Elucidating and harnessing the molecular mechanisms of protective clearance in endogenous and engineered phagocytes
阐明和利用内源性和工程化吞噬细胞保护性清除的分子机制
基本信息
- 批准号:10729935
- 负责人:
- 金额:$ 41.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-08 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:Anti-Inflammatory AgentsAntibodiesAntigen-Antibody ComplexAntigensApoptoticAutoantibodiesAutophagocytosisBehaviorBindingBiologicalBiological AssayBiological ModelsBirthBrainCRISPR/Cas technologyCell Culture TechniquesCell modelCell physiologyCellsCentral Nervous SystemCentral Nervous System DiseasesChildhoodChloride ChannelsChloridesChronicCollaborationsCollectionDataDepositionDevelopmentDiseaseDrosophila genusElementsEngineeringExcisionExtracellular DomainFamilyFunctional disorderGenesGeneticGoalsHomeostasisHumanIgG ReceptorsImmuneIn VitroInflammationInflammatoryInflammatory ResponseIngestionInheritedKnowledgeLearningLigandsLinkLysosomesMacrophageMapsMeasuresMediatingMembraneMendelian disorderMethodsModelingMolecularMusMutateMutationNerve DegenerationNeurodegenerative DisordersNeuronal Ceroid-LipofuscinosisOrthologous GenePathologyPhagocytesPhagocytosisPlayProcessProtein DynamicsProteinsRecoveryRetinaRetinal DegenerationRod Outer SegmentsRoleSignal TransductionSpielmeyer-Vogt DiseaseStructure of retinal pigment epitheliumSynapsesSystemTestingTexasTherapeuticTimeTissuesTransplantationTumor AntigensWorkaxon injurycancer celldesignextracellularin vivomutantnovelparticleprogramsprotein functionreceptorreconstitutionretinal rodssuccesstransplant model
项目摘要
Project Summary/Abstract
Protective clearance describes the process of the removal of membrane-intact cells or parts of cells
without induction of pro-inflammatory responses; it is a central mode of normal development and
homeostasis across tissues and phyla. Executing this process in a regulated and anti-inflammatory
fashion requires exquisite orchestration of a collection of activities including receptor-mediated
phagocytosis, lysosome formation, and intracellular degradation. Protective clearance plays a particularly
important role in maintaining function and homeostasis in the central nervous system (CNS). The
lysosomal storage disorders are a broad family of diseases characterized by dysregulated protective
clearance in the CNS. Batten disease is a class of 13 fatal neurodegenerative lysosomal storage
disorders that usually appear in childhood and comprise the most common inherited pediatric
neurodegenerative disease worldwide. The pathology of Batten disease is linked to synaptic dysfunction
and auto antibody deposition in the CNS. All genetically mapped forms of the disease are monogenic,
caused by mutations in one of 13 ceroid lipofuscinosis (cln) genes. Despite the success mapping the cln
genes, the cell biological mechanisms governing the CLN proteins in space and time remain an open
problem. Further understanding of the fundamental mechanisms underlying CLN protein function may
identify new avenues to treat Batten disease. The goal of this proposal is to elucidate the molecular and
cellular mechanisms underlying protective clearance in endogenous phagocytes and engineer the
process in for therapy by programming phagocytes to eliminate auto antigen-antibody complexes in the
CNS in an anti-inflammatory manner. This project will use three powerful model systems comprised of
living phagocytes and defined targets to define the molecular and cellular mechanisms underlying
protective clearance. In Aim 1, we will use a simplified cell model of protective clearance to explore a
connection we recently discovered between a CLN protein and a conserved phagocyte receptor. In Aim 2,
we will use a novel model of endogenous protective clearance in the retina to systematically define the
functions of each CLN protein during protective clearance. In Aim 3, we will use our expertise in immune
cell programming to engineer phagocytes that eliminate antigen-antibody complexes from the CNS via
protective clearance and test these molecules in vivo in an advanced mouse CNS macrophage transplant
model. Completion of these aims will clarify molecular mechanisms underlying protective clearance,
define how Batten disease mutations dysregulate the process, and investigate the therapeutic potential of
synthetic receptors to eliminate antigen-antibody complexes from the CNS in an anti-inflammatory
manner.
项目总结/文摘
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 }}
Adam Patrick Williamson其他文献
Adam Patrick Williamson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 }}
相似海外基金
University of Aberdeen and Vertebrate Antibodies Limited KTP 23_24 R1
阿伯丁大学和脊椎动物抗体有限公司 KTP 23_24 R1
- 批准号:
10073243 - 财政年份:2024
- 资助金额:
$ 41.86万 - 项目类别:
Knowledge Transfer Partnership
Role of Natural Antibodies and B1 cells in Fibroproliferative Lung Disease
天然抗体和 B1 细胞在纤维增生性肺病中的作用
- 批准号:
10752129 - 财政年份:2024
- 资助金额:
$ 41.86万 - 项目类别:
CAREER: Next-generation protease inhibitor discovery with chemically diversified antibodies
职业:利用化学多样化的抗体发现下一代蛋白酶抑制剂
- 批准号:
2339201 - 财政年份:2024
- 资助金额:
$ 41.86万 - 项目类别:
Continuing Grant
Isolation and characterisation of monoclonal antibodies for the treatment or prevention of antibiotic resistant Acinetobacter baumannii infections
用于治疗或预防抗生素耐药鲍曼不动杆菌感染的单克隆抗体的分离和表征
- 批准号:
MR/Y008693/1 - 财政年份:2024
- 资助金额:
$ 41.86万 - 项目类别:
Research Grant
Developing first-in-class aggregation-specific antibodies for a severe genetic neurological disease
开发针对严重遗传神经系统疾病的一流聚集特异性抗体
- 批准号:
10076445 - 财政年份:2023
- 资助金额:
$ 41.86万 - 项目类别:
Grant for R&D
Discovery of novel nodal antibodies in the central nervous system demyelinating diseases and elucidation of the mechanisms through an optic nerve demyelination model
发现中枢神经系统脱髓鞘疾病中的新型节点抗体并通过视神经脱髓鞘模型阐明其机制
- 批准号:
23K14783 - 财政年份:2023
- 资助金额:
$ 41.86万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of the mechanisms controlling the physicochemical properties and functions of supercharged antibodies and development of their applications
阐明控制超电荷抗体的理化性质和功能的机制及其应用开发
- 批准号:
23KJ0394 - 财政年份:2023
- 资助金额:
$ 41.86万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Role of antibodies in hepatitis E virus infection
抗体在戊型肝炎病毒感染中的作用
- 批准号:
10639161 - 财政年份:2023
- 资助金额:
$ 41.86万 - 项目类别:
Defining the protective or pathologic role of antibodies in Post-Ebola Syndrome
定义抗体在埃博拉后综合症中的保护或病理作用
- 批准号:
10752441 - 财政年份:2023
- 资助金额:
$ 41.86万 - 项目类别:
Human CMV monoclonal antibodies as therapeutics to inhibit virus infection and dissemination
人 CMV 单克隆抗体作为抑制病毒感染和传播的治疗药物
- 批准号:
10867639 - 财政年份:2023
- 资助金额:
$ 41.86万 - 项目类别: