Targeted Abrogation of the FXII-uPAR-pAkt2 Axis in Neutrophils for Treatment of Chronic Wounds
靶向消除中性粒细胞中的 FXII-uPAR-pAkt2 轴以治疗慢性伤口
基本信息
- 批准号:10320385
- 负责人:
- 金额:$ 39.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-01-15 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AdhesionsAmino AcidsAutoimmune DiseasesBasic ScienceBindingBinding SitesBiologicalBiological AssayBloodCaliberCellsChemotaxisChronicDevelopmentEventFab ImmunoglobulinsFactor XIIFormulationFoundationsFundingFutureGoalsGrowth FactorHealth Care CostsHealthcareHealthcare SystemsImpaired wound healingIn VitroInfectionInflammatoryInterphase CellKineticsLeukocyte ElastaseLigandsLipidsLiquid substanceMapsMechanicsMediatingMorbidity - disease rateNanotechnologyNeutrophil ActivationNeutrophil InfiltrationNutritional SupportPathologyPeptidesPharmaceutical PreparationsPhasePhosphorylationPopulationProteinsRecombinantsResearchSamplingSignal TransductionSiteSite-Directed MutagenesisSurfaceSystemTestingTherapeuticTherapeutic AgentsTherapeutic EffectTopical applicationTreatment EfficacyUrokinase Plasminogen Activator ReceptorWound modelsacute woundalpha 1-Antitrypsinautocrinebaseblocking factorcare burdenchronic woundclinical efficacyclinical translationcostdesigndiabetic patientextracellularhealingimprovedin vivoinnovationmortalitymouse modelmutantnanoformulationnanomedicinenanovesicleneutrophilnon-healing woundsnovelnovel strategiesnovel therapeuticspeptide drugpreclinical studyprotein aminoacid sequencereceptor bindingtargeted deliverytechnological innovationtherapeutically effectivetranslational approachtranslational studytumor progressionwoundwound healing
项目摘要
PROJECT SUMMARY
The overall goal of this proposal is to characterize the interaction between Factor XII (FXII) and urokinase
plasminogen activator receptor (uPAR) to design strategies that disrupt their signaling in neutrophils for treatment
of chronic wounds. Chronic, non-healing wounds represent a major health care burden, costing 25 billion dollars
annually in US health care costs, and are associated with high mortality. Current treatments for impaired wound
healing focus mainly on optimization of controllable healing factors, e.g., mechanical protection, nutritional
support and clearance of infections. Targeted approaches have been developed to date, including topical
application of growth factors however, with limited clinical efficacy. Moreover, these approaches only influence
wound healing end-points (e.g. proliferation and remodelling) but do not prevent upstream events such as
excessive neutrophil activation, neutrophil extracellular trap (NET) formation, or unbalanced neutrophil
proteolytic activity, all of which are persistent hallmark events in non-healing wounds. In this framework, we
propose to downregulate neutrophil activation and NET formation through targeted disruption of the FXII-uPAR-
pAkt2 axis. We identified that FXII-uPAR upregulate neutrophil functions. Specifically, we have shown that
following neutrophil activation, autocrine FXII signals through uPAR leading to phosphorylation of Akt2 on Ser474
and to neutrophil adhesion, chemotaxis, and NET formation. Disruption of FXII signaling in neutrophils resulted
in faster wound healing. Based on these findings, our central hypothesis is that selective inhibition of the FXII-
uPAR-pAkt2 axis in neutrophils will be therapeutically effective in treating chronic wounds.
In this application, our goals are to: 1) map the uPAR binding sites on FXII using recombinant FXII deletion
mutants and site-directed mutagenesis. These studies will provide the structural details for the design of FXII
inhibitory peptides that interfere with the FXII-uPAR interaction; 2) use a unique nanovesicle platform that is able
to bind exclusively on activated neutrophils and deliver FXII inhibitory peptides at wound sites. We will first
characterize the biologic effects of these loaded nanovesicles in vitro, and subsequently we will determine their
therapeutic effect in murine models of wound healing in vivo. We will 3) correlate these preclinical studies and
determine the constitutive activity of FXII-uPAR-pAkt2 using blood and wound samples from diabetic patients.
