Molecular mechanisms of allorecognition in a basal chordate
基底脊索动物同种异体识别的分子机制
基本信息
- 批准号:9433671
- 负责人:
- 金额:$ 29.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-03-01 至 2020-12-31
- 项目状态:已结题
- 来源:
- 关键词:AllelesAlternative SplicingAreaAutoimmune DiseasesAutoimmune ProcessAutoimmunityBindingBiochemicalBiological AssayBlood VesselsBone Marrow TransplantationCell surfaceCellsCharacteristicsChordataClinicalComplexDetectionDevelopmentDiscriminationDissectionEducationEpigenetic ProcessEpithelial CellsEventFundingFutureGenesGenetic RecombinationGenotypeGoalsHealthHistocompatibilityHumanImmuneImmune systemImmunityImmunoglobulin Somatic HypermutationImmunoprecipitationImmunosuppressive AgentsIn VitroIndividualInterventionLabelLeadLigandsLinkMaintenanceMemoryModelingMolecularMolecular ChaperonesMonitorMonoclonal AntibodiesNatural Killer CellsNatural regenerationOrganismOutcomePathway interactionsPhenotypePlayPopulationProcessPropertyProteinsProteomeProteomicsRNA SplicingReactionReagentResolutionRoleScaffolding ProteinSeaSeriesSignal PathwaySignal TransductionSignal Transduction PathwaySpecificityStimulusStudy modelsSystemTechniquesTestingTimeTransduction GeneTransplantationTransplanted tissueVariantWorkZAP-70 Geneascidianbasecrosslinkextracellularin vivoin vivo evaluationinsightmRNA sequencingnovelnovel strategiespreventprotein expressionreceptorreceptor bindingresponsetransdifferentiationtumor
项目摘要
When an immune cell interacts with a target cell, and receptors bind their cognate ligands, a
decision is made to react or not. Our long-range goal is to understand the basis of that decision.
How does a cell monitor events at the cell surface? What gets counted, and how are multiple
stimulatory and inhibitory signals integrated? How is that compared to a threshold value, and
during development and education processes, how does a cell know what the threshold is? And
once set, can these thresholds be manipulated? Each of these questions has major biomedical
significance, from understanding the changes in reactivity that lead to autoimmunity, to inducing
tolerance to a transplanted tissue.
We have the ability to study how these processes work during a single immune interaction. Our
model is histocompatibility in the basal chordate Botryllus schlosseri. Allorecognition in Botryllus is
controlled by a single locus (called the fuhc) with the following rules: individuals that share one or
both alleles are compatible; while those that share none are incompatible. Discrimination is based
on the detection of a self-allele, and the specificity of this system is significant: there are ca. 1000
fuhc alleles world-wide, thus the effector system can pick out a self-allele from a sea of competing
specificities. However, Botryllus does not have any recombination or somatic hypermutation
machinery, and this specificity relies on germline-encoded receptors.
This proposal is focused on understanding the biochemical mechanisms that underlie this innate
allorecognition specificity. The unique properties of Botryllus allorecognition make it an ideal model
for these studies: a single locus that determines outcome, the reaction occurs outside the body
between epithelial cells on the tips of macroscopic blood vessel, called ampullae, and the outcome
is determined by the integration of signaling pathways from only two receptors, one activating, and
one inhibitory, both of which can be manipulated in vivo. In Aim 1, we will use a novel fluorescent
labeling technique recently developed in our lab to isolate single ampullae cells and directly assess
the basis of specificity. Our working hypothesis is that this is due to genotype-specific alternative
splicing of a receptor called fester, and that will be directly tested here. Using this technique, we
have also found that ampullae are bifunctional and can reversibly de-differentiate into vascular
cells, which do not express allorecognition proteins, allowing us to characterize reversible changes
in candidate protein expression/alternative splicing, which will reveal the basis of specificity. In Aim
2, we will assess extracellular ligand/receptor interactions in vivo and in vitro. We will test putative
intracellular interactions between receptors and fuhc-encoded chaperones and scaffolding proteins
that may play a role in creating receptor complexes and contribute to specificity. In Aim 3, we will
characterize the signal transduction pathways used in Botryllus allorecognition, using a
combination of FACS and proteomics. We have found that signal transduction molecules such as
Zap-70, LCK, sph-1/2 and SHIP are expressed in ampullae. These genes have an early
evolutionary origin, leading us to hypothesize that the conserved aspects of allorecognition are the
mechanisms that integrate these well-characterized activating and inhibitory signal transduction
pathways. However, integration with Aim 1 will also allow us take an unbiased view of putative
signal transduction genes.
