Asporin, an extracellular protein, regulates cardiac remodeling
阿孢菌素是一种细胞外蛋白,调节心脏重塑
基本信息
- 批准号:10441587
- 负责人:
- 金额:$ 41.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAnabolismAngiotensin IIAutophagocytosisBindingBiologicalBiologyBlood flowCardiacCardiac MyocytesCell DeathCell SurvivalCellsCicatrixCore ProteinDegenerative polyarthritisDepositionEconomicsExhibitsExtracellular MatrixExtracellular Matrix ProteinsExtracellular ProteinFibrillar CollagenFibroblastsFibrosisFunctional disorderGenesGlycosaminoglycansGlycosphingolipidsGoalsGrantHealthHeartHeart BlockHeart InjuriesHeart failureHypertrophyHypoxiaIn VitroInfarctionInvestigationKnockout MiceLeucineLigandsLinkMalignant NeoplasmsMediatingMetabolicModificationMorbidity - disease rateMusMyocardial IschemiaOperative Surgical ProceduresOsteoporosisPathologicPathway interactionsPatientsPeptidesPlayProcessProteinsProteoglycanPublic HealthPyrimidineRecombinantsRegulationReperfusion InjuryResearchRoleSignal TransductionStressTestingTherapeutic InterventionTransforming Growth Factor betaTreatment Efficacyasporinbasebiglycancell behaviorcell typecoronary fibrosisdecorindesignheart functionimprovedin vivoinhibitorinnovationinsightischemic injurymacrophagemetabolic profilemetabolomemortalitymouse modelnovelnovel therapeutic interventionnovel therapeuticspeptide drugpleiotropismpressurepreventprotective effectpublic health relevancepurine metabolismreceptorresponsetherapeutic evaluationtherapeutic targettherapeutically effective
项目摘要
Project Summary
Extracellular matrix (ECM) is critical during cardiac remodeling in altering the cell’s response. Recently, class I
small leucine rich proteoglycans (SLRPs) showed enormous impact on the heart’s function during ischemic injury
or cardiac remodeling. Adverse cardiac remodeling stimulates fibrotic scar deposition due to increased TGFβ
activity on fibroblasts. In the last decade, a non-conventional class I SLRP protein, asporin (ASPN), has been
shown to play a role in regulating TGFβ signaling and cell viability in cancer and osteoporosis. The biological
impact of ASPN in regulating TGFβ and cell viability in heart is unknown. Our long-term goal is to dissect the
detailed mechanisms regulating ASPN activity and its impact on fibroblasts and cardiomyocytes, particularly in
the setting of cardiac remodeling. These discoveries will facilitate design of effective ASPN-based therapies for
heart failure. The objective of this grant is to characterize the role of ASPN in fibrosis and cardiomyocyte cell
viability. Our central hypothesis is that ASPN is released by fibroblasts during cardiac stress and inhibits TGFβ
signaling to reduce fibrosis during cardiac remodeling. Further, released ASPN acts on cardiomyocytes to
upregulate autophagy and prevent cell death. Our rationale is that identification of the mechanisms to stimulate
ASPN-protective effects in cardiac remodeling will offer new therapeutic opportunities. This project will further
test therapeutic peptide delivery as well as AAV9-mediated delivery of ASPN gene for efficacy in mitigating
reperfusion injury and cardiac remodeling. Our specific aims will test the following hypotheses: (Aim 1) ASPN
inhibits fibrosis to maintain cardiac function and prevents adverse cardiac remodeling; (Aim 2) ASPN induces
autophagy in cardiomyocytes; (Aim 3) ASPN regulates cardiomyocyte cell death in the setting of ischemia-
reperfusion injury. Upon conclusion, we will better understand the role of novel role of ASPN in inhibiting fibrosis
and activating autophagy for beneficial cardiac remodeling. This contribution is significant since it will establish
the several pathways targeted by ASPN from ECM to fibroblasts and cardiomyocytes. Furthermore, current
therapies, while promising in limiting ischemic injury, fail to address the key issue of adverse cardiac remodeling
in heart failure patients. The proposed research is innovative as we will investigate the effects of ASPN in
regulating fibrosis and cardiomyocyte cell death, an unexamined process to date. Insight into the mechanisms
of ASPN activity will pave the way for ASPN-based therapies to benefit cardiac remodeling.
