RP3: Targeting ATG gene-dependent immunity for novel anti-infective therapeutics

RP3:针对 ATG 基因依赖性免疫的新型抗感染疗法

基本信息

  • 批准号:
    10573261
  • 负责人:
  • 金额:
    $ 93.95万
  • 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:
    2019-03-15 至 2025-02-28
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY – RP3: The goal of RP3 is to define and pharmacologically target intracellular immune mechanisms utilizing autophagy (Atg) genes (but not degradative autophagy) to control infection and inflammation. We discovered these processes in experiments designed to understand the anti-infective mechanisms of IFNγ, a cytokine essential in both humans and mice for macrophage-mediated resistance to viruses, bacteria, and parasites. IFNγ is used to treat chronic granulomatous disease and osteopetrosis, but other uses of IFNγ have been limited by toxicity, a fact generally attributed to IFNγ inducing the expression of a very large number of pro-inflammatory genes. We theorized that new therapeutics might be generated by defining the effector mechanisms responsible for the potent effects of IFNγ, and then selectively stimulating these mechanisms to generate Atg gene-directed broad-spectrum anti-infectives. This led to the discovery that IFNγ triggers Atg gene-dependent immunity against T. gondii and norovirus (NoV) infection using the same set of Atg genes (Atg5, Atg7, Atg16L1, Atg12), but not Atg14 or degradative autophagy. The fact that Atg gene- dependent mechanism(s) controlled two phylogenetically distinct pathogens suggested to us that we might be able to make compounds that are effective against a broad range of pathogens. During the first CETR funding period we confirmed this prediction by identifying Atg gene-directed broad-spectrum anti-infective compounds with activity against norovirus, salmonella, Mycobacterium tuberculosis and Toxoplasma gondii. This discovery was complemented by discoveries of the role of Atg genes in the regulation of inflammation. RP3 focuses on the Caliciviridae (most importantly NoVs) which are priority pathogens, causing >90% of the epidemic non-bacterial gastroenteritis in the world. We discovered murine NoV (MNoV) and cultured NoVs for the first time, providing a preclinical model in laboratory mice and allowing discovery of Atg gene-dependent immunity. Studies of human NoV (HNoV) infection had been limited until it was recently found that HNoV grows in cells differentiated from biopsy-derived human colonic stem cells. This, together with the discovery that MNoV grows robustly in human cells expressing the proper receptor, and that Atg gene-dependent immunity operates against both T. gondii and MNoV in human cells strongly argues that these mechanisms are evolutionarily conserved and provide the tools to identify compounds relevant to a major human disease via the following aims: Aim 1: Develop Atg gene- directed broad spectrum anti-infective compounds; Aim 2: Define the molecular basis of Atg gene- dependent IFNγ-induced control of norovirus replication, and identify targets and lead compounds that trigger this form of intracellular immunity; Aim 3: Define the molecular basis for the regulation of IFNγ responses by Atg genes and identify lead compounds that up-regulate specific IFNγ effector mechanisms; Aim 4. Collaborate with other CETR projects to identify autophagy- and Atg gene-directed broad-spectrum anti-infective compounds.
项目总结-RP 3:RP 3的目标是定义和靶向细胞内免疫 利用自噬(Atg)基因(但不是降解性自噬)控制感染的机制, 炎症我们在实验中发现了这些过程,旨在了解抗感染药物 IFNγ是人类和小鼠巨噬细胞介导的抗 病毒、细菌和寄生虫。IFNγ用于治疗慢性肉芽肿性疾病和骨硬化症,但 IFNγ的其他用途受到毒性的限制,这一事实通常归因于IFNγ诱导了 大量的促炎基因我们的理论是,新的治疗方法可能会产生, 确定负责IFNγ强效作用的效应器机制,然后选择性刺激 这些机制来产生Atg基因导向的广谱抗感染药物。这导致了一个发现, IFNγ触发抗T.弓形虫和诺如病毒(NoV)感染,使用同一组 Atg基因(Atg 5,Atg 7,Atg 16 L1,Atg 12),而非Atg 14或降解性自噬。Atg基因- 一种依赖机制控制着两种不同的病原体,这向我们表明,我们可能是 能够制造出对多种病原体有效的化合物。在第一次CETR资助期间, 期间,我们通过鉴定Atg基因导向的广谱抗感染化合物证实了这一预测 具有抗诺如病毒、沙门氏菌、结核分枝杆菌和弓形虫的活性。这一发现 与此同时,发现了Atg基因在炎症调节中的作用。RP 3侧重于 杯状病毒科(最重要的是NoV)是优先病原体,导致>90%的非细菌性流行病 世界上最严重的肠胃炎我们首次发现了小鼠NoV(MNoV)并培养了NoV,为人类提供了一个新的研究方向。 实验室小鼠的临床前模型,并允许发现Atg基因依赖性免疫。人类研究 NoV(HNoV)感染一直是有限的,直到最近发现HNoV在从HNoV分化的细胞中生长。 活组织检查衍生的人结肠干细胞。这一点,以及发现MNoV在人类中稳健生长, 细胞表达适当的受体,并且Atg基因依赖的免疫针对T.弓形虫和 人类细胞中的MNoV强烈认为,这些机制在进化上是保守的,并提供了工具, 通过以下目的鉴定与主要人类疾病相关的化合物:目的1:开发Atg基因- 定向广谱抗感染化合物;目的2:确定Atg基因的分子基础- 依赖性IFNγ诱导的诺如病毒复制的控制,并确定靶点和先导化合物, 触发这种形式的细胞内免疫;目的3:确定IFNγ调节的分子基础 通过Atg基因的应答,并鉴定上调特异性IFNγ效应子的先导化合物 机制;目标4.与其他CETR项目合作,以确定自噬和Atg基因指导的 广谱抗感染化合物。

项目成果

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Seungmin Hwang其他文献

Seungmin Hwang的其他文献

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{{ truncateString('Seungmin Hwang', 18)}}的其他基金

RP3: Targeting ATG gene-dependent immunity for novel anti-infective therapeutics
RP3:针对 ATG 基因依赖性免疫的新型抗感染疗法
  • 批准号:
    9893813
  • 财政年份:
    2020
  • 资助金额:
    $ 93.95万
  • 项目类别:
RP3: Targeting ATG gene-dependent immunity for novel anti-infective therapeutics
RP3:针对 ATG 基因依赖性免疫的新型抗感染疗法
  • 批准号:
    10364725
  • 财政年份:
    2019
  • 资助金额:
    $ 93.95万
  • 项目类别:
Novel antiviral activity of interferon-gamma against viral replication complex
干扰素-γ针对病毒复制复合物的新型抗病毒活性
  • 批准号:
    9383726
  • 财政年份:
    2017
  • 资助金额:
    $ 93.95万
  • 项目类别:
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