The Role of the Adaptor Protein SH2B3 in Type 1 Diabetes
接头蛋白 SH2B3 在 1 型糖尿病中的作用
基本信息
- 批准号:9751285
- 负责人:
- 金额:$ 16.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-01 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdaptor Signaling ProteinAdoptive TransferAffectAllelesAnimal ModelAnimalsAntibodiesAntigen PresentationAreaAutoimmune DiseasesAutoimmune ProcessBasic ScienceBeta CellBig DataBiologicalBiological AssayBiologyCD4 Positive T LymphocytesCell LineCellsChildhoodClinicalClinical ResearchComplexCytokine ReceptorsDataData AnalysesDendritic CellsDevelopmentDiabetes MellitusDiseaseEarly InterventionEffector CellEnvironmental Risk FactorEtiologyEuropeanEventExhibitsExocrine pancreasFundingGene FrequencyGenesGeneticGenetic Predisposition to DiseaseGenetic RiskGenetic TranscriptionGenotypeGoalsGranulocyte-Macrophage Colony-Stimulating FactorHomologous GeneHumanHuman GeneticsITGAM geneITGAX geneImmuneImmune responseImmunologyInbred NOD MiceIndividualInflammationInflammatoryInnate Immune SystemInsulin-Dependent Diabetes MellitusIslet CellIslets of LangerhansK-Series Research Career ProgramsKnock-inKnowledgeLaboratoriesLeadLymphocyteMass Spectrum AnalysisMeasuresMentorsMentorshipMethodsModelingMonocytosisMononuclearMusMutationMyelogenousMyeloid CellsMyelopoiesisPathogenesisPathogenicityPathway interactionsPeripheralPhasePhenotypePopulationPrediabetes syndromeProductionProteinsProteomicsPublicationsReceptor SignalingRelapseResearchResearch PersonnelRheumatologyRiskRoleSamplingScientistSepsisSeveritiesShapesSignal TransductionSiteStressSusceptibility GeneTechnical ExpertiseTechniquesTestingTissuesTrainingUnited States National Institutes of HealthUniversitiesVariantVirus DiseasesWashingtonWorkadaptive immune responseadaptive immunitybasecareercareer developmentcytokinediabetes riskdisorder riskembryonic stem cellgenetic risk factorhigh riskhuman subjectin vivoinsulin dependent diabetes mellitus onsetinterestisletknock-downlymph nodesmacrophagemonocytemortalitymouse modelnovelpediatric departmentprofessorprogenitorprotective effectrecruitrepositoryrisk variantsymposiumtraittranslational approach
项目摘要
PROJECT SUMMARY/ABSTRACT:
This project is a NIH Mentored Clinical Scientist Research Career Development Award (K08) application for Dr.
Eric Allenspach, an Acting Assistant Professor in the Department of Pediatrics at the University of
Washington (UW). Dr. Allenspach has completed his clinical training in Pediatric Rheumatology and
Immunology and has both a clinical and research interest in the treatment of pediatric autoimmune conditions.
Dr. Allenspach's specific research interest is understanding the role of genetic risk factors in regulating the
myeloid lineage and the interaction between the innate and adaptive immune responses. His long-term career
goal is to establish himself as an independently-funded principle investigator studying these mechanisms in
both animal models and directly in primary human cells using basic science and translational approaches.
In order to achieve this goal, Dr. Allenspach is requesting the NIH K08 support for additional training and
mentorship in the following specific areas: (1) assessment of murine myelopoiesis and technical skills in ex
vivo manipulating human myeloid cells; (2) training in laboratory techniques related to gene knockdown and
gene editing; (3) additional training in proteomic approaches and big data analysis; (4) NOD murine modeling
of spontaneous diabetes. (5) presenting at scientific conferences, career development seminars, and additional
classroom-based training relevant to this project; and (6) grantsmanship and laboratory management with a
focus on developing an independent research focus with a goal of transitioning to scientific independence.
In the present application, Dr. Allenspach proposes studying the biologic role of an identified autoimmune risk
variant in the adaptor protein SH2B3 on the development of type 1 diabetes (T1D) and in regulating
myelopoiesis. A strong association has been found between a genetic allele (rs3184504) in the SH2B3 gene
and T1D. In this proposal, we utilize murine modeling to understand how reduced SH2B3 function affects
APCs during T1D development and under environmental stress. The overall goal of the project is to test
whether the SH2B3 risk variant alters T1D pathogenesis. These studies will focus on the following areas: In
Aim 1, we test does the SH2B3 T1D risk allele alter the inherent function of the myeloid APCs. As monocytes
are the precursors to several myeloid effector cells, we test in Aim 2 whether having more precursor
monocytes during inflammation lead to increased numbers of progeny including monocyte-derived DCs. In
Aim 3, we ask directly whether the rs3184504*T allele modeled in mice contributes to T1D by introducing the
genetic change on the NOD mouse background. In this proposal, we will directly assess the functional role for
this common risk variant in T1D, and, in parallel, gain new knowledge about monocyte biology relevant to T1D
pathogenesis. It is anticipated these studies would provide the publications and preliminary data needed to
develop an independent research direction and apply for R01 funding at the end of the career development
support.