Completion of the proposed aims will advance our understanding of the mechanisms that underlie
education and tolerance in innate allorecognition systems. These intracellular processes monitor
binding events at the cell surface, integrate activating and inhibitory inputs, and set and maintain
the threshold for a response: the basis of specificity. We hypothesize that these are the conserved
aspects of immunity, have an early evolutionary origin, and are responsible for the rapid
evolutionary change characteristic of immunity- and Botryllus presents a unique and highly
simplified model to study these processes. Understanding and manipulating threshold responses
would be the building blocks of future clinical interventions, including inducing tolerance following
transplantation, blocking autoimmune reactions, or overcoming the immunosuppressive strategies
of tumors, areas of great importance for human health.
当免疫细胞与靶细胞相互作用,并且受体结合其同源配体时,
决定是否作出反应。我们的长期目标是了解这一决定的基础。
细胞如何监测细胞表面的事件?什么被计算,以及如何多个
刺激和抑制信号的整合?这与阈值相比如何,
在发育和教育过程中,细胞如何知道阈值是多少?和
一旦设定,这些阈值是否可以操纵?每一个问题都有重要的生物医学
重要性,从了解导致自身免疫的反应性变化,到诱导
对移植组织的耐受性。
我们有能力研究这些过程如何在单一的免疫相互作用中发挥作用。我们
模型在基底脊索动物Schlosseri中具有组织相容性。葡萄球菌的异源识别
受单一基因座(称为fuhc)控制,具有以下规则:共享一个或多个基因座的个体
两个等位基因都是相容的;而那些没有共享的等位基因是不相容的。歧视是基于
在检测自身等位基因上,该系统的特异性是显著的:存在ca. 1000
fuhc等位基因在世界范围内,因此效应系统可以从竞争的海洋中挑选出一个自我等位基因。
特殊性然而,Botryllus没有任何重组或体细胞超突变
这种特异性依赖于种系编码的受体。
这项建议的重点是了解这种先天性的生化机制,
同种识别特异性葡萄孢菌独特的识别特性使其成为一种理想的识别模型
对于这些研究:一个决定结果的单一位点,反应发生在体外,
在肉眼可见的血管尖端(称为壶腹)的上皮细胞之间,
是由来自两个受体的信号通路的整合决定的,一个是激活的,
一种是抑制性的,两种都可以在体内操纵。在目标1中,我们将使用一种新的荧光
本实验室最近开发了一种标记技术,用于分离单个壶腹细胞并直接评估
特异性的基础。我们的工作假设是,这是由于基因型特异性的替代
一种叫做“溃烂”的受体的剪接,这将在这里直接进行测试。利用这项技术,我们
还发现壶腹是双功能的,可以可逆地去分化为血管,
细胞,不表达同种异体识别蛋白,使我们能够表征可逆的变化
在候选蛋白表达/选择性剪接,这将揭示特异性的基础。在Aim中
2,我们将在体内和体外评估细胞外配体/受体相互作用。我们将测试假定的
受体与fuHC编码的伴侣蛋白和支架蛋白之间的细胞内相互作用
这可能在产生受体复合物中起作用并有助于特异性。在目标3中,我们
特征的信号转导通路中使用的葡萄球菌同种异体识别,使用
流式细胞仪和蛋白质组学的结合。我们已经发现,信号转导分子,如
壶腹部表达Zap-70、LCK、sph-1/2和SHIP。这些基因有一个
进化起源,导致我们假设,同种异体识别的保守方面是
整合这些充分表征的激活和抑制信号转导的机制
途径。然而,与目标1的整合也将使我们能够对假定的
信号转导基因
完成拟议目标将促进我们对基础机制的理解
先天同种异体识别系统中的教育和耐受性。这些细胞内过程监测
在细胞表面的结合事件,整合激活和抑制输入,并设置和维持
反应的阈值:特异性的基础。我们假设这些是保守的
免疫方面,有一个早期的进化起源,并负责快速
进化的变化特点的免疫-和葡萄球菌提出了一个独特的和高度
简化模型来研究这些过程。理解和操纵阈值反应
将是未来临床干预的基石,包括诱导耐受性,
移植,阻断自身免疫反应,或克服免疫抑制策略
肿瘤,对人类健康非常重要的领域。
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 }}
Anthony W De Tomaso其他文献
Anthony W De Tomaso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('Anthony W De Tomaso', 18)}}的其他基金
Developing a new chordate model for stem cell biology and regeneration
开发用于干细胞生物学和再生的新脊索动物模型
- 批准号:
10373777 - 财政年份:2022