The end goal is to show the relative abundance of the FXII-uPAR-pAkt2 axis and downstream effectors in non-
healing wound pathology which will lay the foundation for future translational studies to inhibit its action.
Our scientific innovation is the mechanistic elucidation of the FXII-uPAR-pAkt2 signaling axis in neutrophil-
mediated pathology. Our technological innovation is the development of peptide nanomedicine strategies to
block this axis for therapeutic benefit in chronic wounds. If successful, this strategy will introduce novel and safer
therapies to treat chronic wounds, morbidities that are common among the U.S. population.
项目摘要
该提案的总体目标是描述因子XII(FXII)和尿激酶之间的相互作用
纤溶酶原激活物受体(uPAR),以设计在中性粒细胞中破坏其信号传导的策略用于治疗
慢性创伤。慢性、不愈合的伤口是一个主要的卫生保健负担,耗资250亿美元
每年在美国的医疗保健费用,并与高死亡率。受损伤口的当前治疗
愈合主要集中在可控愈合因素的优化,例如,机械保护,营养的
支持和清除感染。到目前为止,已经制定了有针对性的方法,包括局部
然而,生长因子的应用具有有限的临床功效。此外,这些方法只影响
伤口愈合终点(例如增殖和重塑),但不能阻止上游事件,
中性粒细胞过度活化、中性粒细胞胞外陷阱(NET)形成或中性粒细胞失衡
蛋白水解活性,所有这些都是不愈合伤口中的持续标志事件。在这个框架内,我们
建议通过靶向破坏FXII-uPAR下调中性粒细胞活化和NET形成,
pAkt 2轴。我们确定FXII-uPAR上调中性粒细胞功能。具体来说,我们已经证明,
在中性粒细胞活化后,自分泌FXII信号通过uPAR导致Ser 474上的Akt 2磷酸化,
以及中性粒细胞粘附、趋化性和NET形成。中性粒细胞中FXII信号传导的破坏导致
伤口愈合更快基于这些发现,我们的中心假设是选择性抑制FXII-
中性粒细胞中的uPAR-pAkt 2轴在治疗慢性伤口方面将具有治疗效果。
在本申请中,我们的目标是:1)使用重组FXII缺失来定位FXII上的uPAR结合位点
突变体和定点诱变。这些研究将为FXII的设计提供结构细节
干扰FXII-uPAR相互作用的抑制肽; 2)使用能够
专门结合活化的嗜中性粒细胞并在伤口部位递送FXII抑制肽。我们将首先
表征这些负载的纳米囊泡在体外的生物学效应,随后我们将确定它们的
在体内伤口愈合的鼠模型中的治疗效果。我们将把这些临床前研究与
使用来自糖尿病患者的血液和伤口样品测定FXII-uPAR-pAkt 2的组成活性。
最终目标是显示在非肿瘤细胞中FXII-uPAR-pAkt 2轴和下游效应子的相对丰度。
愈合伤口病理学,这将奠定基础,为未来的翻译研究,以抑制其作用。
我们的科学创新是对中性粒细胞中FXII-uPAR-pAkt 2信号传导轴的机制阐明,
介导的病理学我们的技术创新是肽纳米医学战略的发展,
在慢性伤口中阻断该轴以获得治疗益处。如果成功,这一战略将引入新颖和更安全的
治疗慢性伤口的疗法,美国人口中常见的疾病。
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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Evi X. Stavrou其他文献
Editoral Physiologic Activities of the Contact Activation System
接触激活系统的编辑生理活动
- DOI:
- 发表时间:
2014 - 期刊:
- 影响因子:0
- 作者:
A. Schmaier;Evi X. Stavrou;Chao Fang - 通讯作者:
Chao Fang
with hypertension and faster arterial thrombosis Murine prolylcarboxypeptidase depletion induces vascular dysfunction
患有高血压和更快的动脉血栓形成小鼠脯氨酰羧肽酶耗竭会导致血管功能障碍
- DOI:
- 发表时间:
2012 - 期刊:
- 影响因子:0
- 作者:
G. D'Alecy;A. Schmaier;Yingjie Cui;Yuan Lu;M. Jain;F. Mahdi;Z. Shariat;Y. Okada;G. Adams;G. Larusch;Evi X. Stavrou;Yihua Zhou;M. Nieman - 通讯作者:
