Proteolytic control of local inflammatory macrophage proliferation
局部炎症巨噬细胞增殖的蛋白水解控制
基本信息
- 批准号:9038435
- 负责人:
- 金额:$ 49.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-04-01 至 2019-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdipose tissueArterial Fatty StreakAtherosclerosisAutomobile DrivingBlood VesselsCardiovascular DiseasesCell surfaceCellsChronicCleaved cellCytoplasmic GranulesDataDietDiseaseDisease ProgressionEnzymesEventHealthHematopoieticHumanIncidenceInfiltrationInflammationInflammatoryInflammatory ResponseInjection of therapeutic agentInsulinInsulin ResistanceKnowledgeLaboratoriesLesionMacrophage Colony-Stimulating FactorMediatingModelingMolecularMorbidity - disease rateMusNon-Insulin-Dependent Diabetes MellitusObesityObesity associated cardiovascular diseasePeptide HydrolasesProcessProliferatingProtein IsoformsProteinsProteolysisRecruitment ActivityRegulationReportingRoleSiteSourceStromal CellsTestingWestern Worldatherogenesisdiabeticmacrophagemonocytemortalitymouse modelneutrophilnovelnovel strategiespreventresponsetrafficking
项目摘要
DESCRIPTION (provided by applicant): Proteolytic control of local inflammatory macrophage proliferation Atherosclerosis and its complications remain the leading cause of morbidity and mortality worldwide, and the increased incidence of obesity and associated cardiovascular disease further exacerbates this major health problem. In human atherosclerotic lesions and obese adipose tissue, and in mouse models, macrophages accumulate in large numbers within lesions, and interference with inflammatory macrophage accumulation can reduce lesion formation, adipose tissue inflammation and insulin resistance. Recent findings suggest that local macrophage proliferation, rather than monocyte recruitment, is the key event, but mechanisms initiating the proliferative response in disease are poorly understood. This proposal will address this knowledge gap by building on novel observations made by our laboratory that identify proteolytic cleavage by the transmembrane protease ADAM17 of the cell surface form of macrophage colony stimulating factor (csCSF-1), a potent stimulant of monoycte and macrophage proliferation and survival, as a major event controlling proliferation of macrophages recruited to inflammatory sites. We propose three specific aims 1. Test the impact of neutrophil deletion of ADAM17 on inflammatory macrophage proliferation under conditions of acute and chronic inflammation; 2. Investigate contributions of iRhom proteins that regulate ADAM17, and compartmentalization of csCSF-1, to control of csCSF-1 release from neutrophils; and 3. Directly test the role of ADAM17-mediated cleavage of csCSF-1 in macrophage proliferation within atherosclerotic lesions and inflamed adipose tissue, and develop and test novel strategies to selectively prevent its cleavage. Thus our proposed studies will clarify molecular mechanisms controlling macrophage proliferation in acute and chronic inflammation, and have the potential to develop strategies to interfere with macrophage accumulation, a major factor driving cardiovascular disease.
