interaction for the Treatment of Leishmaniasis

干扰蛋白质-蛋白质相互作用治疗利什曼病

基本信息

  • 批准号:
    7692203
  • 负责人:
  • 金额:
    $ 20.09万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-09-29 至 2010-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Leishmaniasis is an endemic disease in tropical and subtropical regions of over 80 countries with more than 2 million new cases occurring annually http://www.who.int/tdr/diseases/leish/diseaseinfo.htm. Receptor for activated C kinase 1 (RACK1), a ubiquitous and highly conserved scaffold protein, binds to proteins involved in many signaling processes leading to cell survival, growth and differentiation. We have successfully generated short peptide regulators that either disrupt or enhance the interactions of RACK1 with these signaling proteins and thus regulate their biological effects. Little is known about the cellular function of the Leishmania homolog of RACK1, Leishmania homolog of receptors for activated C kinase, LACK. We believe that LACK, due to its highly conserved nature, is also a key scaffolding protein involved in essential signaling processes of the Leishmania parasite. We propose a novel approach, utilizing our well established methods of peptide design, to identify and characterize LACK- binding partners and to target protein-protein interactions between LACK and these Leishmaniasis- signaling enzymes. These peptides may serve as leads for the development of new therapeutics for the treatment of Leishmaniasis. Specifically, in this early feasibility proposal, we plan to: 1. Identify and characterize Leishmania signaling proteins that are LACK-binding partners (LACK-BP). 2. Rationally design peptides that selectively inhibit the interactions between the scaffold LACK and LACK-BP and test their activity towards Leishmania sp. proliferation and in vitro infection. To identify and characterize LACK-BP, we will utilize several methodologies including protein overlays (Far Western), in vitro pull-down assays, and expression interaction cloning. To design peptide modulators of protein-protein interactions, we will use sequences in RACK-BP that are required for RACK binding and identify homologous sequences in LACK-BP. Additionally, we will identify evolutionary conserved sequences in homologs of RACK-BP and use structural modeling to look for regions of homology for peptide design. Finally, we will identify short peptides derived from LACK that are likely to disrupt the binding and hence the signaling of LACK-BPs. The peptide modulators will be tethering to cell-permeable vectors and tested for their biological activity on proliferation of Leishmania promastigotes in culture and on Leishmania-infected murine macrophages. The peptides developed as part of the proposed project are likely to exert significant biological effects. Importantly, identification of LACK-binding proteins and peptides that interfere with their biological activities can help guide the development of new therapeutics for patients suffering from Leishmania infection. PROJECT NARRATIVE: Two million new cases of Leishmania infection are reported annually, with a resultant death rate of 3%. The current treatment for Leishmaniasis, chemotherapy, is highly toxic and ineffective. Our proposed studies will use a new approach to identify key players involved in Leishmania viability, allowing us to identify and create highly specific therapeutics that disrupt these cellular processes. This therapeutic approach is likely to provide a less toxic, highly specific and effective way of treating Leishmaniasis.
描述(申请人提供):利什曼病是一种地方性疾病,分布在80多个国家的热带和亚热带地区,每年有200多万新病例发生http://www.who.int/tdr/diseases/leish/diseaseinfo.htm.活化C激酶受体1(RACK1)是一种普遍存在的高度保守的支架蛋白,它与多种参与细胞存活、生长和分化的信号转导过程中的蛋白结合。我们已经成功地产生了短肽调节剂,可以破坏或增强RACK1与这些信号蛋白的相互作用,从而调节它们的生物学效应。关于RACK1的利什曼原虫同源物、活化C激酶受体的利什曼原虫同源物LASK的细胞功能知之甚少。我们认为,由于其高度保守的性质,LACK也是参与利什曼原虫基本信号传递过程的关键支架蛋白。我们提出了一种新的方法,利用我们成熟的多肽设计方法来识别和表征LACK结合伙伴,并针对LACK和这些利什曼病信号转导酶之间的蛋白质-蛋白质相互作用。这些多肽可能成为开发治疗利什曼病新疗法的先导。具体地说,在这个早期的可行性提案中,我们计划:1.鉴定和鉴定作为缺失结合伙伴的利什曼原虫信号蛋白(LACK-BP)。2.合理设计选择性抑制支架LINK和LACK-BP相互作用的多肽,并检测其对利什曼原虫的活性。增殖和体外感染。为了鉴定和鉴定LACK-BP,我们将利用几种方法,包括蛋白质覆盖(Far Western)、体外下拉试验和表达相互作用克隆。为了设计蛋白质-蛋白质相互作用的多肽调节剂,我们将使用Rack-BP中与Rack结合所需的序列,并在LACK-BP中鉴定同源序列。此外,我们将在Rack-BP的同源物中鉴定进化保守的序列,并使用结构建模来寻找多肽设计的同源性区域。最后,我们将识别来自LACK的短肽,这些短肽可能会破坏LACK-BPS的结合,从而破坏LACK-BPS的信号转导。这些肽调节剂将被拴在细胞渗透载体上,并在培养的利什曼原虫前鞭毛体和感染利什曼原虫的小鼠巨噬细胞上测试它们对增殖的生物活性。作为拟议项目的一部分开发的多肽可能会产生显著的生物效应。重要的是,识别干扰其生物活性的缺乏结合的蛋白质和多肽有助于指导利什曼原虫感染患者的新疗法的开发。 项目简介:每年报告200万新的利什曼原虫感染病例,其结果死亡率为3%。目前治疗利什曼病的方法是化疗,毒性很大,效果不佳。我们提议的研究将使用一种新的方法来确定参与利什曼原虫生存能力的关键因素,使我们能够确定并创造高度特异性的疗法来扰乱这些细胞过程。这种治疗方法可能提供一种毒性较小、高度特异和有效的治疗利什曼病的方法。