M. Nieman
THROMBOSIS AND HEMOSTASIS Reduced thrombosis in Klkb 1 2 / 2 mice is mediated by increased Mas receptor , prostacyclin , Sirt 1 , and KLF 4 and decreased tissue factor
血栓形成和止血 Klkb 1 2 / 2 小鼠中血栓形成的减少是由 Mas 受体、前列环素、Sirt 1 和 KLF 4 增加以及组织因子减少介导的。
- DOI:
- 发表时间:
2015 - 期刊:
- 影响因子:0
- 作者:
Evi X. Stavrou;Chao Fang;A. Merkulova;Omar Alhalabi;N. Grobe;S. Antoniak;N. Mackman;A. Schmaier - 通讯作者:
A. Schmaier
receptor, prostacyclin, Sirt1 and KLF4 and decreased tissue factor mice is mediated by increased Mas -/- Klkb1 Reduced thrombosis in
受体、前列环素、Sirt1 和 KLF4 以及组织因子减少的小鼠是由 Mas -/- Klkb1 增加介导的 减少血栓形成
- DOI:
- 发表时间:
2014 - 期刊:
- 影响因子:0
- 作者:
A. Schmaier;Evi X. Stavrou;Chao Fang;A. Merkulova;Omar Alhalabi;N. Grobe;S. Antoniak - 通讯作者:
S. Antoniak
A Flow Cytometry‐Based Assay for Procoagulant Platelet Polyphosphate
基于流式细胞术的促凝血小板聚磷酸盐测定
- DOI:
- 发表时间:
2018 - 期刊:
- 影响因子:0
- 作者:
L. Labberton;Andy T. Long;S. Gendler;Christine L H Snozek;Evi X. Stavrou;Katrin F Nickel;C. Maas;S. Blankenberg;James S. Hernandez;T. Renné - 通讯作者:
T. Renné
Evi X. Stavrou的其他文献
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{{ truncateString('Evi X. Stavrou', 18)}}的其他基金
Treatment of Deep Vein Thrombosis via Targeted Inhibition of the FXII-uPAR-pAkt2 Axis in Neutrophils
通过靶向抑制中性粒细胞中的 FXII-uPAR-pAkt2 轴治疗深静脉血栓形成
- 批准号:
10421248 - 财政年份:2019
- 资助金额:
$ 39.08万 - 项目类别:
Treatment of Deep Vein Thrombosis via Targeted Inhibition of the FXII-uPAR-pAkt2 Axis in Neutrophils
通过靶向抑制中性粒细胞中的 FXII-uPAR-pAkt2 轴治疗深静脉血栓形成
- 批准号:
10516085 - 财政年份:2019
- 资助金额:
$ 39.08万 - 项目类别:
Targeted Abrogation of the FXII-uPAR-pAkt2 Axis in Neutrophils for Treatment of Chronic Wounds
靶向消除中性粒细胞中的 FXII-uPAR-pAkt2 轴以治疗慢性伤口
- 批准号:
10542838 - 财政年份:2019
- 资助金额:
$ 39.08万 - 项目类别:
Treatment of Deep Vein Thrombosis via Targeted Inhibition of the FXII-uPAR-pAkt2 Axis in Neutrophils
通过靶向抑制中性粒细胞中的 FXII-uPAR-pAkt2 轴治疗深静脉血栓形成
- 批准号:
10044407 - 财政年份:2019
- 资助金额:
$ 39.08万 - 项目类别:
Treatment of Deep Vein Thrombosis via Targeted Inhibition of the FXII-uPAR-pAkt2 Axis in Neutrophils
通过靶向抑制中性粒细胞中的 FXII-uPAR-pAkt2 轴治疗深静脉血栓形成
- 批准号:
9771144 - 财政年份:2019
- 资助金额:
$ 39.08万 - 项目类别:
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