描述(申请人提供):局部炎性巨噬细胞增殖的蛋白分解控制动脉粥样硬化及其并发症仍然是全球发病率和死亡率的主要原因,肥胖症和相关心血管疾病的发病率增加进一步加剧了这一重大健康问题。在人类动脉粥样硬化病变和肥胖脂肪组织中,以及在小鼠模型中,巨噬细胞在病变内大量聚集,干扰炎性巨噬细胞聚集可以减少病变形成、脂肪组织炎症和胰岛素抵抗。最近的发现表明,局部巨噬细胞增殖,而不是单核细胞募集,是关键事件,但在疾病中启动增殖反应的机制尚不清楚。这项建议将通过建立在我们实验室新的观察结果的基础上来解决这一知识差距,这些新观察确定巨噬细胞集落刺激因子(csCSF-1)的细胞表面形式的跨膜蛋白酶ADAM17的蛋白水解性切割是控制巨噬细胞被招募到炎症部位的增殖的一个重大事件。我们提出了三个特定的目标:1.检测急性和慢性炎症条件下中性粒细胞ADAM17缺失对炎性巨噬细胞增殖的影响;2.研究调节ADAM17的iRhom蛋白和csCSF-1的区划,对控制中性粒细胞释放csCSF-1的作用;3.直接测试ADAM17介导的csCSF-1裂解在动脉粥样硬化病变和炎症脂肪组织中巨噬细胞增殖中的作用,并开发和测试选择性阻止其裂解的新策略。因此,我们提出的研究将阐明在急、慢性炎症中控制巨噬细胞增殖的分子机制,并有可能开发干预巨噬细胞聚集的策略,巨噬细胞聚集是导致心血管疾病的主要因素。
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 }}
Elaine W Raines其他文献
Nogo puts the brake on vascular lesions
Nogo 阻止血管损伤
- DOI:
10.1038/nm0404-348 - 发表时间:
2004-04-01 - 期刊:
- 影响因子:50.000
- 作者:
Elaine W Raines - 通讯作者:
Elaine W Raines
Elaine W Raines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('Elaine W Raines', 18)}}的其他基金
Proteolytic control of local inflammatory macrophage proliferation
局部炎症巨噬细胞增殖的蛋白水解控制
- 批准号:
8892773 - 财政年份:2015
- 资助金额:
$ 49.42万 - 项目类别:
Cloaking Key MMP-9 Substrates to Probe the role of Their Cleavage in Plaque Ruptu
隐藏关键 MMP-9 底物以探究其裂解在斑块破裂中的作用
- 批准号:
8055931 - 财政年份:2010
- 资助金额:
$ 49.42万 - 项目类别:
Cloaking Key MMP-9 Substrates to Probe the role of Their Cleavage in Plaque Ruptu
隐藏关键 MMP-9 底物以探究其裂解在斑块破裂中的作用
- 批准号:
7872152 - 财政年份:2010
- 资助金额:
$ 49.42万 - 项目类别:
MACROPHAGE CELL-SURFACE PROTEOLYSIS IN ATHEROGENESIS
动脉粥样硬化形成中的巨噬细胞表面蛋白水解
- 批准号:
6861526 - 财政年份:2005
- 资助金额:
$ 49.42万 - 项目类别:
MMP-9 AS A PROINFLAMMATORY REGULATOR IN ATHEROGENESIS
MMP-9 作为动脉粥样硬化形成中的促炎调节剂
- 批准号:
7923973 - 财政年份:2005
- 资助金额:
$ 49.42万 - 项目类别:
MMP-9 AS A PROINFLAMMATORY REGULATOR IN ATHEROGENESIS
MMP-9 作为动脉粥样硬化形成中的促炎调节剂
- 批准号:
7729741 - 财政年份:2005
- 资助金额:
$ 49.42万 - 项目类别:
MMP-9 AS A PROINFLAMMATORY REGULATOR IN ATHEROGENESIS
MMP-9 作为动脉粥样硬化形成中的促炎调节剂
- 批准号:
7074635 - 财政年份:2005
- 资助金额:
$ 49.42万 - 项目类别:
Macrophage Cell-Surface Proteolysis and Inflammation
巨噬细胞表面蛋白水解和炎症
- 批准号:
7140029 - 财政年份:2005
- 资助金额:
$ 49.42万 - 项目类别:
MMP-9 AS A PROINFLAMMATORY REGULATOR IN ATHEROGENESIS
MMP-9 作为动脉粥样硬化形成中的促炎调节剂
- 批准号:
7236746 - 财政年份:2005
- 资助金额:
$ 49.42万 - 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:
$ 49.42万 - 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:
$ 49.42万 - 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:
$ 49.42万 - 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:
$ 49.42万 - 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:
$ 49.42万 - 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:
$ 49.42万 - 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:
$ 49.42万 - 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:
$ 49.42万 - 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:
$ 49.42万 - 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:
$ 49.42万 - 项目类别:
Research Grant