Cellular and Circulating Fortilin in Vascular Diseases
细胞和循环 Fortilin 在血管疾病中的应用
基本信息
- 批准号:10669123
- 负责人:
- 金额:$ 68.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-01-15 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAmericanAmino AcidsAnti-Inflammatory AgentsAortaApoptosisApplications GrantsArteriesAtherosclerosisBindingBiological AssayBiological ProcessBloodBlood capillariesCardiovascular systemCause of DeathCell secretionCellsCirculationCoronary ArteriosclerosisCoronary arteryCytosolDataDevelopmentExtracellular SpaceGenesGeneticGoalsHealthHigh Fat DietHormonesImmunoglobulin GInflammatoryKnock-outLow-Density LipoproteinsLuciferasesMacrophageMicrocirculationMolecular WeightMonoclonal AntibodiesMorbidity - disease rateMouse StrainsMusNuclearOrganOxidation-ReductionPathway interactionsPatientsPhenotypePhosphorylationProcessProteinsRNAReactive Oxygen SpeciesReceptor ActivationRegulationRoleSignal TransductionSignaling MoleculeTPT1 geneTestingTissuesTransforming Growth Factor betaVascular DiseasesVisionapoB mRNA editing catalytic subunitcostcytokineendoplasmic reticulum stressextracellularhypercholesterolemiainhibitorinnovationmortalitymutantnovel therapeutic interventionoxygen transportpharmacologicpreventtranscriptome sequencing
项目摘要
Project Summary
The main goal of this grant proposal titled “Cellular and Circulating Fortilin in Vascular Diseases” is to
test the central hypothesis that both cellular and circulating fortilin inhibit the TGFβ1 pathway and
promote atherosclerosis by binding and inhibiting the key intracellular and extracellular components of
the pathway. The innovative hypothesis is well supported by abundant and exciting preliminary data.
Atherosclerosis is the thickening of the wall of arteries that limits transport of oxygen-containing blood to vital
organs and affects every level of the vasculature from the aorta and coronary arteries to capillaries and
microcirculation. It remains one of the most serious health problems in the U.S. today and costs nearly $286
billion every year. Lowering of the low-density lipoprotein (LDL) levels alone does not eliminate atherosclerosis,
as the Cochrane Organization showed that a drastic reduction of LDL by PCSK9 inhibitors only modestly
decreased cardiovascular morbidity/mortality. Thus, new molecules, the targeting of which would lead to halting
of the progression of atherosclerotic vasculopathy, must be identified. Fortilin is a 172-amino acid multi-
functional protein that is not only abundantly expressed in atherosclerotic tissue but is also present in
circulation (like cytokines and hormones) at higher levels in the presence of atherosclerosis. Fortilin is
implicated in various biological functions but most notably in regulation of reactive oxygen species (ROS,
redox), ER stress, and apoptosis. We found that when circulating fortilin was neutralized, hypercholesterolemic
(HC) mice developed less atherosclerosis. In addition, we found that the deletion of fortilin in macrophages
(MФ) led to less atherosclerosis in HC mice. To explore the mechanism by which fortilin facilitates
atherosclerosis, we performed a systematic, unbiased NGS RNA-Seq assay and found that the lack of MФ
fortilin robustly activated the anti-atherosclerotic TGFβ1 pathway. Further studies showed that fortilin binds and
inhibits the key molecules of the pathway—extracellular TGFβ1 and intracellular Smad3—and kept MФ in the
pro-inflammatory, pro-atherosclerotic phenotype. In the current project, we will first test the hypothesis that
circulating fortilin facilitates atherosclerosis by binding and inhibiting TGFβ1 and by polarizing MФ to the anti-
inflammatory phenotype (Aim 1). We will then test the hypothesis that cellular fortilin in MФ facilitates
atherosclerosis by binding and inhibiting Smad3 and by polarizing MФ to the anti-inflammatory phenotype (Aim
2). With all Aims successfully completed, the project will lead to two distinct and highly innovative strategies to
halt atherosclerosis: (i) using α-fortilin mAb to disrupt the interaction between circulating fortilin and TGFβ1 in
the extracellular space to free up anti-atherosclerotic TGFβ1 from its inhibitor fortilin and (ii) generating and
using small molecular weight (SMW) compounds that disrupt the fortilin-Smad3 interaction to allow Smad3 to
be activated.
