Genetic Regulation of Human Beta Cell Destruction
人类β细胞破坏的基因调控
基本信息
- 批准号:8813679
- 负责人:
- 金额:$ 311.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-30 至 2019-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAllelesAntigensAutoimmune ProcessAutoimmunityBeta CellBiologyBlood VesselsCD8-Positive T-LymphocytesCD8B1 geneCell DeathCellsCessation of lifeComplexCoupledCytolysisDataDefectDendritic CellsDendritic cell activationDevelopmentDisciplineDiseaseDisease ProgressionDisease ResistanceElementsEndogenous FactorsEndothelial CellsEnvironmentEventExogenous FactorsFigs - dietaryFutureGenesGeneticGenetic RiskGoalsGrantHomingHumanImmuneImmune ToleranceImmune systemImmunogeneticsImmunologyIndividualInflammationInsulinInsulin-Dependent Diabetes MellitusInvestigationKnowledgeLinkLymphocyte ActivationLymphocyte FunctionLymphoidMediatingModelingMolecularMusPTPN22 genePancreasPathogenesisPlayPolygenic TraitsPopulationPredispositionProcessRegulationRelative (related person)Research DesignResistanceRiskRoleSolutionsStem cellsSusceptibility GeneSystemT-LymphocyteTechnologyTestingVariantbasecell typecellular engineeringcytotoxicdiabetes mellitus geneticsgenetic elementgenetic risk factorhuman PTPN22 proteinimmunogenicimprovedinduced pluripotent stem cellinnovationinsulin dependent diabetes mellitus onsetisletnovelpublic health relevanceresponserisk variantstem cell technologyuptakevascular inflammation
项目摘要
DESCRIPTION (provided by applicant): The development of Type 1 Diabetes (T1D) relies on complex interrelationships between cells of the immune system [e.g., DC, CD8+ T cells] and genes imparting susceptibility or resistance to the disease that underlie the autoimmune destruction of insulin producing pancreatic β cells. While a broad body of evidence certainly exists to support this notion (and we ourselves believe it true), the exact mechanism by which autoimmune β cell destruction is facilitated remains unclear. In addition, the relative contributions of each facet (i.e., cells, genes) play in the process remain, to a large extent, unknown. Mechanistic studies of T1D-associated susceptibility alleles are complicated by polygenic inheritance such that no two individuals are truly alike. Hence, studies are severely hampered by a lack of power in populations, and the inability to isolate the functional impact of a
variant to a specific cell type. Here we present a solution that focuses on individual alleles usin an innovative isogenic mode that takes advantage of cutting edge technologies. We have created an experimental platform to study how specific genetic risk variants precipitate immune dysregulation leading to cytotoxic CD8+ T lymphocyte (CTL) activation and β cell destruction. We hypothesize that genetically regulated defects in PTPN22 promote; i) immunogenic DC, ii) TH1 responses, iii) pancreatic vascular inflammation and CTL homing, and iv) pathogenic CTL activity towards β cells coupled with reduced activation induced CTL death: each of these tenants form an aim of this grant. Further, we posit that defects reach full potential when immune cells and endothelial cells are excessively sensitive to activation by endogenous or exogenous factors that stimulate inflammation, thus linking environment and immunogenetics in T1D. Here we will utilize a novel experimental pipeline where PTPN22R (T1D resistant), PTPN22W (T1D susceptible) or PTPN22 deletion (PTPN22-/-) alleles are carried by isogenic human immune and endothelial cells engineered from induced pluripotent stem cells [iPSC]. The iPSC system allows exquisite control of T1D disease alleles, where the susceptible allele can be replaced by the resistant allele (and vice versa) providing a constant genetic background upon which effects of a single risk allotype can be studied without complicating epistatic effects,
in a manner analogous to studies in genetically modified mice. This system proposed here will provide an unprecedented capacity to interrogate molecular and cellular interactions under isogenic conditions to provide mechanistic understanding of how PTPN22 alleles regulate individual steps of T1D pathogenesis and how those steps interrelate to bring upon T1D onset. Importantly, this study will also lay the groundwork for future investigations of single or multipl T1D susceptibility genes using this innovative strategy.
