6mer seed toxicity and AIDS
6mer 种子毒性和艾滋病
基本信息
- 批准号:10132980
- 负责人:
- 金额:$ 23.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-25 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated RegionsAcquired Immunodeficiency SyndromeAntioxidantsApoptosisAutomobile DrivingAutophagocytosisBasic ScienceBiogenesisCD4 Positive T LymphocytesCell DeathCell Death InductionCell LineCellsCessation of lifeCodeComplexDataData SetDicer EnzymeDown-RegulationGenerationsGenesGoalsHIVHIV InfectionsHIV-1HybridsInfectionKnock-outLigationMediatingMessenger RNAMicroRNAsMitoticMolecularNecrosisPathway interactionsPharmacotherapyProductionProteinsProvirusesRNARNA InterferenceRNA-Induced Silencing ComplexReactive Oxygen SpeciesRouteSeedsShockSiteSmall Interfering RNASmall RNAStressT-LymphocyteTestingTherapeuticTissuesToxic effectUntranslated RNAViralVirusVirus ReplicationWorkantiretroviral therapybasecell killingcrosslinkeffective therapyimmunoregulationin vivoknock-downmutantneuron lossnoveloverexpressionpreventresponsetranscriptome sequencingvirology
项目摘要
! 1!
Summary
The proposal is in response to PA-19-237: Novel RNAs in Virology (including HIV) and Immune Regulation:
Basic Science and Therapeutic Discovery.
HIV-1 (HIV) infects CD4 positive cells causing acquired immunodeficiency syndrome (AIDS). Many forms of
cell death (apoptosis, necrosis, necroptosis, autophagy, pyroptosis, mitotic catastrophe, and others) have been
shown to be involved in virus induced cell loss of directly infected and bystander cells. While current
antiretroviral therapy (ART) now prevents CD4 decline and restores their numbers to nearly normal in most
cases, a major unsolved problem is why some cells survive HIV infection rather than dying, persist with latent
provirus. A fundamental understanding of mechanisms of cell death induction by HIV could provide the means
to kill those cells that constitute a reservoir of reactivatable virus that mandates lifelong ART. Such cells have
so far evaded death from experimental “shock and kill” cure strategies. We have recently discovered a novel
form of cell death that is a combination of almost all of the above-mentioned mechanisms implicated to date in
cell death associated with untreated HIV infection. 6mer Seed Toxicity (6mer Seed Tox) is an RNA interference
(RNAi) based mechanism that kills cells through toxic seeds that target reverse complementary seed matches
in the 3'UTR of a large number of genes that are critical for the survival of all cells. Our recent data suggest
that primary tissues are protected from 6mer Seed Tox by highly expressed miRNAs that do not carry a toxic
seed and block access of the potentially toxic small RNAs to the RNA induced silencing complex (RISC) that
mediates RNAi. Our new preliminary data demonstrate that HIV infection kills cells that lack these protective
miRNAs much more efficiently and it kills cells less efficiently that cannot form a functional RISC to mediate
RNAi. These data suggest that cell death induced by HIV involves the RNAi machinery. The first hypothesis of
this proposal is that HIV kills infected cells by engaging the 6mer Seed Tox mechanism either by triggering the
generation of cell-endogenous toxic sRNAs or by producing virus-encoded toxic sRNAs that enter the RISC.
The second hypothesis is that HIV stresses infected cells in a way that causes downregulation of the miRNA
biogenesis enzyme Dicer decreases maturation of protective miRNAs, sensitizing infected cells to toxic siRNAs
that are generated independently of Dicer. These hypotheses will be studied in two aims: Specific Aim 1:
Determine whether HIV-1 triggers 6mer Seed Tox in infected cells through the production of toxic viral or
cellular sRNAs. Specific Aim 2: Determine whether modulation of protective miRNAs in either direction renders
HIV-1 infected cells more or less susceptible to 6mer Seed Tox. Our work will establish whether HIV kills
infected cells through 6mer seed toxicity. It may pave the way to advance current HIV eradication strategies by
sensitizing cells to induction of 6mer Seed Tox after latency reversal and decreasing neuronal death in HAND.
!1!
