Elucidating the Chemistry and Biology of Nucleic Acid Cytidine Deaminases in HIV

阐明 HIV 核酸胞苷脱氨酶的化学和生物学

基本信息

  • 批准号:
    7928544
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-02-15 至 2010-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The primary investigator is an MD/PhD trained infectious diseases physician with an interest in understanding enzymes that generate diversity in host-pathogen interactions. In the proposed work, the PI aims to bring his prior experience in enzyme mechanisms and develop new training through virologic experiments and immunologic studies. A remarkable group of enzymes, the polynucleotide cytidine deaminases of the AID/APOBEC family, play both constructive and destructive roles in struggle against HIV. On one hand, deamination by the family member APOBEC3G interferes with the integrity of the pathogen genome. In turn, HIV has evolved the lentiviral protein Vif as an evasive means to counteract human APOBEC3G. Infection with HIV is also associated with immune activation, which can result in increased expression of a B-cell specific deaminase family member, AID. AID physiologically serves as the chief catalyst governing antibody diversity through the introduction of targeted uracil lesions in antibody variable genes or switch regions which ultimately result in higher affinity antibodies of altered isotype. Aberrant regulation and expression of AID has increasingly been associated with Non-Hodgkins lymphoma, the leading AIDS-defining malignancy in HIV infected patients. Despite the importance of these cytidine deaminases, little is known about the nature of their interaction with their nucleic acid targets. This proposal addresses the hypothesis that the molecular interactions that lead to catalysis and binding of nucleic acids are critical determinants of their proper physiologic function. The studies aim to decipher and perturb these molecular interactions. Initially, structure-based hypotheses will be used to localize the protein determinants of sequence preference and resolve the mode of binding to the nucleic acid backbone. By utilizing novel loop graft mutant enzymes with altered sequence preference, the impact of perturbed sequence specificity on retroviral restriction (APOBEC3G) or antibody diversity and chromosomal translocations (AID) will be explored. To understand catalysis by AID/APOBEC enzymes, nucleoside analogs will be introduced into oligonucleotides via chemical or chemoenzymatic methods and are used to characterize the kinetics of deamination and the inhibition of pro-oncogenic AID activity. Taken together, a full characterization of the AID/APOBEC-nucleic acid complex - binding and catalysis - will provide a molecular basis for the action of this important enzyme family in vitro and in vivo. Through mentored training, the PI will develop the broad based research skills necessary to examine biological and biochemical aspects of diversity generation in host-pathogen interactions upon an ultimate transition to independence. RELEVANCE The immune system uses enzymes that catalyze the targeted deamination of cytosine to restrict HIV and make high affinity antibodies, though the same mechanisms can potentially be pro-oncogenic. This proposal aims to biochemically define and biologically perturb the molecular interactions that allow polynucleotide cytidine deaminase enzymes of the AID/APOBEC family to protect against infection.
描述(由申请人提供):主要研究人员是一名医学博士/博士学位的传染病内科医生,对了解在宿主-病原体相互作用中产生多样性的酶感兴趣。在拟议的工作中,PI的目标是利用他在酶机制方面的先前经验,并通过病毒学实验和免疫学研究开发新的培训。AID/APOBEC家族的多核苷酸胞苷脱氨酶是一组值得注意的酶,在抗击艾滋病毒的斗争中既发挥了建设性的作用,也发挥了破坏性的作用。一方面,APOBEC3G家族成员的脱氨基作用干扰了病原体基因组的完整性。反过来,HIV进化出慢病毒蛋白Vif,作为一种逃避手段来对抗人类APOBEC3G。感染艾滋病毒还与免疫激活有关,免疫激活可导致B细胞特异性脱氨酶家族成员AID表达增加。生理学上,AID通过在抗体可变区或转换区引入靶向的尿嘧啶损伤,最终导致同型改变的高亲和力抗体,从而成为控制抗体多样性的主要催化剂。AID的异常调控和表达与非霍奇金淋巴瘤的相关性越来越大,非霍奇金淋巴瘤是HIV感染患者中定义艾滋病的主要恶性肿瘤。尽管这些胞苷脱氨酶很重要,但人们对它们与核酸靶标相互作用的性质知之甚少。这一建议解决了这样的假设,即导致核酸催化和结合的分子相互作用是其适当生理功能的关键决定因素。这些研究旨在破译和扰乱这些分子相互作用。最初,基于结构的假说将被用来定位序列偏好的蛋白质决定因素,并解析与核酸骨架结合的模式。通过利用改变了序列偏好的新型环状嫁接突变酶,将探索干扰序列特异性对逆转录病毒限制性内切酶(APOBEC3G)或抗体多样性和染色体易位(AID)的影响。为了了解AID/APOBEC酶的催化作用,将核苷类似物通过化学或化学酶方法引入到寡核苷酸中,用于表征脱氨反应的动力学和对致癌AID活性的抑制。综上所述,对AID/APOBEC-核酸复合体-结合和催化-的全面表征将为这个重要的酶家族在体外和体内的作用提供分子基础。通过有指导的培训,PI将发展必要的基础广泛的研究技能,以在最终过渡到独立时检查宿主-病原体相互作用中多样性产生的生物学和生化方面。 相关性免疫系统使用催化胞嘧啶的靶向脱氨基的酶来限制艾滋病毒并制造高亲和力抗体,尽管相同的机制可能是促癌的。这项建议旨在生物化学定义和生物扰动分子相互作用,使AID/APOBEC家族的多核苷酸胞苷脱氨酶酶能保护免受感染。

项目成果

期刊论文数量(0)
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Rahul Manu Kohli其他文献

Rahul Manu Kohli的其他文献

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{{ truncateString('Rahul Manu Kohli', 18)}}的其他基金

Inhibition and Catalytic Degradation of Promutagenic DNA Deaminases
促诱变 DNA 脱氨酶的抑制和催化降解
  • 批准号:
    10729968
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
Engineering Efficient and Controllable Base Editors
工程高效且可控的碱基编辑器
  • 批准号:
    10396080
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Engineering Efficient and Controllable Base Editors
工程高效且可控的碱基编辑器
  • 批准号:
    10609857
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Engineering Efficient and Controllable Base Editors
工程高效且可控的碱基编辑器
  • 批准号:
    10796080
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Engineering Efficient and Controllable Base Editors
工程高效且可控的碱基编辑器
  • 批准号:
    10209723
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Non-destructive epigenetic sequencing with DNA deaminase enzymes
使用 DNA 脱氨酶进行非破坏性表观遗传测序
  • 批准号:
    10186786
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Non-destructive epigenetic sequencing with DNA deaminase enzymes
使用 DNA 脱氨酶进行非破坏性表观遗传测序
  • 批准号:
    9797035
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Non-destructive epigenetic sequencing with DNA deaminase enzymes
使用 DNA 脱氨酶进行非破坏性表观遗传测序
  • 批准号:
    10004705
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Combating Bacterial Drug Resistance by Targeting the Enzymes of Evolution
通过针对进化酶来对抗细菌耐药性
  • 批准号:
    8355227
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
Elucidating the Chemistry and Biology of Nucleic Acid Cytidine Deaminases in HIV
阐明 HIV 核酸胞苷脱氨酶的化学和生物学
  • 批准号:
    8136827
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:

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