项目摘要
细胞外基质(ECM)在心脏重塑过程中改变细胞的反应是至关重要的。最近,I班
富含亮氨酸的小分子蛋白多糖(SLRPs)在缺血性损伤时对心脏功能有巨大影响
或心脏重塑。不良心脏重塑刺激由于TGFβ增加的纤维化瘢痕沉积
对成纤维细胞的活性。在过去的十年中,一种非常规的I类SLRP蛋白asporin(ASPN)已经被发现。
显示在调节TGFβ信号传导和癌症和骨质疏松症中的细胞活力中起作用。生物
ASPN在调节心脏中TGFβ和细胞活力方面的影响尚不清楚。我们的长期目标是解剖
ASPN活性调节的详细机制及其对成纤维细胞和心肌细胞的影响,特别是在
心脏重塑的背景。这些发现将有助于设计有效的基于ASPN的治疗方法,
心衰这项研究的目的是研究ASPN在心肌纤维化和心肌细胞凋亡中的作用。
生存能力我们的中心假设是ASPN在心脏应激时由成纤维细胞释放并抑制TGFβ
在心脏重塑过程中减少纤维化的信号传导。此外,释放的ASPN作用于心肌细胞,
上调自噬并防止细胞死亡。我们的基本原理是,识别刺激的机制
ASPN在心脏重塑中的保护作用将提供新的治疗机会。该项目将进一步
测试治疗性肽递送以及AAV 9介导ASPN基因的递送在减轻
再灌注损伤和心脏重塑。我们的具体目标将测试以下假设:(目标1)ASPN
抑制纤维化以维持心脏功能并防止不利的心脏重构;(目的2)ASPN诱导
心肌细胞中的自噬;(目的3)ASPN调节缺血环境中的心肌细胞死亡-
再灌注损伤综上所述,我们将更好地了解ASPN在抑制纤维化中的新作用
以及激活自噬以实现有益的心脏重塑。这一贡献意义重大,因为它将建立
ASPN靶向的从ECM到成纤维细胞和心肌细胞的几个途径。此外,当前
虽然有希望限制缺血性损伤,但不能解决不利的心脏重塑的关键问题,
心力衰竭患者中。这项研究具有创新性,因为我们将研究ASPN在
调节纤维化和心肌细胞死亡,这是一个迄今尚未研究的过程。深入了解机制
ASPN活性的增加将为基于ASPN的治疗有益于心脏重塑铺平道路。
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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Sarah J Parker其他文献
Influenza vaccination coverage among an urban pediatric asthma Influenza vaccination coverage among an urban pediatric asthma population: Implications for population health population: Implications for population health
城市儿童哮喘人群的流感疫苗接种覆盖率 城市儿童哮喘人群的流感疫苗接种覆盖率:对人口健康的影响 人口:对人口健康的影响
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
Sarah J Parker;Amy M DeLaroche;Alex B. Hill;Rajan Arora;ID JulieGleason - 通讯作者:
ID JulieGleason
Clinical factors associated with the use of dexamethasone for asthma in the pediatric emergency department
儿科急诊室使用地塞米松治疗哮喘的相关临床因素
- DOI:
- 发表时间:
2020 - 期刊:
- 影响因子:1.9
- 作者:
Amy M DeLaroche;F. Mowbray;Sarah J Parker;Y. Ravichandran;A. Jones - 通讯作者:
A. Jones
Monitoring Diagnostic Safety Risks in Emergency Departments: Protocol for a Machine Learning Study
监测急诊科的诊断安全风险:机器学习研究协议
- DOI:
10.2196/preprints.24642 - 发表时间:
2020 - 期刊:
- 影响因子:1.7
- 作者:
Moein Enayati;M. Sir;Xingyu Zhang;Sarah J Parker;Elizabeth Duffy;Hardeep Singh;P. Mahajan;K. Pasupathy - 通讯作者:
K. Pasupathy
Sarah J Parker的其他文献
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{{ truncateString('Sarah J Parker', 18)}}的其他基金
Mechanisms of sex-biased risk and resiliency in aneurysm and dissection
动脉瘤和夹层的性别偏见风险和弹性机制
- 批准号:
10705715 - 财政年份:2022
- 资助金额:
$ 41.75万 - 项目类别:
Mechanisms of sex-biased risk and resiliency in aneurysm and dissection
动脉瘤和夹层的性别偏见风险和弹性机制
- 批准号:
10532033 - 财政年份:2022
- 资助金额:
$ 41.75万 - 项目类别:
Asporin, an extracellular protein, regulates cardiac remodeling
阿孢菌素是一种细胞外蛋白,调节心脏重塑
- 批准号:
10658863 - 财政年份:2021
- 资助金额:
$ 41.75万 - 项目类别:
Mapping the Angiotensin II-TGFB-Integrin signaling triad to reveal therapeutic targets in aortic aneurysm
绘制血管紧张素 II-TGFB-整合素信号三联体图谱以揭示主动脉瘤的治疗靶点
- 批准号:
9108213 - 财政年份:2016
- 资助金额:
$ 41.75万 - 项目类别:
Mapping the Angiotensin II-TGFB-Integrin signaling triad to reveal therapeutic targets in aortic aneurysm
绘制血管紧张素 II-TGFB-整合素信号三联体图谱以揭示主动脉瘤的治疗靶点
- 批准号:
9274098 - 财政年份:2016
- 资助金额:
$ 41.75万 - 项目类别:
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