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 }}

DARIA MOCHLY-ROSEN其他文献

DARIA MOCHLY-ROSEN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('DARIA MOCHLY-ROSEN', 18)}}的其他基金

ALDH Activation to treat Fanconi Anemia
激活 ALDH 治疗范可尼贫血
  • 批准号:
    10178078
  • 财政年份:
    2018
  • 资助金额:
    $ 20.09万
  • 项目类别:
ALDH Activation to treat Fanconi Anemia
激活 ALDH 治疗范可尼贫血
  • 批准号:
    9980975
  • 财政年份:
    2018
  • 资助金额:
    $ 20.09万
  • 项目类别:
Development of a novel treatment for hyperbilirubinemia-induced kernicterus
开发治疗高胆红素血症引起的核黄疸的新疗法
  • 批准号:
    9926721
  • 财政年份:
    2016
  • 资助金额:
    $ 20.09万
  • 项目类别:
Translational Incubator Core
转化孵化器核心
  • 批准号:
    8643875
  • 财政年份:
    2014
  • 资助金额:
    $ 20.09万
  • 项目类别:
Mechanisms of Ethanol-Induced Cardiac Protection
乙醇诱导的心脏保护机制
  • 批准号:
    7860783
  • 财政年份:
    2009
  • 资助金额:
    $ 20.09万
  • 项目类别:
Interfering with Protein-Protein Interaction for the Treatment of Leishmaniasis
干扰蛋白质-蛋白质相互作用治疗利什曼病
  • 批准号:
    7449189
  • 财政年份:
    2008
  • 资助金额:
    $ 20.09万
  • 项目类别:
Hypertrophy, Heart Failure and PKC
肥厚、心力衰竭和 PKC
  • 批准号:
    7214740
  • 财政年份:
    2004
  • 资助金额:
    $ 20.09万
  • 项目类别:
Hypertrophy, Heart Failure and PKC
肥厚、心力衰竭和 PKC
  • 批准号:
    7023830
  • 财政年份:
    2004
  • 资助金额:
    $ 20.09万
  • 项目类别:
Hypertrophy, Heart Failure and PKC
肥厚、心力衰竭和 PKC
  • 批准号:
    7386626
  • 财政年份:
    2004
  • 资助金额:
    $ 20.09万
  • 项目类别:
Hypertrophy, Heart Failure and PKC
肥厚、心力衰竭和 PKC
  • 批准号:
    6766324
  • 财政年份:
    2004
  • 资助金额:
    $ 20.09万
  • 项目类别:

相似海外基金

How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 20.09万
  • 项目类别:
    Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 20.09万
  • 项目类别:
    Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 20.09万
  • 项目类别:
    Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 20.09万
  • 项目类别:
    Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 20.09万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 20.09万
  • 项目类别:
    Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 20.09万
  • 项目类别:
    Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 20.09万
  • 项目类别:
    Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
  • 批准号:
    23K00129
  • 财政年份:
    2023
  • 资助金额:
    $ 20.09万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
  • 批准号:
    2883985
  • 财政年份:
    2023
  • 资助金额:
    $ 20.09万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了