描述(申请人提供):1型糖尿病(T1D)的发展依赖于免疫系统细胞(例如,DC、CD8+T细胞)和赋予疾病易感性或抵抗力的基因之间的复杂相互关系,这些基因是产生胰岛素的胰腺β细胞的自身免疫破坏的基础。虽然大量的证据肯定支持这一观点(我们自己也相信这是真的),但促进自身免疫β细胞破坏的确切机制仍不清楚。此外,在这一过程中,每个方面(即细胞、基因)的相对贡献在很大程度上仍然是未知的。T1D相关易感等位基因的机制研究因多基因遗传而变得复杂,因此没有两个个体是真正相似的。因此,研究严重受阻于人群中缺乏动力,以及无法分离出
一种特定细胞类型的变体。在这里,我们提出了一种专注于单个等位基因的解决方案,使用了一种利用尖端技术的创新等基因模式。我们已经建立了一个实验平台来研究特定的遗传风险变异如何导致免疫失调,导致细胞毒性CD8+T淋巴细胞激活和β细胞破坏。我们假设,PTPN22的基因缺陷促进了:i)免疫原性DC,ii)TH1反应,iii)胰腺血管炎症和CTL归巢,以及iv)致病的CTL活性与β细胞的激活减少导致的CTL死亡:每个租户都形成了这项赠款的目标。此外,我们假设,当免疫细胞和内皮细胞对刺激炎症的内源性或外源性因素激活过度敏感时,缺陷达到完全潜力,从而将环境和免疫遗传学联系在一起。在这里,我们将利用一种新的实验管道,其中PTPN22R(T1D抗性)、PTPN22W(T1D易感)或PTPN22缺失(PTPN22-/-)等位基因由同源的人免疫和诱导多能干细胞工程内皮细胞[IPSC]携带。IPSC系统允许精确控制T1D疾病等位基因,其中敏感等位基因可以被抗性等位基因取代(反之亦然),提供了一个恒定的遗传背景,在该背景下可以研究单一风险同种异型的影响,而不会使上位效应复杂化。
以一种类似于对转基因小鼠的研究的方式。该系统将提供前所未有的能力,以询问分子和细胞在等基因条件下的相互作用,以提供机制的理解如何PTPN22等位基因调节的T1D发病的个别步骤,以及这些步骤如何相互关联,导致T1D的发病。重要的是,这项研究还将为未来使用这一创新策略研究单个或多个T1D易感基因奠定基础。
项目成果
期刊论文数量(1)
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 }}
CLAYTON E MATHEWS其他文献
CLAYTON E MATHEWS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('CLAYTON E MATHEWS', 18)}}的其他基金
Discovery and Roles of In Situ Islet Neoantigens in Human Type 1 Diabetes
原位胰岛新抗原在人类 1 型糖尿病中的发现及其作用
- 批准号:
10589578 - 财政年份:2023
- 资助金额:
$ 311.66万 - 项目类别:
Determining the mechanism of IFIH1 disease-associated variants on beta-cell and immune responses in Type 1 diabetes
确定 1 型糖尿病中 IFIH1 疾病相关变异对 β 细胞和免疫反应的机制
- 批准号:
10903049 - 财政年份:2023
- 资助金额:
$ 311.66万 - 项目类别:
Determining the mechanism of IFIH1 disease-associated variants on beta-cell and immune responses in Type 1 diabetes
确定 1 型糖尿病中 IFIH1 疾病相关变异对 β 细胞和免疫反应的机制
- 批准号:
10417267 - 财政年份:2020
- 资助金额:
$ 311.66万 - 项目类别:
Multi-omic 3D tissue maps for a Human BioMolecular Atlas
人类生物分子图谱的多组学 3D 组织图谱
- 批准号:
10649957 - 财政年份:2020
- 资助金额:
$ 311.66万 - 项目类别:
Determining the mechanism of IFIH1 disease-associated variants on beta-cell and immune responses in Type 1 diabetes
确定 1 型糖尿病中 IFIH1 疾病相关变异对 β 细胞和免疫反应的机制
- 批准号:
10263321 - 财政年份:2020
- 资助金额:
$ 311.66万 - 项目类别:
mt-Nd2 and Resistance to Autoimmune Diabetes
mt-Nd2 与自身免疫性糖尿病的抵抗力
- 批准号:
7998873 - 财政年份:2010
- 资助金额:
$ 311.66万 - 项目类别:
mt-Nd2 and Resistance to Autoimmune Diabetes
mt-Nd2 与自身免疫性糖尿病的抵抗力
- 批准号:
