Bridging the gap between type 2 diabetes GWAS and therapeutic targets
缩小 2 型糖尿病 GWAS 与治疗目标之间的差距
基本信息
- 批准号:10649602
- 负责人:
- 金额:$ 186.37万
- 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:2020-08-20 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAddressAdipocytesAdipose tissueAffectAfricanAllelesAnimal ModelBiologicalBiological AssayCatalogsCell modelCellsChromatinCollaborationsCollectionCommunitiesComplementComputer AnalysisComputing MethodologiesDNADNA SequenceDataData SetDiseaseDistantDrug TargetingEast AsianElectrophysiology (science)EnvironmentEthnic OriginEuropeanEvaluationFrequenciesFunctional disorderGenerationsGenesGeneticGenetic VariationGenetic studyGenomeGenomicsGenotypeGluconeogenesisHepatic TissueHepatocyteHeritabilityHispanicHumanHuman GeneticsImpairmentIndividualInheritedInsulinInsulin deficiencyInternationalInvestigationIslet CellLatinoLinkLipidsLiverMapsMeta-AnalysisMethodsMitochondriaMolecularMorbidity - disease rateMuscleMuscle CellsNamesNon-Insulin-Dependent Diabetes MellitusNucleic Acid Regulatory SequencesNucleotidesPathway interactionsPharmaceutical PreparationsPhysiologicalPlayPopulationPopulation HeterogeneityRegulationRegulatory ElementResearch PersonnelResistanceRoleSeriesSignal PathwaySignal TransductionSouth AsianStructure of beta Cell of isletSystemTestingTissuesTranscriptTranslatingUntranslated RNAValidationVariantVisionVisualizationanalytical methodcandidate markercausal variantcell typeclinical phenotypecomputerized toolsdiabetes mellitus geneticsdiabetes pathogenesisdiabetes riskdisease heterogeneitydisorder riskepigenomicsexperimental studyfunctional genomicsgene regulatory networkgenetic architecturegenetic associationgenetic variantgenome annotationgenome editinggenome wide association studygenome-widegenome-wide analysisgenomic dataglucose uptakeimprovedin vivoinsightinsulin secretionisletlipid metabolismmortalitymultidisciplinarynew therapeutic targetnovelnovel therapeutic interventionpancreatic juiceprotein functionrisk variantskeletal tissuetherapeutic targettraittranscriptomics
项目摘要
Type 2 diabetes (T2D) is a heterogeneous disorder characterized by resistance of hepatic, skeletal muscle and
adipose tissues to insulin and a relative deficiency of insulin secretion by pancreatic β cells. T2D has a substantial
genetic component, and over the past decade human genetic studies have identified over 400 association
signals across diverse populations. However, in most cases the specific variants and genes responsible for these
association signals are not known. T2D signals include loci for which functions of the protein products encoded
by nearby genes are poorly characterized, the closest known gene is distant, or more than one gene appears to
be a plausible biological candidate. Identifying the causal variants, the regulatory gene networks affected by the
change in DNA sequence, and the mechanisms by which such variation leads to disease are critical steps toward
understanding the genetic architecture of T2D, validating potential drug targets, and developing novel therapeutic
strategies. Here, we propose large-scale multi-disciplinary functional genomics projects in islet, liver, adipose
and muscle cells to determine the contributions and mechanisms underlying T2D risk-associated variants and
their downstream effector transcripts. Throughout the project, we leverage our prior and ongoing generation of
genomic data sets and genome-wide and targeted screens for function of variants and genes. To complement
these efforts, we will first collect genome-wide array and sequencing-based association study results, identify
conditionally distinct association signals and construct credible sets of variants. We propose to link variants to
effector transcripts through analyses of genome-wide transcriptomic and epigenomic data, perturbation assays
that alter thousands of variant-containing regulatory elements and effector transcripts, perturbations of tens of
specific variants, and integrative computational analyses. Next, we propose systematic evaluation of hundreds
of potential effector transcripts through use of genome-wide and targeted screens of insulin secretion, lipid
accumulation, mitochondrial function, glucose uptake, and differentiation state, with assay selection depending
on cell type. Based on these results, we propose focused studies on tens to hundreds of potential effector
transcripts to evaluate electrophysiology, gluconeogenesis, lipid metabolism and signaling pathways, and we
propose thorough investigation the context-specific mechanism of action of individual genes. Finally, we propose
to analyze, integrate, and visualize all data by placing effector transcripts into cell-type and environmental
context-specific networks, selecting network nodes as candidate biomarkers and modulation points for drugs,
and building a framework to understand the tissue-specific contribution of variants and transcripts to individual
disease heterogeneity. Successful completion of these aims will translate T2D association signals into biological
insights and therapeutic targets.