- 资助金额:
$ 29.06万 - 项目类别:
Developing a new chordate model for stem cell biology and regeneration
开发用于干细胞生物学和再生的新脊索动物模型
- 批准号:
10580589 - 财政年份:2022
- 资助金额:
$ 29.06万 - 项目类别:
Allorecognition, parasitic stem cells and regeneration in a basal chordate
基底脊索动物的同种识别、寄生干细胞和再生
- 批准号:
10322423 - 财政年份:2021
- 资助金额:
$ 29.06万 - 项目类别:
Allorecognition, parasitic stem cells and regeneration in a basal chordate
基底脊索动物的同种识别、寄生干细胞和再生
- 批准号:
10557096 - 财政年份:2021
- 资助金额:
$ 29.06万 - 项目类别:
Cell competition and stem cell parasitism in a basal chordate
基底脊索动物的细胞竞争和干细胞寄生
- 批准号:
10017299 - 财政年份:2019
- 资助金额:
$ 29.06万 - 项目类别:
Molecular mechanisms of allorecognition in a basal chordate
基底脊索动物同种异体识别的分子机制
- 批准号:
9290237 - 财政年份:2017
- 资助金额:
$ 29.06万 - 项目类别:
Cellular and gene regulatory mechanisms of whole body regeneration in Botryllus Schlosseri
灰霉病菌全身再生的细胞和基因调控机制
- 批准号:
9375865 - 财政年份:2017
- 资助金额:
$ 29.06万 - 项目类别:
相似海外基金
Alternative splicing of Grin1 controls NMDA receptor function in physiological and disease processes
Grin1 的选择性剪接控制生理和疾病过程中的 NMDA 受体功能
- 批准号:
488788 - 财政年份:2023
- 资助金额:
$ 29.06万 - 项目类别:
Operating Grants
RBFOX2 deregulation promotes pancreatic cancer progression through alternative splicing
RBFOX2 失调通过选择性剪接促进胰腺癌进展
- 批准号:
10638347 - 财政年份:2023
- 资助金额:
$ 29.06万 - 项目类别:
Long Noncoding RNA H19 Mediating Alternative Splicing in ALD Pathogenesis
长非编码 RNA H19 介导 ALD 发病机制中的选择性剪接
- 批准号:
10717440 - 财政年份:2023
- 资助金额:
$ 29.06万 - 项目类别:
Using proteogenomics to assess the functional impact of alternative splicing events in glioblastoma
使用蛋白质基因组学评估选择性剪接事件对胶质母细胞瘤的功能影响
- 批准号:
10577186 - 财政年份:2023
- 资助金额:
$ 29.06万 - 项目类别:
Alternative splicing regulation of CLTC in the heart
心脏中 CLTC 的选择性剪接调节
- 批准号:
10749474 - 财政年份:2023
- 资助金额:
$ 29.06万 - 项目类别:
Nitric oxide as a novel regulator of alternative splicing
一氧化氮作为选择性剪接的新型调节剂
- 批准号:
10673458 - 财政年份:2023
- 资助金额:
$ 29.06万 - 项目类别:
Alternative splicing as an evolutionary driver of phenotypic plasticity
选择性剪接作为表型可塑性的进化驱动力
- 批准号:
2884151 - 财政年份:2023
- 资助金额:
$ 29.06万 - 项目类别:
Studentship
Rescuing SYNGAP1 haploinsufficiency by redirecting alternative splicing
通过重定向选择性剪接挽救 SYNGAP1 单倍体不足
- 批准号:
10660668 - 财政年份:2023
- 资助金额:
$ 29.06万 - 项目类别:
CAREER: Mechanotransduction, transcription, and alternative splicing in cell biology
职业:细胞生物学中的机械转导、转录和选择性剪接
- 批准号:
2239056 - 财政年份:2023
- 资助金额:
$ 29.06万 - 项目类别:
Continuing Grant
Investigating the role of alternative splicing in the islets of Langerhans in developing diabetes.
研究朗格汉斯岛中选择性剪接在糖尿病发生中的作用。
- 批准号:
468851650 - 财政年份:2022
- 资助金额:
$ 29.06万 - 项目类别:
Research Grants