8297271 - 财政年份:2006
- 资助金额:
$ 311.66万 - 项目类别:
相似海外基金
Linkage of HIV amino acid variants to protective host alleles at CHD1L and HLA class I loci in an African population
非洲人群中 HIV 氨基酸变异与 CHD1L 和 HLA I 类基因座的保护性宿主等位基因的关联
- 批准号:
502556 - 财政年份:2024
- 资助金额:
$ 311.66万 - 项目类别:
Olfactory Epithelium Responses to Human APOE Alleles
嗅觉上皮对人类 APOE 等位基因的反应
- 批准号:
10659303 - 财政年份:2023
- 资助金额:
$ 311.66万 - 项目类别:
Deeply analyzing MHC class I-restricted peptide presentation mechanistics across alleles, pathways, and disease coupled with TCR discovery/characterization
深入分析跨等位基因、通路和疾病的 MHC I 类限制性肽呈递机制以及 TCR 发现/表征
- 批准号:
10674405 - 财政年份:2023
- 资助金额:
$ 311.66万 - 项目类别:
An off-the-shelf tumor cell vaccine with HLA-matching alleles for the personalized treatment of advanced solid tumors
具有 HLA 匹配等位基因的现成肿瘤细胞疫苗,用于晚期实体瘤的个性化治疗
- 批准号:
10758772 - 财政年份:2023
- 资助金额:
$ 311.66万 - 项目类别:
Identifying genetic variants that modify the effect size of ApoE alleles on late-onset Alzheimer's disease risk
识别改变 ApoE 等位基因对迟发性阿尔茨海默病风险影响大小的遗传变异
- 批准号:
10676499 - 财政年份:2023
- 资助金额:
$ 311.66万 - 项目类别:
New statistical approaches to mapping the functional impact of HLA alleles in multimodal complex disease datasets
绘制多模式复杂疾病数据集中 HLA 等位基因功能影响的新统计方法
- 批准号:
2748611 - 财政年份:2022
- 资助金额:
$ 311.66万 - 项目类别:
Studentship
Recessive lethal alleles linked to seed abortion and their effect on fruit development in blueberries
与种子败育相关的隐性致死等位基因及其对蓝莓果实发育的影响
- 批准号:
22K05630 - 财政年份:2022
- 资助金额:
$ 311.66万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Genome and epigenome editing of induced pluripotent stem cells for investigating osteoarthritis risk alleles
诱导多能干细胞的基因组和表观基因组编辑用于研究骨关节炎风险等位基因
- 批准号:
10532032 - 财政年份:2022
- 资助金额:
$ 311.66万 - 项目类别:
Investigating the Effect of APOE Alleles on Neuro-Immunity of Human Brain Borders in Normal Aging and Alzheimer's Disease Using Single-Cell Multi-Omics and In Vitro Organoids
使用单细胞多组学和体外类器官研究 APOE 等位基因对正常衰老和阿尔茨海默病中人脑边界神经免疫的影响
- 批准号:
10525070 - 财政年份:2022
- 资助金额:
$ 311.66万 - 项目类别:
Leveraging the Evolutionary History to Improve Identification of Trait-Associated Alleles and Risk Stratification Models in Native Hawaiians
利用进化历史来改进夏威夷原住民性状相关等位基因的识别和风险分层模型
- 批准号:
10689017 - 财政年份:2022
- 资助金额:
$ 311.66万 - 项目类别: