JAK inhibition as a novel treatment for hemophagocytic lymphohistiocytosis
JAK 抑制作为噬血细胞性淋巴组织细胞增多症的新型治疗方法
基本信息
- 批准号:8907502
- 负责人:
- 金额:$ 31.15万
- 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:2014-09-01 至 2016-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdultAllogenicBindingBiological Response ModifiersBiologyBlocking AntibodiesBloodBody Weight decreasedBone Marrow SuppressionC57BL/6 MouseCD8B1 geneCellsChildChronicClinicCytokine Network PathwayCytokine ReceptorsCytokine SignalingDNADefectDevelopmentDexamethasoneDiseaseDoseEtoposideExhibitsFDA approvedFerritinFunctional disorderFutureGene MutationGenerationsGeneticGenetic TranscriptionGrantHealthHemophagocytic LymphohistiocytosesHepaticHigh Dose ChemotherapyHumanHypotensionImmuneImmune Cell ActivationImmune System DiseasesImmune responseImmunityImmunologic Deficiency SyndromesImmunologicsInborn Genetic DiseasesInfectionInflammationInflammatoryInjection of therapeutic agentInterferonsInterleukin-12Interleukin-6InvestigationJAK1 geneJanus kinaseJordanLaboratoriesLifeLymphocyteLymphocytic choriomeningitis virusMacrophage ActivationMediatingMedical centerModelingMusOrganOutcomePathogenesisPatientsPatternPediatric HospitalsPennsylvaniaPharmaceutical PreparationsPharmacodynamicsPhiladelphiaPhosphorylationPilot ProjectsPre-Clinical ModelProductionProteinsPublic HealthReceptor SignalingRecurrenceRefractoryRegimenRoleScheduleSepsisSerumSignal TransductionSplenomegalyStem cell transplantSteroidsSyndromeT-LymphocyteTLR9 geneTestingTherapeuticTherapeutic EffectTimeToxic effectTranslational ResearchUniversitiesViralVirulencebasebench to bedsideclinically significantcytokinecytopeniacytotoxiceffective therapyexperiencehuman diseaseimmunopathologyimprovedinhibitor/antagonistinsightinterestinterleukin-10 receptorintraperitonealkinase inhibitormacrophagemembernon-geneticnovelperforin
项目摘要
DESCRIPTION (provided by applicant): The hemophagocytic lymphohistiocytoses (HLH) comprise a growing number of inherited and non-inherited disorders of the immune system characterized by the generation of abnormal and severely damaging immune responses. HLH patients experience spontaneous and often recurring episodes of hyper-inflammation marked by the activation and expansion of CD8+ T cells and macrophages that produce copious amounts of pro-inflammatory cytokines, including interleukins (IL)-6, IL-12, and interferon (IFN)-?. Despite current treatments, up to 50% of HLH patients die due to the toxic effects of these cytokines, which further drive immune cell activation and promote a sepsis-like syndrome of hypotension, bone marrow suppression and multisystem organ dysfunction. The Janus kinases (JAKs) transduce STAT-dependent intracellular signals initiated following engagement of the Types I and II cytokine receptors, which bind a broad array of cytokines including those over-produced in HLH. Based on the critical role for pro-inflammatory cytokines in the pathogenesis of HLH, we hypothesize that pharmacologic inhibition of the JAKs will diminish inflammation and ameliorate disease. Indeed, in pilot studies in mice, we observe that the FDA-approved JAK inhibitor ruxolitinib significantly lessens the manifestations of HLH, including weight loss, splenomegaly, cytopenias, hyper-cytokinemias and hepatic inflammation. In this Exploratory Grant Investigation (PA-13-315), we plan to further test this hypothesis by determining the therapeutic effects of ruxolitinib and deciphering its underlying mechanism(s) of action. Using 2 complementary murine HLH models, we will refine the dosing and schedule of ruxolitinib administration and assess its efficacy when used as a single agent or in combination with more conventional HLH therapies (i.e. dexamethasone, etoposide). We will complete immunologic studies to examine how ruxolitinib influences patterns of immune cell activation and cytokine production, JAK and/or STAT phosphorylation and STAT-dependent gene transcription. Despite the inadequacy of current HLH therapies, there have been no significant advances in treatment in more than a decade. Through the proposed studies, we intend to improve the outcome for HLH patients by targeting JAK-dependent cytokine networks, a new and rational approach to treatment. To facilitate the successful completion of these studies, we have gathered a strong investigative team that includes Drs. Kim Nichols, Ed Behrens and David Teachey (The Children's Hospital of Philadelphia), John Wherry (The University of Pennsylvania) and Michael Jordan (Cincinnati Children's Hospital Medical Center). Together, the members of this team are experts in the biology of HLH and cytokine signaling, pre-clinical modeling of human diseases and the bench-to-bedside translation of research findings. Therefore, should this study continue to demonstrate a beneficial effect, we anticipate that its results can be readily transitioned to te clinic in the form of a future ruxolitinib-based trial for children and adults with HLH.
