RSK3 Anchoring Disruptor Therapy for Heart Failure
RSK3 锚定破坏器治疗心力衰竭
基本信息
- 批准号:8977557
- 负责人:
- 金额:$ 29.9万
- 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:2015-08-01 至 2016-07-31
- 项目状态:已结题
- 来源:
- 关键词:3-Phosphoinositide Dependent Protein Kinase-1A kinase anchoring proteinAffinityAmericanAnimal ModelAnimalsAortic Valve StenosisApoptosisAttenuatedBindingBiological ProductsCardiacCardiac MyocytesCardiovascular DiseasesCause of DeathCell NucleusCessation of lifeCicatrixClinicalCoronary ArteriosclerosisCoronary arteryCytosolDataDependovirusDevelopmentDiagnosisDiseaseEnzymesEtiologyFamilyFibrosisFunctional disorderFutureGene ExpressionGene Transduction AgentGenetic ModelsGoalsGrantGrowthHeartHeart failureHypertensionHypertrophyIn VitroInfarctionInfusion proceduresInvestigational New Drug ApplicationKnock-outLeftLigationMEKKsMEKsModelingMusMuscleMuscle CellsMyocardialMyocardial InfarctionN-terminalNuclearPathologyPathway interactionsPatientsPeptidesPhasePhosphatidylinositolsPhosphorylationPhosphotransferasesPlayPreventionProtein IsoformsProtein KinaseQuality of lifeRPS6KA geneRegulationResearchRibosomal Protein S6 KinaseRoleScaffolding ProteinSignal PathwaySignal TransductionSmall Business Technology Transfer ResearchSpecificityStressSyndromeTertiary Protein StructureTestingTherapeuticbasecommercializationcommon treatmentconstrictionimprovedin vivoinhibitor/antagonistinsightinterstitialmembermortalitynovelnovel therapeutic interventionnovel therapeuticspatient populationpressurepreventprotein protein interactionpublic health relevanceresponsescaffoldselective expression
项目摘要
DESCRIPTION (provided by applicant): Pathological cardiac remodeling, including myocyte hypertrophy and apoptosis and myocardial interstitial fibrosis, constitutes a common pathway to heart failure in disease. Despite current pharmacologic therapy and other advances that attenuate remodeling, mortality due to heart failure remains high. New, more effective therapeutic options are desperately needed in an increasing patient population to improve both the survival and quality of life for patients with or susceptible to heart failure. We recently discovered that the protein kinase p90 ribosomal S6 kinase type 3 (RSK3) plays a critical role in the regulation of pathological cardiac remodeling. In 2013, Anchored RSK3 Inhibitors, LLC, was founded by Dr. Michael Kapiloff to develop novel therapeutics based upon RSK3 inhibition that will prevent and/or treat heart failure. RSK3 was required for pathological remodeling even though RSK3 is less abundant in the cardiac myocyte than other members of the RSK protein kinase family. We found that in myocytes RSK3's unique N- terminal domain conferred high affinity, regulated binding to the scaffold protein muscle A-kinase anchoring protein (mAKAPß). This novel protein-protein interaction explained the selective binding of that kinase isoform to the scaffold. New preliminary data show that expression both in vitro and in vivo of an anchoring disruptor peptide that blocks mAKAPß-RSK3 binding will attenuate pathological remodeling, preventing the development of heart failure in response to pressure overload. The goal of this STTR application is to support the development of a new adeno-associated virus (AAV) gene therapy vector that expresses the RSK3 anchoring disruptor peptide. The proposed research will provide proof-of-concept for a new therapeutic approach for the treatment and/or prevention of heart failure based upon RSK3 displacement within the myocyte. SPECIFIC AIM 1: Treatment of Pressure Overload-induced Heart Failure by Anchoring Disruptor Therapy. Cardiac myocyte-selective expression of a mAKAPß RSK3-binding peptide (RBD) using AAV prevents transverse aortic constriction-induced heart failure in vivo. In this Aim we will test whether RSK3 anchoring disruptor therapy can induce reverse remodeling and treat heart failure in mice with established pathology due to pressure overload. SPECIFIC AIM 2: Prevention of Myocardial Infarction-induced Heart Failure by Anchoring Disruptor Therapy. In this Aim, we will test whether AAV-RBD can block remodeling following myocardial infarction without having deleterious effects on infarct size or scar formation. Results obtained through this
phase I STTR grant will provide insight into how broadly AAV-RBD therapy may be applied in cardiovascular disease and inform the choice of subsequent large animal studies necessary to progress to a FDA Investigational New Drug Application.
