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:10297208
- 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 vivoinhibitor/antagonistinnovationinsightischemic 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)在改变细胞反应的心脏重塑过程中起着至关重要的作用。最近,一班
富含亮氨酸的小分子蛋白多糖(SLRPs)在缺血损伤中对心脏功能有巨大影响
或者心脏重塑。不利的心脏重塑刺激转化生长因子β增加所致的纤维化瘢痕沉积
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(Asporin),已经被
研究表明,在癌症和骨质疏松症中,它在调节转化生长因子β信号转导和细胞活性方面发挥作用。生物学的
ASPN对心脏转化生长因子β和细胞活力的调节作用尚不清楚。我们的长期目标是剖析
调节ASPN活性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
心力衰竭。这项资助的目的是确定ASPN在纤维化和心肌细胞中的作用。
生存能力。我们的中心假设是心脏应激时成纤维细胞释放天冬氨酸氨基转移酶并抑制转化生长因子β
在心脏重塑过程中减少纤维化的信号。此外,释放的ASPN作用于心肌细胞以
上调自噬,防止细胞死亡。我们的理论基础是确定刺激机制
ASPN在心脏重构中的保护作用将提供新的治疗机会。该项目将进一步
检测治疗性多肽和AAV9介导的ASPN基因转导的缓解效果
再灌注损伤与心脏重构。我们的具体目标将检验以下假设:(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;(目标2)ASPN诱导
心肌细胞自噬;(目标3)ASPN调节心肌细胞在缺血状态下的死亡。
再灌注损伤。在结论中,我们将更好地理解ASPN在抑制纤维化中的新作用
激活自噬,有利于心脏重塑。这一贡献意义重大,因为它将建立
ASPN靶向的几条从ECM到成纤维细胞和心肌细胞的通路。此外,目前
虽然治疗方法在限制缺血性损伤方面很有希望,但未能解决心脏不良重构这一关键问题。
在心力衰竭患者中。建议的研究是创新的,因为我们将调查ASPN在
调节纤维化和心肌细胞死亡,这是一个迄今未被研究的过程。对机制的洞察
ASPN活性的研究将为基于ASPN的治疗铺平道路,从而有利于心脏重塑。
项目成果
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