项目总结/摘要:
该项目是NIH指导临床科学家研究职业发展奖(K 08)的应用程序博士。
埃里克·艾伦斯帕奇是明尼苏达大学儿科系的代理助理教授,
华盛顿(UW)。Allenspach博士已经完成了儿科流变学的临床培训,
免疫学博士,在儿科自身免疫性疾病的治疗方面具有临床和研究兴趣。
博士Allenspach的具体研究兴趣是了解遗传风险因素在调节
骨髓谱系以及先天性和适应性免疫应答之间的相互作用。他的长期职业生涯
目标是建立自己作为一个独立资助的主要研究人员研究这些机制,
动物模型和直接在原代人类细胞中使用基础科学和转化方法。
为了实现这一目标,Allenspach博士请求NIH K 08支持额外的培训,
在以下具体领域提供指导:(1)评估小鼠骨髓细胞生成和在体外培养中的技术技能
体内操作人骨髓细胞;(2)与基因敲除相关的实验室技术培训,
基因编辑;(3)蛋白质组学方法和大数据分析的额外培训;(4)NOD小鼠建模
自发性糖尿病(5)在科学会议、职业发展研讨会和其他
与本项目相关的课堂培训;以及(6)
专注于发展独立的研究重点,目标是向科学独立过渡。
在本申请中,Allenspach博士建议研究已确定的自身免疫风险的生物学作用。
衔接蛋白SH 2B 3变异体对1型糖尿病(T1 D)的发展和调节
骨髓生成在SH 2B 3基因的一个遗传等位基因(rs3184504)与
T1D。在这个提议中,我们利用小鼠模型来了解SH 2B 3功能降低如何影响
在T1 D发展和环境压力下的APC。该项目的总体目标是测试
SH 2B 3风险变体是否改变T1 D发病机制。这些研究将侧重于以下领域:
目的1:检测SH 2B 3 T1 D危险等位基因是否改变了骨髓APC的固有功能。如单核细胞
是几种骨髓效应细胞的前体,我们在Aim 2中测试是否具有更多的前体细胞,
炎症期间单核细胞的增殖导致包括单核细胞衍生的DC的后代数量增加。在
目的3,我们直接询问在小鼠中建模的rs3184504*T等位基因是否通过引入
NOD小鼠背景的遗传变化。在本提案中,我们将直接评估的职能角色
这种常见的T1 D风险变异,并同时获得有关T1 D相关单核细胞生物学的新知识
发病机制预计这些研究将提供所需的出版物和初步数据,
发展独立的研究方向,并在职业发展结束时申请R 01资助
支持.
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)
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Eric J Allenspach其他文献
Septin-6 Regulates Murine and Human Hematopoiesis, and Its Dysregulation Is Associated with Pediatric Myelodysplasia
- DOI:
10.1182/blood-2022-163606 - 发表时间:
2022-11-15 - 期刊:
- 影响因子:
- 作者:
Safa F Mohamad;Meaghan McGuinness;Gabriele Casirati;Alejo E Rodriguez-Fraticelli;Chad E. Harris;Fernando D. Camargo;Pietro Genovese;Eric J Allenspach;David A. Williams - 通讯作者:
David A. Williams
Eric J Allenspach的其他文献
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{{ truncateString('Eric J Allenspach', 18)}}的其他基金
The role of SH2B3 in regulating CD8 T cells in Type 1 Diabetes
SH2B3 在 1 型糖尿病中调节 CD8 T 细胞的作用
- 批准号:
10574346 - 财政年份:2023
- 资助金额:
$ 16.2万 - 项目类别:
The Role of the Adaptor Protein SH2B3 in Type 1 Diabetes
接头蛋白 SH2B3 在 1 型糖尿病中的作用
- 批准号:
10241937 - 财政年份:2018
- 资助金额:
$ 16.2万 - 项目类别:
The Role of the Adaptor Protein SH2B3 in Type 1 Diabetes
接头蛋白 SH2B3 在 1 型糖尿病中的作用
- 批准号:
10458084 - 财政年份:2018
- 资助金额:
$ 16.2万 - 项目类别: