The Role of Interferon-gamma in the Regulation of Hematopoietic Stem Cells
干扰素-γ在造血干细胞调节中的作用
基本信息
- 批准号:7772591
- 负责人:
- 金额:$ 13.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-05-01 至 2015-02-28
- 项目状态:已结题
- 来源:
- 关键词:Academic TrainingAplastic AnemiaArtsAutophagocytosisBiological AssayBiological ModelsBiological PreservationBiometryBlood CellsBone MarrowBone Marrow TransplantationCancer BiologyCaringCell Cycle ProgressionCell ProliferationCell physiologyCellsChild CareChildhoodChronicClinicalCollaborationsCommunicable DiseasesComplementCyclin D1DataDevelopment PlansDiseaseEnrollmentEnsureEthicsFellowshipFlow CytometryFunctional disorderFutureGene Expression ProfilingGenesGenus MycobacteriumGoalsGrantGuanosine Triphosphate PhosphohydrolasesHematologistHematopoietic Stem Cell ResearchHematopoietic SystemHematopoietic stem cellsHomeostasisHomologous GeneHost resistanceHumanImmuneImmune responseImmune systemImmunityImmunohistochemistryImmunologyIn VitroInfectionInfectious Disease ImmunologyInflammationInterferon Type IIInterferonsInternationalInterventionInvestigationKnock-outKnockout MiceKnowledgeLeadLifeLinkLong-Term EffectsMedicalMedicineMentorsMethodsMicroscopyMusMutant Strains MiceMycobacterium InfectionsMycobacterium avium-intracellulare InfectionMyelosuppressionOncologistOrganismPathogenesisPatientsPediatric HospitalsPediatricsPeripheralPhysiologicalPopulationPositioning AttributePrincipal InvestigatorProcessProliferatingProteinsQualifyingRecoveryRegulationResearchResearch Project GrantsResidenciesResourcesRoleSamplingScienceScientistSerumSignal PathwaySignal TransductionStem Cell ResearchStem cellsStimulusSystemSystemic infectionTechnologyTestingTexasTherapeuticTherapeutic AgentsTimeTraining ActivityTraining ProgramsTransgenic OrganismsTransplant RecipientsTransplantationTuberculosisUnited StatesUniversitiesViralVirusVirus DiseasesWashingtonWorkcareercareer developmentcollegecytokineexhaustionexperienceimprovedinhibitor/antagonistinsightmacrophagemeetingsmicrobialmouse modelpathogenpediatric departmentpluripotencypreventprofessorprogenitorprogramspublic health relevanceresearch studyresponseself-renewalskillsstemstem cell biologysuccesstool
项目摘要
DESCRIPTION (provided by applicant): The Candidate: I am highly motivated and exceptionally qualified to pursue a career in academic medicine in the field of Pediatric Infectious Diseases. A graduate of Harvard University, the Medical Scientist Training Program at Washington University in St. Louis, and the Pediatrics Residency Program at Baylor College of Medicine (BCM), I have pursued excellence throughout my academic training. I am motivated by a desire to improve the medical care of children with infectious diseases, both in the United States and throughout the world. I believe that advances in care will arise from studying the interactions between pathogens and the host immune response. Cells of the host immune response are ultimately derived from hematopoietic stem cells (HSCs) in bone marrow. I have capitalized on the institutional strength of BCM in the field of stem cell biology to pursue hematopoietic stem cell research during my fellowship. I intend to combine my prior experience in microbial pathogenesis with stem cell research to study the effect of infections on HSC function. This research will have immediate application for patients recovering from bone marrow transplantation. Furthermore, this work will lead to insight and potential interventions for myelosuppression as a result of chronic infections such as severe viral infections and tuberculosis. Research Career Development Plan: I will utilize an array of educational and research resources in Houston to strengthen my research career development. Within the BCM graduate programs in biomedical sciences, I will enroll in courses on new research in cancer biology and