项目摘要
这项题为“血管疾病中的细胞和循环Fortilin”的拨款提案的主要目标是
检验细胞和循环fortilin抑制TGFβ1通路的中心假设,
促进动脉粥样硬化的结合和抑制关键的细胞内和细胞外成分,
道路。这一创新性的假设得到了丰富而令人兴奋的初步数据的充分支持。
动脉粥样硬化是指动脉壁增厚,限制含氧血液向重要血管的输送。
器官,并影响从主动脉和冠状动脉到毛细血管的每一个层次的脉管系统,
微循环它仍然是当今美国最严重的健康问题之一,花费近286美元
每年十亿。单独降低低密度脂蛋白(LDL)水平不能消除动脉粥样硬化,
因为科克伦组织表明,PCSK 9抑制剂对LDL的急剧降低仅是适度的
降低心血管发病率/死亡率。因此,新的分子,其目标将导致停止
动脉粥样硬化性血管病变的进展,必须加以确定。Fortilin是一种172个氨基酸的多
一种功能性蛋白质,不仅在动脉粥样硬化组织中大量表达,
在动脉粥样硬化的存在下,血液循环(如细胞因子和激素)处于较高水平。福尔替林群岛
涉及多种生物学功能但最显著的是调节活性氧(ROS,
氧化还原)、ER应激和细胞凋亡。我们发现,当循环中的福替林被中和时,
(HC)小鼠的动脉粥样硬化较少。此外,我们发现巨噬细胞中fortilin的缺失
(M)导致HC小鼠中较少的动脉粥样硬化。探讨Fortilin促进大鼠心肌细胞凋亡的机制
在动脉粥样硬化中,我们进行了一项系统的,无偏倚的NGS RNA-Seq测定,发现缺乏M
Fortilin强烈激活抗动脉粥样硬化TGFβ1通路。进一步的研究表明,福替林结合,
抑制该途径的关键分子-细胞外TGFβ1和细胞内Smad 3-并使MФ保持在
促炎、促动脉粥样硬化表型。在当前的项目中,我们将首先测试假设,
循环中的福替林通过结合和抑制TGFβ1以及将MФ极化为抗-β 1来促进动脉粥样硬化。
炎症表型(Aim 1)。然后,我们将测试的假设,细胞fortilin在M β促进
通过结合和抑制Smad 3以及通过使M β极化为抗炎表型来治疗动脉粥样硬化(Aim
2)。随着所有目标的成功完成,该项目将导致两个不同的和高度创新的战略,
停止动脉粥样硬化:(i)使用α-fortilin mAb破坏循环中fortilin和TGFβ1之间的相互作用,
细胞外空间以从其抑制剂fortilin释放抗动脉粥样硬化TGFβ1,和(ii)产生和
使用小分子量(SMW)化合物破坏福替林-Smad 3相互作用,
被激活。
项目成果
期刊论文数量(13)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
ADAR1 exacerbates ischemic brain injury via astrocyte-mediated neuron apoptosis.
- DOI:10.1016/j.redox.2023.102903
- 发表时间:2023-11
- 期刊:
- 影响因子:11.4
- 作者:Cai, Dunpeng;Fraunfelder, Mikayla;Fujise, Ken;Chen, Shi-You
- 通讯作者:Chen, Shi-You
Fortilin potentiates the peroxidase activity of Peroxiredoxin-1 and protects against alcohol-induced liver damage in mice.
- DOI:10.1038/srep18701
- 发表时间:2016-01-04
- 期刊:
- 影响因子:4.6
- 作者:Chattopadhyay A;Pinkaew D;Doan HQ;Jacob RB;Verma SK;Friedman H;Peterson AC;Kuyumcu-Martinez MN;McDougal OM;Fujise K
- 通讯作者:Fujise K
Fortilin interacts with TGF-β1 and prevents TGF-β receptor activation.
- DOI:10.1038/s42003-022-03112-6
- 发表时间:2022-02-23
- 期刊:
- 影响因子:5.9
- 作者:Pinkaew D;Martinez-Hackert E;Jia W;King MD;Miao F;Enger NR;Silakit R;Ramana K;Chen SY;Fujise K
- 通讯作者:Fujise K
Elevation of serum fortilin levels is specific for apoptosis and signifies cell death in vivo.
- DOI:10.1016/j.bbacli.2014.10.002
- 发表时间:2014-12-01
- 期刊:
- 影响因子:0
- 作者:Sinthujaroen, Patuma;Wanachottrakul, Nattaporn;Pinkaew, Decha;Petersen, John R;Phongdara, Amornrat;Sheffield-Moore, Melinda;Fujise, Ken
- 通讯作者:Fujise, Ken
Fortilin: A Potential Target for the Prevention and Treatment of Human Diseases.
- DOI:10.1016/bs.acc.2017.06.006
- 发表时间:2017
- 期刊:
- 影响因子:0
- 作者:Pinkaew D;Fujise K
- 通讯作者:Fujise K
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Shiyou Chen其他文献
Shiyou Chen的其他文献
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{{ truncateString('Shiyou Chen', 18)}}的其他基金
Novel Mechanisms Underlying the Development of Atherosclerosis
动脉粥样硬化发展的新机制
- 批准号:
10589484 - 财政年份:2023
- 资助金额:
$ 68.19万 - 项目类别:
Dedicator of cytokinesis 2 in abdominal aortic aneurysm
腹主动脉瘤胞质分裂2的奉献者
- 批准号:
10417112 - 财政年份:2019
- 资助金额:
$ 68.19万 - 项目类别:
Dedicator of cytokinesis 2 in abdominal aortic aneurysm
腹主动脉瘤胞质分裂2的奉献者
- 批准号:
10063651 - 财政年份:2019
- 资助金额:
$ 68.19万 - 项目类别:
Dedicator of cytokinesis 2 in abdominal aortic aneurysm
腹主动脉瘤胞质分裂2的奉献者
- 批准号:
10199018 - 财政年份:2019
- 资助金额:
$ 68.19万 - 项目类别:
Smad2 in vascular smooth muscle homeostasis
Smad2 在血管平滑肌稳态中的作用
- 批准号:
10062643 - 财政年份:2016
- 资助金额:
$ 68.19万 - 项目类别:
Novel mechanism of smooth muscle phenotypic modulation and vascular remodeling
平滑肌表型调节和血管重塑的新机制
- 批准号:
8794466 - 财政年份:2014
- 资助金额:
$ 68.19万 - 项目类别:
Novel mechanism of smooth muscle phenotypic modulation and vascular remodeling
平滑肌表型调节和血管重塑的新机制
- 批准号:
8653749 - 财政年份:2014
- 资助金额:
$ 68.19万 - 项目类别:
Dedicator of Cytokinesis 2 in smooth muscle phenotype modulation
细胞分裂 2 在平滑肌表型调节中的奉献者
- 批准号:
8998055 - 财政年份:2014
- 资助金额:
$ 68.19万 - 项目类别:
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