摘要
该提案是对PA-19-237:病毒学(包括艾滋病毒)和免疫调节中的新RNA的回应:
基础科学和治疗发现。
HIV-1(HIV)感染CD4阳性细胞,导致获得性免疫缺陷综合征(AIDS)。多种形式的
细胞死亡(细胞凋亡、坏死、坏死性下垂、自噬、下垂、有丝分裂灾难等)
表明参与了病毒引起的直接感染细胞和旁观者细胞的丢失。当当前
现在,抗逆转录病毒疗法(ART)可以防止CD4的下降,并使大多数患者的CD4细胞数量恢复到接近正常的水平
在一些病例中,一个尚未解决的主要问题是为什么一些细胞在艾滋病毒感染后存活下来,而不是死亡,持续潜伏
普罗鲁斯。对艾滋病毒诱导细胞死亡机制的基本了解可以提供手段
杀死那些构成可激活病毒储存库的细胞,这些病毒决定了终身抗逆转录病毒。这样的细胞有
到目前为止,通过实验性的“电击并杀死”治愈策略避免了死亡。我们最近发现了一本小说
一种细胞死亡的形式,是到目前为止所涉及的几乎所有上述机制的组合
与未经治疗的艾滋病毒感染有关的细胞死亡。6聚体种子毒性(6聚体种子毒素)是一种RNA干扰
基于(RNAi)的机制,通过针对反向互补种子匹配的有毒种子杀死细胞
在3‘非编码区中有大量对所有细胞的生存至关重要的基因。我们最近的数据表明
初级组织受到高度表达的miRNAs的保护,不受6聚体种子毒素的影响,这些miRNAs不携带有毒的
种子和阻止潜在有毒小RNA对RNA诱导的沉默复合体(RISC)的访问
介导RNAi。我们的新的初步数据表明,艾滋病毒感染会杀死缺乏这些保护的细胞
MiRNAs的效率要高得多,但它杀死无法形成功能RISC的细胞的效率较低
RNAi。这些数据表明,HIV诱导的细胞死亡涉及RNAi机制。第一个假设是
这一建议是,艾滋病毒通过启动6聚体种子毒素机制来杀死受感染的细胞,要么通过触发
产生细胞内源性有毒sRNA,或通过产生病毒编码的有毒sRNA进入RISC。
第二种假设是,HIV以一种导致miRNA下调的方式对感染细胞施加压力。
生物生成酶Disher降低保护性miRNAs的成熟度,使受感染的细胞对有毒的siRNAs敏感
它们是独立于迪特尔生成的。这些假设将在两个目标下进行研究:具体目标1:
确定HIV-1是否通过产生有毒病毒或在感染细胞中触发6聚体种子毒素
细胞sRNA。具体目标2:确定保护性miRNAs在两个方向上的调制是否呈现
HIV-1感染细胞对6聚体种子毒素有不同程度的敏感性。我们的工作将确定艾滋病毒是否会导致
通过6聚体种子毒性感染细胞。它可能通过以下方式为推进当前的艾滋病毒根除战略铺平道路
在潜伏期逆转后使细胞对6聚体种子毒素的诱导敏感,并减少手部神经元死亡。
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 }}
Marcus E. Peter其他文献
Expression of c-FLIP<sub>L</sub> and resistance to CD95-mediated apoptosis of monocyte-derived dendritic cells: inhibition by bisindolylmaleimide
- DOI:
10.1182/blood.v95.11.3478 - 发表时间:
2000-06-01 - 期刊:
- 影响因子:
- 作者:
Fabienne Willems;Zoulikha Amraoui;Nathalie Vanderheyde;Valérie Verhasselt;Ezra Aksoy;Carsten Scaffidi;Marcus E. Peter;Peter H. Krammer;Michel Goldman - 通讯作者:
Michel Goldman
Mapping of Ras-related GTP-binding proteins by GTP overlay following two-dimensional gel electrophoresis.
二维凝胶电泳后通过 GTP 覆盖图绘制 Ras 相关 GTP 结合蛋白。
- DOI:
- 发表时间:
1994 - 期刊:
- 影响因子:11.1
- 作者:
Lukas A. Huber;Oliver Ullrich;Y. Takai;Anne Lütcke;Paul Dupree;V. Olkkonen;H. Virta;M. J. D. Hoop;Kirill Alexandrov;Marcus E. Peter;Marino Zerial;Kai Simons - 通讯作者:
Kai Simons
AIDS and the death receptors.