2型糖尿病(T2D)是一种异质性疾病,其特征是肝脏、骨骼肌和
脂肪组织对胰岛素的敏感性和胰腺β细胞分泌胰岛素的相对不足。T2D有很大的
基因成分,在过去的十年中,人类基因研究已经确定了400多种关联
不同人群的信号。然而,在大多数情况下,导致这些的特定变异和基因
关联信号未知。T2D信号包括蛋白质产物的功能编码的基因座
由于邻近的基因特征不佳,最接近的已知基因是遥远的,或者似乎有不止一个基因
成为一个看似合理的生物候选人。确定因果变异,受影响的调控基因网络
DNA序列的变化以及这种变化导致疾病的机制是实现
了解T2D的遗传结构,验证潜在的药物靶点,并开发新的治疗方法
战略。在这里,我们提出了在胰岛、肝脏、脂肪等领域的大规模多学科功能基因组计划
和肌肉细胞,以确定T2D风险相关变体和T2D的作用和机制
它们下游的效应器转录本。在整个项目中,我们利用我们的上一代和正在进行的
基因组数据集以及对变异和基因功能的全基因组和有针对性的筛选。来补充
这些努力,我们将首先收集全基因组阵列和基于测序的关联研究结果,确定
有条件地不同的关联信号,并构建可信的变种集合。我们建议将变体链接到
通过全基因组转录和表观基因组数据的分析,扰动分析,效应转录本
它改变了数千个含有变体的调控元件和效应器转录,数十个
具体的变种和综合的计算分析。接下来,我们建议对数百人进行系统评估
通过使用全基因组和靶向筛选胰岛素分泌、脂质
积累、线粒体功能、葡萄糖摄取和分化状态,取决于检测选择
关于细胞类型。基于这些结果,我们建议对数十到数百个潜在的效应器进行集中研究
转录本,以评估电生理学,糖异生,脂代谢和信号通路,我们
建议深入研究个别基因在特定背景下的作用机制。最后,我们建议
通过将效应器转录放入细胞类型和环境中来分析、集成和可视化所有数据
上下文特定网络,选择网络节点作为药物的候选生物标记物和调制点,
并建立一个框架,以了解变体和转录本对个体的组织特异性贡献
疾病异质性。这些目标的成功完成将把T2D关联信号转化为生物
洞察力和治疗目标。
项目成果
期刊论文数量(19)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Genetics of Type 2 Diabetes: Opportunities for Precision Medicine: JACC Focus Seminar.
- DOI:10.1016/j.jacc.2021.03.346
- 发表时间:2021-08-03
- 期刊:
- 影响因子:24
- 作者:Kim DS;Gloyn AL;Knowles JW
- 通讯作者:Knowles JW
100 YEARS OF INSULIN: A brief history of diabetes genetics: insights for pancreatic beta-cell development and function.
- DOI:10.1530/joe-21-0067
- 发表时间:2021-07-22
- 期刊:
- 影响因子:4
- 作者:Ikle, Jennifer M.;Gloyn, Anna L.
- 通讯作者:Gloyn, Anna L.
Multi-ancestry Polygenic Mechanisms of Type 2 Diabetes Elucidate Disease Processes and Clinical Heterogeneity.
2 型糖尿病的多祖先多基因机制阐明了疾病过程和临床异质性。
- DOI:10.1101/2023.09.28.23296294
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Smith,Kirk;Deutsch,AaronJ;McGrail,Carolyn;Kim,Hyunkyung;Hsu,Sarah;Mandla,Ravi;Schroeder,PhilipH;Westerman,KennethE;Szczerbinski,Lukasz;Majarian,TimothyD;Kaur,Varinderpal;Williamson,Alice;Claussnitzer,Melina;Florez,JoseC;Ma
- 通讯作者:Ma
The use of precision diagnostics for monogenic diabetes: a systematic review and expert opinion.
- DOI:10.1038/s43856-023-00369-8
- 发表时间:2023-10-05
- 期刊:
- 影响因子:0
- 作者:Murphy, Rinki;Colclough, Kevin;Pollin, Toni I;Ikle, Jennifer M;Svalastoga, Pernille;Maloney, Kristin A;Saint-Martin, Cecile;Molnes, Janne;Misra, Shivani;Aukrust, Ingvild;de Franco, Elisa;Flanagan, Sarah E;Njolstad, Pal R;Billings, Liana K;Owen, Katharine R;Gloyn, Anna L
- 通讯作者:Gloyn, Anna L
A genome-wide CRISPR screen identifies CALCOCO2 as a regulator of beta cell function influencing type 2 diabetes risk.
- DOI:10.1038/s41588-022-01261-2
- 发表时间:2023-01
- 期刊:
- 影响因子:30.8
- 作者:Rottner, Antje K.;Ye, Yingying;Navarro-Guerrero, Elena;Rajesh, Varsha;Pollner, Alina;Bevacqua, Romina J.;Yang, Jing;Spigelman, Aliya F.;Baronio, Roberta;Bautista, Austin;Thomsen, Soren K.;Lyon, James;Nawaz, Sameena;Smith, Nancy;Wesolowska-Andersen, Agata;Fox, Jocelyn E. Manning;Sun, Han;Kim, Seung K.;Ebner, Daniel;MacDonald, Patrick E.;Gloyn, Anna L.
- 通讯作者:Gloyn, Anna L.
{{
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 }}
Melina C Claussnitzer其他文献
Melina C Claussnitzer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('Melina C Claussnitzer', 18)}}的其他基金
Bridging the gap between type 2 diabetes GWAS and therapeutic targets
缩小 2 型糖尿病 GWAS 与治疗目标之间的差距
- 批准号:
10438836 - 财政年份:2020
- 资助金额:
$ 186.37万 - 项目类别:
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:
$ 186.37万 - 项目类别:
Fellowship
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:
$ 186.37万 - 项目类别:
Research Grant
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:
$ 186.37万 - 项目类别:
Continuing 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:
$ 186.37万 - 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:
$ 186.37万 - 项目类别:
Standard Grant
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:
$ 186.37万 - 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:
$ 186.37万 - 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:
$ 186.37万 - 项目类别:
EU-Funded
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:
$ 186.37万 - 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:
$ 186.37万 - 项目类别:
Research Grant














{{item.name}}会员




