Targeting CNS Neuroinflammation in Traumatic Brain Injury by Nasal Anti-CD3
通过鼻抗 CD3 靶向治疗创伤性脑损伤中的 CNS 神经炎症
基本信息
- 批准号:10597247
- 负责人:
- 金额:$ 23.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAcuteAcute Brain InjuriesAdaptive Immune SystemAftercareAmericanAnimal ModelAnimalsAnti-Inflammatory AgentsAntibodiesAreaAttenuatedAutoimmune DiseasesBehaviorBehavioralBiochemicalBioinformaticsBiologicalBrainBrain InjuriesC57BL/6 MouseCD3 AntigensCellsCervical lymph node groupChronicChronic PhaseCoculture TechniquesCognitiveCortical ContusionsDataDiseaseDisease ProgressionFOXP3 geneFlow CytometryFundingGoalsHealthHippocampusHourHumanImmune responseImmune systemImmunologic StimulationImmunologyImmunotherapeutic agentImmunotherapyIn VitroInflammationInflammatoryInflammatory ResponseInjuryInnate Immune ResponseInnate Immune SystemInterleukin-10Interleukin-4IpsilateralKnowledgeLearningLesionMechanicsMediatingMentorsMicrogliaModelingMolecularMonoclonal AntibodiesMotorMultiple SclerosisMusNatureNeurologic DeficitNoseOutcomePathogenesisPathway interactionsPatient-Focused OutcomesPatientsPhasePhenotypePlayRegulationRegulatory T-LymphocyteRehabilitation therapyResearchResearch PersonnelRoleShort-Term MemorySignal TransductionSurveysT cell responseT-LymphocyteTBI treatmentTamoxifenTestingTherapeutic EffectTimeTrainingTransforming Growth Factor betaTraumatic Brain InjuryTraumatic Brain Injury recoveryTravelUnited States National Institutes of HealthUp-RegulationWorkadaptive immune responseadaptive immunitybehavioral outcomebrain cellcareercell motilityclinical applicationcognitive functioncontrolled cortical impactcostcytokinedisabilityeffective therapyeffector T cellexperienceexperimental studyglial activationimmunoregulationimprovedin vivoinsightinterleukin-10 receptormigrationmouse modelneuralneuroimmunologyneuroinflammationneurological recoveryneuropathologyneurotoxicneurotoxicitynovelnovel therapeuticsprotective effectresponsetranscriptometranscriptome sequencing
项目摘要
PROJECT SUMMARY / ABSTRACT
Traumatic brain injury (TBI) is a major health problem; 2.5 million Americans sustain TBI each year at a cost of
80 billion dollars annually. Few therapies reduce long-term cognitive sequelae of TBI, and there are only
limited options for rehabilitation. Brain injury causes a primary structural injury followed by a secondary phase,
which involves the activation of the innate and adaptive immune systems. Neuroinflammation with microglia’s
involvement has been identified as a major contributor to the pathogenesis of TBI. However, there is still no
effective immune therapy to modulate the microglial response post-injury. Nasal administration of anti-CD3
monoclonal antibody induces an anti-inflammatory immune response that down-regulates microglial activation
in animal models of multiple sclerosis. The mechanism involves localization of nasal anti-CD3 to cervical lymph
nodes where it induces IL-10-secreting (CD4+LAP+ and CD4+FoxP3+) regulatory T cells (Tregs) that migrate
to the brain and inhibit microglial activation. Nasal anti-CD3 therapy is an unexplored area in TBI, and the
mechanisms by which Tregs modulate microglia in TBI are largely unknown. Dr. Saef Izzy, a trained
neurointensivist with a background in acute brain injury research, hypothesized that nasal anti-CD3 represents
a unique, clinically applicable immunomodulatory approach for the treatment of TBI. Dr. Izzy worked closely
with his primary mentor, Dr. Howard Weiner, to investigate the effects of nasal anti-CD3 on TBI outcomes in
mice. His preliminary data showed that nasal anti-CD3 increases CD4+Tregs and IL 10 expression and
reduces microglial activation in the brain 7 days after controlled cortical impact injury (CCI). It also improves
behavioral outcomes at 1-month post-injury. In this K08 proposal, Dr. Izzy will determine the effects of nasal
anti-CD3 on long-term histopathological and behavioral outcomes after CCI (Aim 1). He will survey the
microglial, effector, and regulatory T cell responses after injury and study the effects of Tregs on microglial
inflammatory response in vitro after CCI (Aim 2). He will investigate the effect of nasal anti-CD3 on IL-10/IL-
10R signaling in microglia using a C57BL6/J mouse harboring IL-10Rflox/floxTMEM119CreETR2, which does not
express the IL-10 receptor on microglia after tamoxifen administration. He will also delineate the role(s) of
other anti-inflammatory cytokines produced by Tregs by neutralizing TGF-β and IL-4 in vitro and in vivo and
study their effects on behavior and microglial inflammatory response post-CCI (Aim 3). Dr. Izzy's career goal is
to better understand how the adaptive immune response interfaces with the innate immune system after TBI.
Successful completion of this proposal will provide insight into the mechanisms by which Tregs modulate the
microglial response after TBI and the identification of novel immune-based therapeutics to improve patients’
outcomes. The proposed K08 application leverages Dr. Izzy’s mentor’s expertise in immunology, mouse
models of acute brain injury, and bioinformatics to provide him with the additional knowledge and experience
necessary to become an independent NIH-funded investigator and expert in the neuroimmunology of TBI.
项目摘要/摘要
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 }}
Saef Izzy其他文献
Saef Izzy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('Saef Izzy', 18)}}的其他基金
Targeting CNS Neuroinflammation in Traumatic Brain Injury by Nasal Anti-CD3
通过鼻抗 CD3 靶向治疗创伤性脑损伤中的 CNS 神经炎症
- 批准号:
10449540 - 财政年份:2022
- 资助金额:
$ 23.07万 - 项目类别:
相似海外基金
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
- 批准号:
MR/Y009568/1 - 财政年份:2024
- 资助金额:
$ 23.07万 - 项目类别:
Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
- 批准号:
10090332 - 财政年份:2024
- 资助金额:
$ 23.07万 - 项目类别:
Collaborative R&D
Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
- 批准号:
MR/X02329X/1 - 财政年份:2024
- 资助金额:
$ 23.07万 - 项目类别:
Fellowship
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
- 批准号:
MR/X021882/1 - 财政年份:2024
- 资助金额:
$ 23.07万 - 项目类别:
Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
- 批准号:
MR/X029557/1 - 财政年份:2024
- 资助金额:
$ 23.07万 - 项目类别:
Research Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
- 批准号:
EP/Y003527/1 - 财政年份:2024
- 资助金额:
$ 23.07万 - 项目类别:
Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
- 批准号:
EP/Y030338/1 - 财政年份:2024
- 资助金额:
$ 23.07万 - 项目类别:
Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
- 批准号:
2312694 - 财政年份:2024
- 资助金额:
$ 23.07万 - 项目类别:
Standard Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
- 批准号:
24K19395 - 财政年份:2024
- 资助金额:
$ 23.07万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Acute human gingivitis systems biology
人类急性牙龈炎系统生物学
- 批准号:
484000 - 财政年份:2023
- 资助金额:
$ 23.07万 - 项目类别:
Operating Grants