Modular Reagents for Programmable RNA Manipulation by Endogenous Proteins
用于内源蛋白可编程 RNA 操作的模块化试剂
基本信息
- 批准号:10605050
- 负责人:
- 金额:$ 6.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-02-27 至 2026-02-26
- 项目状态:未结题
- 来源:
- 关键词:AblationAddressAdenosineAffectBase Pair MismatchBindingBiological AssayBiological ModelsBiologyCCND1 geneCellsChemicalsChemistryClinicalClustered Regularly Interspaced Short Palindromic RepeatsComplementary RNAComplexDevelopmentDiseaseDown-RegulationEngineeringEnvironmentEventFOXM1 geneFoundationsGelGene ExpressionGenesGenetic DiseasesGenetic TranscriptionGoalsGuide RNAHealthHumanImmunoprecipitationIn VitroIncidenceInterventionLaboratoriesLearningLengthLibrariesLigandsLuciferasesMalignant NeoplasmsMammalsMediatingMedicineMessenger RNAMethylationMethyltransferaseModelingModificationN-terminalNerve DegenerationNuclearOligonucleotidesPharmaceutical PreparationsPositioning AttributePost-Transcriptional RegulationPrimary carcinoma of the liver cellsProliferatingProteinsRNARNA InterferenceRNA libraryReagentReporterResearchResourcesScientistSignal TransductionSmall Interfering RNAStructure-Activity RelationshipSynthesis ChemistrySystemTherapeuticTranscriptTranslationsUntranslated RNAValidationWorkchemical synthesisdesignexperimental studyfallsin vivomembernovelposttranscriptionalpreventrecruitside effectskillssmall moleculetooltranscriptome sequencing
项目摘要
PROJECT SUMMARY:
New strategies to targeted difficult-to-drug diseases such as cancers, neurodegeneration, and genetic disorders
are urgently needed. RNA manipulation is an emerging, therapeutically attractive paradigm which allows target
intervention orthogonal to drugging proteins and without the permanence of gene editing. A variety of tools for
RNA manipulation have been developed, but they rely on ribonuclear proteins, which are difficult to deliver in
vivo or are limited in scope of effect. This proposal aims to develop RNA-based bifunctional molecules (RBMs)
which will consist of an RNA oligonucleotide liked to a small molecule which recruits an effector protein, and will
enable modular, programmable targeting of RNA with a variety of manipulations. The proposed mechanism for
RBMs is based on small interfering RNA (siRNA) oligonucleotides which are widely used as research tools and
have resulted in multiple approved therapeutics. In cells, siRNAs are loaded into Argonaute (AGO) proteins
which are part of the RNA silencing complex (RISC). AGO then guides RISC to mRNA targets complementary
to its loaded siRNA guide, which are cleaved upon binding, resulting in translational silencing. The
oligonucleotide portion of RBMs will function much like siRNAs but will feature key mismatches with the target
RNA. Such mismatches have been shown to oblate the cleavage activity of RISC while maintaining target
binding. Target binding will induce proximity between the target RNA and an effector protein recruited by the
small molecule ligand of the RBM, allowing the effector to act on the target. I will synthesize a small library of
RBMs with variable linker lengths and positions, and verify that they can interact with AGO and a model effector
protein in vitro (Aim 1). Next, I will use AGO pulldown to show that these interactions can be recapitulated in
cells, then use two model systems to show that RBMs can enable post-transcriptional control of mRNA targets
(Aim 2). Finally, I will show that RBMs targeting nuclear, long non-coding RNAs can enable control of gene
expression (Aim 3). Overall, this will create a platform in which the siRNA paradigm is expanded to enable a
much wider variety of manipulations, which will enable novel research tools and therapies.
This project will use my existing skills in synthetic chemistry as a foundation and then allow me to branch out
in the field of chemical biology. The laboratory of my sponsor, Prof. Steven Banik, is a supportive research
environment which will enable me to successfully learn the new skills required to execute this proposal. Prof.
Banik is a member of Stanford's Chemistry Engineering and Medicine for Human Health (ChEM-H), a highly
collaborative and interdisciplinary institute. Stanford and ChEM-H will afford me all necessary research
resources, a variety of opportunities for professional development, and the opportunity to work with, and learn
from many, different scientists.
项目概要:
针对癌症、神经变性和遗传性疾病等难治性疾病的新策略
是迫切需要的。RNA操作是一种新兴的、具有治疗吸引力的范例,其允许靶向RNA。
干预正交于药物蛋白质,而没有基因编辑的永久性。各种工具,
RNA操纵已经开发出来,但它们依赖于核糖核蛋白,这是很难交付的。
体内或作用范围有限。该提案旨在开发基于RNA的双功能分子(RBM)
其将由与募集效应蛋白的小分子连接的RNA寡核苷酸组成,并且将
使模块化,可编程的RNA靶向与各种操作。的拟议机制
RBM基于小干扰RNA(siRNA)寡核苷酸,其被广泛用作研究工具,
已经产生了多种被批准的治疗方法。在细胞中,siRNA被装载到Argonaute(AGO)蛋白中,
RNA沉默复合物(RISC)AGO然后引导RISC到mRNA靶点互补
与其加载的siRNA引导物结合,所述siRNA引导物在结合时被切割,导致翻译沉默。的
RBM的寡核苷酸部分的功能与siRNA非常相似,但其特征在于与靶分子的关键错配
核糖核酸已经显示这种错配使RISC的切割活性变小,同时维持靶向的细胞分裂。
约束力靶结合将诱导靶RNA与由靶RNA募集的效应蛋白之间的接近。
RBM的小分子配体,允许效应物作用于靶标。我会合成一个小型的
RBM与可变接头长度和位置,并验证它们可以与AGO和模型效应物相互作用
体外蛋白质(目的1)。接下来,我将使用AGO下拉来说明这些交互可以在
细胞,然后使用两个模型系统,以表明RBM可以使转录后控制的mRNA目标
(Aim 2)。最后,我将展示RBM靶向细胞核,长的非编码RNA可以使基因控制,
表达式(目标3)。总的来说,这将创建一个平台,其中siRNA范例被扩展以使得能够实现对siRNA的扩增。
更广泛的操作,这将使新的研究工具和疗法。
这个项目将利用我现有的合成化学技能作为基础,然后让我分支出来
在化学生物学领域。我的赞助人Steven Banik教授的实验室是一项支持性研究,
环境,这将使我能够成功地学习新的技能所需的执行这一建议。教授
Banik是斯坦福大学的化学工程和人类健康医学(ChEM-H)的成员,这是一个非常重要的研究领域。
合作和跨学科研究所。斯坦福大学和ChEM-H会提供我所有必要的研究经费
资源,各种专业发展的机会,以及与之合作和学习的机会
来自许多不同的科学家
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 }}
Robert Follett Lusi其他文献
Robert Follett Lusi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 }}
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 6.87万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 6.87万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 6.87万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 6.87万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 6.87万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 6.87万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 6.87万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 6.87万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 6.87万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 6.87万 - 项目类别:
Research Grant