immunology. I will gain expertise in biostatistics, research conduct and ethics, and state-of-the-art technology in microscopy and flow cytometry. I will participate in local, national, and international meetings in the fields of infectious diseases, immunology, and stem cell biology. I have established a collaboration with hematologist-oncologists at Texas Children's Hospital and will work with them to study the effects of infection on human bone marrow samples. Beyond these training activities, I will continue my highly productive research fellowship with my mentor Dr. Margaret Goodell. Dr. Goodell is a nationally recognized stem cell biologist with expertise in regulation of hematopoietic stem cells. While she directs a very productive research group, Dr. Goodell is also recognized for her mentoring skills and is the PI on a recently renewed T32 grant. Dr. Goodell has provided me the full complement of research tools, space, and scientific guidance that will ensure my success as I transition into an independent research career. Furthermore, BCM and my department of Pediatric Infectious Diseases have invested in my research career development by assuring me 100% protected time in a tenure-track assistant professor position at the completion of my fellowship during the first two years of the grant period. Research Project: During an infection, peripheral immune cells are consumed and must be replenished by progenitor cells. Hematopoietic stem cells (HSCs) are the earliest of these progenitors, and they maintain pluripotency and self-renewal potential throughout the life of an organism. Surprisingly little is known about how HSCs sense and respond to systemic infection. In this proposal, I describe the use of a mouse model of chronic Mycobacterium avium infection to understand changes in HSC function triggered by the innate immune response. My preliminary data suggest that HSCs are activated to proliferate during M. avium infection, and that the process is dependent on interferon-3 (IFN3) and its downstream effector Irgm1 (Immunity-related GTPase M). I propose to delineate the role of IFN3 in the HSC response to infection by conducting M. avium infections in mice lacking components of the IFN3 signaling pathway, including IFN3, IFN3R1, and Stat1- deficient mice. Furthermore, I will determine whether HSC proliferation can be triggered by IFN3 stimulation alone. Since the interferon-inducible protein Irgm1 is known to participate in autophagy in murine macrophages, we suspected and confirmed that autophagy occurs in HSCs of infected mice. To further explore this finding, we propose to investigate whether autophagy is dependent on Irgm1 in murine HSCs, and whether this process participates in HSC regulation. Specifically, we will investigate whether autophagy occurs in HSCs of infected Irgm1-deficient mice, and we will determine if HSC proliferation and/or function change in the presence of inhibitors of autophagy. Finally, we will determine whether interferon signaling and autophagy have functional significance for human HSCs isolated from bone marrow transplant patients. The significance of these studies is that they will elucidate the mechanisms by which the immune system triggers replenishment of the pool of peripheral immune cells during infection. Understanding the immediate and long-term effects of infection on HSCs has direct implications for treatment of patients recovering from bone marrow transplantation. Furthermore, these studies will lead to critical information about use of interferons or inhibitors of autophagy as therapeutic agents for aplastic anemia and myelosuppression due to severe viral and mycobacterial infections. My work and future career will focus on how HSCs respond to infection, a basic physiologic response that can be aberrant in disease states, disrupted by infectious pathogens, or co-opted for therapeutic purposes.