描述(由申请人提供):噬血细胞性淋巴组织细胞增多症(HLH)包括越来越多的遗传性和非遗传性免疫系统疾病,其特征是产生异常和严重破坏性的免疫反应。 HLH 患者会经历自发且经常反复发作的过度炎症,其特征是 CD8+ T 细胞和巨噬细胞的激活和扩增,产生大量促炎细胞因子,包括白细胞介素 (IL)-6、IL-12 和干扰素 (IFN)-α。尽管目前有治疗方法,但高达 50% 的 HLH 患者死于这些细胞因子的毒性作用,这进一步驱动免疫细胞激活并促进低血压、骨髓抑制和多系统器官功能障碍的脓毒症样综合征。 Janus 激酶 (JAK) 转导在 I 型和 II 型细胞因子受体参与后启动的 STAT 依赖性细胞内信号,这些信号与多种细胞因子结合,包括 HLH 中过量产生的细胞因子。基于促炎细胞因子在 HLH 发病机制中的关键作用,我们假设 JAK 的药理学抑制将减少炎症并改善疾病。事实上,在小鼠试验中,我们观察到 FDA 批准的 JAK 抑制剂鲁索替尼显着减轻了 HLH 的表现,包括体重减轻、脾肿大、血细胞减少、高细胞因子血症和肝脏炎症。在本次探索性拨款调查 (PA-13-315) 中,我们计划通过确定鲁索替尼的治疗效果并破译其潜在的作用机制来进一步检验这一假设。使用 2 个互补的小鼠 HLH 模型,我们将完善鲁索替尼给药的剂量和时间表,并评估其作为单一药物或与更传统的 HLH 疗法(即地塞米松、依托泊苷)联合使用时的疗效。我们将完成免疫学研究,以检查鲁索替尼如何影响免疫细胞激活和细胞因子产生、JAK 和/或 STAT 磷酸化以及 STAT 依赖性基因转录的模式。尽管目前的 HLH 疗法存在不足,但十多年来治疗方法并未取得重大进展。通过拟议的研究,我们打算通过靶向 JAK 依赖性细胞因子网络(一种新的合理治疗方法)来改善 HLH 患者的预后。为了促进这些研究的成功完成,我们聚集了一个强大的调查团队,其中包括博士。 Kim Nichols、Ed Behrens 和 David Teachey(费城儿童医院)、John Wherry(宾夕法尼亚大学)和 Michael Jordan(辛辛那提儿童医院医疗中心)。该团队的成员都是 HLH 生物学和细胞因子信号转导、人类疾病临床前建模以及研究结果从实验室到临床转化的专家。因此,如果这项研究继续证明其有益效果,我们预计其结果可以很容易地以未来针对 HLH 儿童和成人的鲁索替尼试验的形式转移到临床。
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 }}
KIM Erika NICHOLS其他文献
KIM Erika NICHOLS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('KIM Erika NICHOLS', 18)}}的其他基金
Targeting the immunoproteasome as a novel therapeutic strategy for hemophagocytic lymphohistiocytosis
靶向免疫蛋白酶体作为噬血细胞性淋巴组织细胞增多症的新型治疗策略
- 批准号:
10741624 - 财政年份:2023
- 资助金额:
$ 31.15万 - 项目类别:
Pathogenesis of ETV6-Related Acute Lymphoblastic Leukemia
ETV6相关急性淋巴细胞白血病的发病机制
- 批准号:
10837399 - 财政年份:2020
- 资助金额:
$ 31.15万 - 项目类别:
Pathogenesis of ETV6-Related Acute Lymphoblastic Leukemia
ETV6相关急性淋巴细胞白血病的发病机制
- 批准号:
10247963 - 财政年份:2020
- 资助金额:
$ 31.15万 - 项目类别:
Role of SAP,SLAM and Fyn in NKT Cell Ontogeny and Activation
SAP、SLAM 和 Fyn 在 NKT 细胞个体发育和激活中的作用
- 批准号:
8110525 - 财政年份:2007
- 资助金额:
$ 31.15万 - 项目类别:
Role of SAP,SLAM and Fyn in NKT Cell Ontogeny and Activation
SAP、SLAM 和 Fyn 在 NKT 细胞个体发育和激活中的作用
- 批准号:
7662291 - 财政年份:2007
- 资助金额:
$ 31.15万 - 项目类别:
Role of SAP,SLAM and Fyn in NKT Cell Ontogeny and Activation
SAP、SLAM 和 Fyn 在 NKT 细胞个体发育和激活中的作用
- 批准号:
7302925 - 财政年份:2007
- 资助金额:
$ 31.15万 - 项目类别:
Role of SAP,SLAM and Fyn in NKT Cell Ontogeny and Activation
SAP、SLAM 和 Fyn 在 NKT 细胞个体发育和激活中的作用
- 批准号:
7886595 - 财政年份:2007
- 资助金额:
$ 31.15万 - 项目类别:
Role of SAP,SLAM and Fyn in NKT Cell Ontogeny and Activation
SAP、SLAM 和 Fyn 在 NKT 细胞个体发育和激活中的作用
- 批准号:
7473119 - 财政年份:2007
- 资助金额:
$ 31.15万 - 项目类别:
ROLE OF SH2D1A/SAP IN NKT CELL DEVELOPMENT AND FUNCTION
SH2D1A/SAP 在 NKT 细胞发育和功能中的作用
- 批准号:
6987827 - 财政年份:2004
- 资助金额:
$ 31.15万 - 项目类别:
ROLE OF SH2D1A/SAP IN NKT CELL DEVELOPMENT AND FUNCTION
SH2D1A/SAP 在 NKT 细胞发育和功能中的作用
- 批准号:
6852322 - 财政年份:2004
- 资助金额:
$ 31.15万 - 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:
$ 31.15万 - 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:
$ 31.15万 - 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:
$ 31.15万 - 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:
$ 31.15万 - 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:
$ 31.15万 - 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:
$ 31.15万 - 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:
$ 31.15万 - 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:
$ 31.15万 - 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:
$ 31.15万 - 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:
$ 31.15万 - 项目类别:
Research Grant