Molecular impact of mutations in monogenic disease and cancer
单基因疾病和癌症突变的分子影响
基本信息
- 批准号:9156099
- 负责人:
- 金额:$ 37.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-26 至 2019-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAmino Acid SubstitutionClinicClinicalCommunitiesComprehensionComputer AnalysisComputer softwareComputing MethodologiesConsensusDNADNA SequenceDataDatabasesDiagnosisDiseaseGoalsHumanInformation ResourcesKnowledgeLiteratureMachine LearningMalignant NeoplasmsMendelian disorderMethodsMissense MutationModelingMolecularMutationMutation AnalysisPatientsPlayProbabilityProceduresProcessProteinsRare DiseasesReportingResourcesRoleScientistStructural ModelsStructureTertiary Protein StructureTextUncertaintybaseclinically relevantcrowdsourcingdata structureexperiencegenome-widehuman diseaseimprovedin vivointerestlearning strategynext generationprimary outcomeprotein functionprotein protein interactionprotein structureprototypetargeted treatmenttooltraitwiki
项目摘要
ABSTRACT
Next generation genome scale sequencing of patients is now becoming routine for two classes of disease: rare
Mendelian traits and cancer. In favorable cases, these data allow identification of relevant mutations and thus
aid diagnosis and therapy. In both classes of disease, the most common type of mutation is missense - single
base changes that result in an amino acid substitution in a protein. Uncertainty as to the impact of these
mutations on in vivo protein activity has resulted in a very conservative approach to their interpretation in the
clinic, so causing many missed opportunities for targeted treatment. The goal of this project is to use a
combination of three strategies to make the interpretation of these mutations much more applicable in the clinic.
There are already a large number of computational methods that attempt to determine the impact of missense
mutations on function, and there is substantial evidence that these have useful accuracy. The primary difficulty
is that the accuracy in any particular case is not reliably calibrated. Therefore, our first aim is to use a combination
of these methods to develop an approach focused on more reliable estimates for the probability of high impact
on protein function (i.e. more confident P values). The second aim is to maximize the utilization of three-
dimensional structural information, largely ignored by most computational methods. A large fraction of missense
mutations in these classes of disease act by destabilizing protein structure and knowledge of structure allows
these to be identified with much higher reliability. Also, structure provides a framework for detailed annotation
and comprehension of function. To facilitate the utilization of structure, we will implement a modeling platform
that leverages available experimental information to maximize the structural data available for analyzing mutation
impact. An important aspect of the platform is incorporation of methods for evaluating the reliability of the
structural features relevant to analysis of each mutation. In the third aim we will build specific functional models
for each protein of interest, integrating information from current databases, the literature, and community input,
so as to provide the richest possible background against which to judge the impact of mutations. Proteopedia, a
well established media wiki for proteins, will be used to provide an integrated view of text, data, and structure. A
key component of the information resource will be contributions from curators, who will provide annotation and
also solicit input from other experts. This aspect of the project builds on experience with other crowdsourcing
endeavors, including CASP, CAGI and Proteopedia. There will be three primary outcomes from the project:
First, improved reliability for the interpretation of missense mutations. Second, a prototype mutation annotation
procedure suitable for use in a clinical setting. Third, the resource will provide information of benefit to a range
of other scientists, thus facilitating the analysis of disease related mutations.
摘要
下一代患者基因组规模测序现在成为两类疾病的常规:罕见
在有利的情况下,这些数据允许识别相关的突变,
辅助诊断和治疗。在这两类疾病中,最常见的突变类型是错义突变,
导致蛋白质中氨基酸取代的碱基变化。这些影响的不确定性
突变对体内蛋白质活性的影响导致了对它们的解释的非常保守的方法,
临床,因此造成许多错失的机会,有针对性的治疗。这个项目的目标是使用一个
三种策略的组合使这些突变的解释更适用于临床。
已经有大量的计算方法试图确定错义的影响
突变的功能,有大量的证据表明,这些有有用的准确性。
在任何特定情况下的准确度都没有可靠的校准。因此,我们的首要目标是使用组合
开发一种方法,重点是对高影响概率进行更可靠的估计
第二个目标是最大限度地利用三种蛋白质的功能(即更可信的P值)。
三维结构信息,在很大程度上被大多数计算方法忽略。
这些类型疾病的突变通过破坏蛋白质结构而起作用,
此外,结构为详细的注释提供了一个框架
为了便于对结构的利用,我们将实现一个建模平台,
利用现有的实验信息,最大限度地利用可用于分析突变的结构数据
该平台的一个重要方面是纳入了用于评估平台可靠性的方法,
在第三个目标中,我们将建立特定的功能模型,
对于每种感兴趣的蛋白质,整合来自当前数据库、文献和社区输入的信息,
从而提供尽可能丰富的背景来判断突变的影响。Proteopedia,a
一个成熟的蛋白质媒体维基,将用于提供文本、数据和结构的综合视图。
信息资源的关键组成部分将是策展人的贡献,他们将提供注释,
也征求其他专家的意见。这方面的项目建立在与其他众包的经验,
努力,包括CASP,CAGI和Proteopedia。 该项目将产生三个主要成果:
第一,提高了解释错义突变的可靠性。第二,原型突变注释
第三,该资源将为一系列受益者提供信息,
其他科学家,从而促进疾病相关突变的分析。
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 }}
JOHN MOULT其他文献
JOHN MOULT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('JOHN MOULT', 18)}}的其他基金
Molecular impact of mutations in monogenic disease and cancer
单基因疾病和癌症突变的分子影响
- 批准号:
9504498 - 财政年份:2016
- 资助金额:
$ 37.29万 - 项目类别:
Mechanisms underlying complex trait human disease
复杂特征人类疾病的潜在机制
- 批准号:
8854112 - 财政年份:2013
- 资助金额:
$ 37.29万 - 项目类别:
Mechanisms underlying complex trait human disease
复杂特征人类疾病的潜在机制
- 批准号:
8431505 - 财政年份:2013
- 资助金额:
$ 37.29万 - 项目类别:
Mechanisms underlying complex trait human disease
复杂特征人类疾病的潜在机制
- 批准号:
8738688 - 财政年份:2013
- 资助金额:
$ 37.29万 - 项目类别:
Analysis of the Functional Impact of Coding Region SNPs
编码区 SNP 的功能影响分析
- 批准号:
6320208 - 财政年份:2001
- 资助金额:
$ 37.29万 - 项目类别:
Analysis of the Functional Impact of Coding Region SNPs
编码区 SNP 的功能影响分析
- 批准号:
6538222 - 财政年份:2001
- 资助金额:
$ 37.29万 - 项目类别:
Analysis of the Functional Impact of Coding Region SNPs
编码区 SNP 的功能影响分析
- 批准号:
6642811 - 财政年份:2001
- 资助金额:
$ 37.29万 - 项目类别:
相似海外基金
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:
$ 37.29万 - 项目类别:
Standard 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:
$ 37.29万 - 项目类别:
Standard Grant
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:
$ 37.29万 - 项目类别:
Training 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:
$ 37.29万 - 项目类别:
Fellowship
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:
$ 37.29万 - 项目类别:
Research Grant
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:
$ 37.29万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
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:
$ 37.29万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 37.29万 - 项目类别:
Standard Grant
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:
$ 37.29万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 37.29万 - 项目类别:
Grant-in-Aid for Early-Career Scientists