艾滋病和死亡受体。
- DOI:
- 发表时间:
1997 - 期刊:
- 影响因子:6.7
- 作者:
Marcus E. Peter;A. Ehret;Christina Berndt;P. H. Krammer - 通讯作者:
P. H. Krammer
The two CD95 apoptosis signaling pathways may be a way of cells to respond to different amounts and/or forms of CD95 ligand produced in different tissues
这两条CD95凋亡信号通路可能是细胞对不同组织中产生的不同量和/或形式的CD95配体作出反应的一种方式
- DOI:
10.1038/sj.cdd.4400707 - 发表时间:
2000 - 期刊:
- 影响因子:12.4
- 作者:
Ingo Schmitz;Henning Walczak;P. H. Krammer;Marcus E. Peter - 通讯作者:
Marcus E. Peter
APO‐1(CD95)‐mediated apoptosis in Jurkat cells does not involve src kinases or CD45
Jurkat 细胞中 APO-1(CD95) 介导的细胞凋亡不涉及 src 激酶或 CD45
- DOI:
- 发表时间:
1995 - 期刊:
- 影响因子:3.5
- 作者:
B. Schraven;Marcus E. Peter - 通讯作者:
Marcus E. Peter
Marcus E. Peter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('Marcus E. Peter', 18)}}的其他基金
Novel immune suppressive activities of Fas/CD95 in triple negative breast cancer
Fas/CD95 在三阴性乳腺癌中的新型免疫抑制活性
- 批准号:
10514907 - 财政年份:2022
- 资助金额:
$ 23.85万 - 项目类别:
Novel immune suppressive activities of Fas/CD95 in triple negative breast cancer
Fas/CD95 在三阴性乳腺癌中的新型免疫抑制活性
- 批准号:
10661817 - 财政年份:2022
- 资助金额:
$ 23.85万 - 项目类别:
DISE - a natural cancer surveillance mechanism - a new road to cancer therapy
DISE——天然癌症监测机制——癌症治疗新之路
- 批准号:
9313238 - 财政年份:2015
- 资助金额:
$ 23.85万 - 项目类别:
DISE - a natural cancer surveillance mechanism - a new road to cancer therapy
DISE——天然癌症监测机制——癌症治疗新之路
- 批准号:
9753713 - 财政年份:2015
- 资助金额:
$ 23.85万 - 项目类别:
DISE - a natural cancer surveillance mechanism - a new road to cancer therapy
DISE——天然癌症监测机制——癌症治疗新之路
- 批准号:
10224839 - 财政年份:2015
- 资助金额:
$ 23.85万 - 项目类别:
DICE - a natural cancer surveillance mechanism - a new road to cancer therapy
DICE——自然癌症监测机制——癌症治疗新之路
- 批准号:
9122387 - 财政年份:2015
- 资助金额:
$ 23.85万 - 项目类别:
相似海外基金
Impact of alternative polyadenylation of 3'-untranslated regions in the PI3K/AKT cascade on microRNA
PI3K/AKT 级联中 3-非翻译区的替代多聚腺苷酸化对 microRNA 的影响
- 批准号:
573541-2022 - 财政年份:2022
- 资助金额:
$ 23.85万 - 项目类别:
University Undergraduate Student Research Awards
How do untranslated regions of cannabinoid receptor type 1 mRNA determine receptor subcellular localisation and function?
1 型大麻素受体 mRNA 的非翻译区如何决定受体亚细胞定位和功能?
- 批准号:
2744317 - 财政年份:2022
- 资助金额:
$ 23.85万 - 项目类别:
Studentship
MICA:Synthetic untranslated regions for direct delivery of therapeutic mRNAs
MICA:用于直接递送治疗性 mRNA 的合成非翻译区
- 批准号:
MR/V010948/1 - 财政年份:2021
- 资助金额:
$ 23.85万 - 项目类别:
Research Grant
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10019570 - 财政年份:2019
- 资助金额:
$ 23.85万 - 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10223370 - 财政年份:2019
- 资助金额:
$ 23.85万 - 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10455108 - 财政年份:2019
- 资助金额:
$ 23.85万 - 项目类别:
Synergistic microRNA-binding sites, and 3' untranslated regions: a dialogue of silence
协同的 microRNA 结合位点和 3 非翻译区:沉默的对话
- 批准号:
255762 - 财政年份:2012
- 资助金额:
$ 23.85万 - 项目类别:
Operating Grants
Analysis of long untranslated regions in Nipah virus genome
尼帕病毒基因组长非翻译区分析
- 批准号:
20790351 - 财政年份:2008
- 资助金额:
$ 23.85万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Search for mRNA elements involved in the compatibility between 5' untranslated regions and coding regions in chloroplast translation
寻找参与叶绿体翻译中 5 非翻译区和编码区之间兼容性的 mRNA 元件
- 批准号:
19370021 - 财政年份:2007
- 资助金额:
$ 23.85万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Post-transcriptional Regulation of PPAR-g Expression by 5'-Untranslated Regions
5-非翻译区对 PPAR-g 表达的转录后调控
- 批准号:
7131841 - 财政年份:2006
- 资助金额:
$ 23.85万 - 项目类别:














{{item.name}}会员