PUBLIC HEALTH RELEVANCE: During an infection, peripheral immune cells are consumed and must be replenished, ultimately through increased proliferation of hematopoietic stem cells (HSCs). We will use a mouse model of chronic Mycobacterium avium infection to understand changes in HSC function triggered by interferon-gamma signaling. Since some interferon-regulated genes are required for autophagy, we will examine the role of autophagy in the regulation of mouse and human HSCs.
候选人:我非常积极,非常有资格在儿科传染病领域从事学术医学事业。我毕业于哈佛大学、圣路易斯华盛顿大学医学家培训项目和贝勒医学院儿科住院医师项目,在我的学术培训中一直追求卓越。我的动机是希望改善美国和全世界患有传染病的儿童的医疗保健。我相信,通过研究病原体和宿主免疫反应之间的相互作用,护理将取得进展。宿主免疫应答的细胞最终来源于骨髓中的造血干细胞(hsc)。我利用BCM在干细胞生物学领域的机构优势,在学习期间进行造血干细胞的研究。我打算将我之前在微生物发病机制方面的经验与干细胞研究结合起来,研究感染对HSC功能的影响。这项研究将对骨髓移植患者的康复有直接的应用价值。此外,这项工作将导致对慢性感染(如严重病毒感染和结核病)导致的骨髓抑制的深入了解和潜在的干预措施。研究职业发展计划:我将利用休斯顿的一系列教育和研究资源来加强我的研究职业发展。在BCM生物医学研究生课程中,我将参加癌症生物学和免疫学的新研究课程。我将获得生物统计学、研究行为和伦理方面的专业知识,以及显微镜和流式细胞术方面的最新技术。我将参加传染病、免疫学和干细胞生物学领域的地方、国家和国际会议。我已经与德克萨斯儿童医院的血液学肿瘤学家建立了合作关系,并将与他们一起研究感染对人类骨髓样本的影响。在这些培训活动之外,我将继续与我的导师玛格丽特·古德尔博士进行卓有成效的研究。Goodell博士是全国公认的干细胞生物学家,在造血干细胞的调节方面拥有专业知识。虽然她领导着一个非常富有成效的研究小组,但古德尔博士也因其指导技能而受到认可,并且是最近更新的T32拨款的PI。古德尔博士为我提供了完整的研究工具、空间和科学指导,这将确保我在过渡到独立研究生涯时取得成功。此外,BCM和我的儿科传染病系对我的研究生涯发展进行了投资,在资助期的前两年,他们保证在我完成奖学金后,我将获得100%的终身助理教授职位。研究项目:在感染期间,外周免疫细胞被消耗,必须由祖细胞补充。造血干细胞(hsc)是这些祖细胞中最早的,它们在生物体的整个生命周期中都保持着多能性和自我更新的潜力。令人惊讶的是,我们对造血干细胞如何感知和应对全身性感染知之甚少。在这个提议中,我描述了慢性鸟分枝杆菌感染的小鼠模型的使用,以了解先天免疫反应引发的HSC功能的变化。我的初步数据表明,在鸟分枝杆菌感染期间,造血干细胞被激活增殖,这一过程依赖于干扰素-3 (IFN3)及其下游效应物Irgm1(免疫相关GTPase M)。我建议通过在缺乏IFN3信号通路成分的小鼠(包括IFN3、IFN3R1和Stat1-缺陷小鼠)中进行鸟分枝杆菌感染来描述IFN3在HSC对感染的反应中的作用。此外,我将确定是否可以通过IFN3刺激单独触发HSC增殖。由于已知干扰素诱导蛋白Irgm1参与小鼠巨噬细胞的自噬,我们怀疑并证实了自噬发生在感染小鼠的hsc中。为了进一步探索这一发现,我们拟研究小鼠HSC中的自噬是否依赖Irgm1,以及该过程是否参与HSC的调节。具体来说,我们将研究感染irgm1缺陷小鼠的HSC是否发生自噬,我们将确定在自噬抑制剂存在下,HSC的增殖和/或功能是否发生变化。最后,我们将确定干扰素信号和自噬是否对骨髓移植患者分离的人造血干细胞具有功能意义。这些研究的意义在于,它们将阐明免疫系统在感染期间触发外周免疫细胞池补充的机制。了解感染对造血干细胞的即时和长期影响,对骨髓移植术后患者的治疗具有直接意义。此外,这些研究将为使用干扰素或自噬抑制剂作为治疗由严重病毒和分枝杆菌感染引起的再生障碍性贫血和骨髓抑制的药物提供重要信息。我的工作和未来的职业将集中在造血干细胞如何对感染做出反应,这是一种基本的生理反应,在疾病状态下可能是异常的,被传染性病原体破坏,或被用于治疗目的。
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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Katherine Yudeh King其他文献
Katherine Yudeh King的其他文献
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{{ truncateString('Katherine Yudeh King', 18)}}的其他基金
Project 1: Effects of inflammation on clonal competition and malignant transformation
项目1:炎症对克隆竞争和恶性转化的影响
- 批准号:
10332335 - 财政年份:2022
- 资助金额:
$ 13.05万 - 项目类别:
Project 1: Effects of inflammation on clonal competition and malignant transformation
项目1:炎症对克隆竞争和恶性转化的影响
- 批准号:
10606551 - 财政年份:2022
- 资助金额:
$ 13.05万 - 项目类别:
Impact of Infection and Inflammation on Primitive Hematopoiesis
感染和炎症对原始造血的影响
- 批准号:
10647847 - 财政年份:2021
- 资助金额:
$ 13.05万 - 项目类别:
Impact of Infection and Inflammation on Primitive Hematopoiesis
感染和炎症对原始造血的影响
- 批准号:
10406150 - 财政年份:2021
- 资助金额:
$ 13.05万 - 项目类别:
Inflammatory Regulation of Hematopoietic Stem and Progenitor Cells to Enhance Innate Immunity
造血干细胞和祖细胞的炎症调节以增强先天免疫
- 批准号:
9383703 - 财政年份:2017
- 资助金额:
$ 13.05万 - 项目类别:
The Contribution ofInfection to Preleukemic Clonal Hematopoiesis
感染对白血病前期克隆造血的贡献
- 批准号:
9921465 - 财政年份:2017
- 资助金额:
$ 13.05万 - 项目类别:
The Role of Interferon-gamma in the Regulation of Hematopoietic Stem Cells
干扰素-γ在造血干细胞调节中的作用
- 批准号:
8617858 - 财政年份:2010
- 资助金额:
$ 13.05万 - 项目类别:
The Role of Interferon-gamma in the Regulation of Hematopoietic Stem Cells
干扰素-γ在造血干细胞调节中的作用
- 批准号:
8058771 - 财政年份:2010
- 资助金额:
$ 13.05万 - 项目类别:
The Role of Interferon-gamma in the Regulation of Hematopoietic Stem Cells
干扰素-γ在造血干细胞调节中的作用
- 批准号:
8423745 - 财政年份:2010
- 资助金额:
$ 13.05万 - 项目类别:
The Role of Interferon-gamma in the Regulation of Hematopoietic Stem Cells
干扰素-γ在造血干细胞调节中的作用
- 批准号:
8230673 - 财政年份:2010
- 资助金额:
$ 13.05万 - 项目类别:
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