描述(由申请人提供):病理性心脏重塑,包括心肌细胞肥大和凋亡以及心肌间质纤维化,构成疾病中心力衰竭的常见途径。尽管目前的药物治疗和其他进展减轻了重构,但心力衰竭引起的死亡率仍然很高。越来越多的患者群体迫切需要新的、更有效的治疗方案,以提高患有心力衰竭或易患心力衰竭的患者的生存率和生活质量。我们最近发现蛋白激酶 p90 核糖体 S6 激酶 3 型 (RSK3) 在病理性心脏重塑的调节中发挥着关键作用。 2013 年,Michael Kapiloff 博士创立了 Anchored RSK3 Inhibitors, LLC,旨在开发基于 RSK3 抑制的新型疗法,以预防和/或治疗心力衰竭。尽管 RSK3 在心肌细胞中的含量低于 RSK 蛋白激酶家族的其他成员,但 RSK3 是病理重塑所必需的。我们发现,在肌细胞中,RSK3 独特的 N 末端结构域赋予了与支架蛋白肌 A 激酶锚定蛋白 (mAKAPß) 的高亲和力、受调节的结合。这种新颖的蛋白质-蛋白质相互作用解释了该激酶亚型与支架的选择性结合。新的初步数据表明,阻断 mAKAPß-RSK3 结合的锚定干扰肽在体外和体内的表达将减弱病理重塑,防止因压力超负荷而发生心力衰竭。该 STTR 应用的目标是支持开发表达 RSK3 锚定破坏肽的新型腺相关病毒 (AAV) 基因治疗载体。拟议的研究将为基于 RSK3 在肌细胞内移位的治疗和/或预防心力衰竭的新治疗方法提供概念验证。具体目标 1:通过锚定破坏器疗法治疗压力过载引起的心力衰竭。使用 AAV 心肌细胞选择性表达 mAKAPß RSK3 结合肽 (RBD) 可预防体内横向主动脉缩窄诱发的心力衰竭。在此目标中,我们将测试 RSK3 锚定破坏剂疗法是否可以诱导逆转重塑并治疗因压力超负荷而患有既定病理的小鼠的心力衰竭。具体目标 2:通过锚定破坏疗法预防心肌梗塞诱发的心力衰竭。在这个目标中,我们将测试 AAV-RBD 是否可以阻止心肌梗塞后的重塑,而不会对梗塞面积或疤痕形成产生有害影响。通过此得到的结果
第一阶段 STTR 资助将深入了解 AAV-RBD 疗法在心血管疾病中的应用范围,并为后续大动物研究的选择提供信息,以推进 FDA 新药研究申请。
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 }}
Michael Seth Kapiloff其他文献
Michael Seth Kapiloff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('Michael Seth Kapiloff', 18)}}的其他基金
Calcineurin compartmentation and regulation of pathological cardiac remodeling
钙调神经磷酸酶的划分和病理性心脏重塑的调节
- 批准号:
10231978 - 财政年份:2021
- 资助金额:
$ 29.9万 - 项目类别:
Calcineurin compartmentation and regulation of pathological cardiac remodeling
钙调神经磷酸酶的划分和病理性心脏重塑的调节
- 批准号:
10361509 - 财政年份:2021
- 资助金额:
$ 29.9万 - 项目类别:
Calcineurin compartmentation and regulation of pathological cardiac remodeling
钙调神经磷酸酶的划分和病理性心脏重塑的调节
- 批准号:
10594426 - 财政年份:2021
- 资助金额:
$ 29.9万 - 项目类别:
VRC: The Role of Perinuclear cAMP in Retinal Ganglion Cell Neuroprotection and Optic Nerve Regeneration
VRC:核周 cAMP 在视网膜神经节细胞神经保护和视神经再生中的作用
- 批准号:
9913728 - 财政年份:2019
- 资助金额:
$ 29.9万 - 项目类别:
VRC: The Role of Perinuclear cAMP in Retinal Ganglion Cell Neuroprotection and Optic Nerve Regeneration
VRC:核周 cAMP 在视网膜神经节细胞神经保护和视神经再生中的作用
- 批准号:
10085140 - 财政年份:2019
- 资助金额:
$ 29.9万 - 项目类别:
VRC: The Role of Perinuclear cAMP in Retinal Ganglion Cell Neuroprotection and Optic Nerve Regeneration
VRC:核周 cAMP 在视网膜神经节细胞神经保护和视神经再生中的作用
- 批准号:
10220042 - 财政年份:2019
- 资助金额:
$ 29.9万 - 项目类别:
Role of the F-Bar Protein CIP4 in Cardiac Hypertrophy
F-Bar 蛋白 CIP4 在心脏肥大中的作用
- 批准号:
9024232 - 财政年份:2016
- 资助金额:
$ 29.9万 - 项目类别:
Role of the mAKAP Complex in Cardiac Hypertrophy
mAKAP 复合物在心脏肥大中的作用
- 批准号:
8299972 - 财政年份:2003
- 资助金额:
$ 29.9万 - 项目类别:
Role of the mAKAP Complex in Cardiac Hypertrophy
mAKAP 复合物在心脏肥大中的作用
- 批准号:
6832758 - 财政年份:2003
- 资助金额:
$ 29.9万 - 项目类别:
Role of the mAKAP Complex in Cardiac Hypertrophy
mAKAP 复合物在心脏肥大中的作用
- 批准号:
8472387 - 财政年份:2003
- 资助金额:
$ 29.9万 - 项目类别:
相似海外基金
A-Kinase Anchoring Protein Dysregulation during Alcohol-Associated Liver Disease
酒精相关性肝病期间 A 激酶锚定蛋白失调
- 批准号:
10416315 - 财政年份:2022
- 资助金额:
$ 29.9万 - 项目类别:
A-Kinase Anchoring Protein Dysregulation during Alcohol-Associated Liver Disease
酒精相关性肝病期间 A 激酶锚定蛋白失调
- 批准号:
10705602 - 财政年份:2022
- 资助金额:
$ 29.9万 - 项目类别:
Clustering of individual and diverse ion channels together into complexes, and their functional coupling, mediated by A-kinase anchoring protein 79/150 in neurons
单个和不同的离子通道聚集成复合物,以及它们的功能耦合,由神经元中的 A-激酶锚定蛋白 79/150 介导
- 批准号:
9212929 - 财政年份:2015
- 资助金额:
$ 29.9万 - 项目类别:
Duplin: A Novel A-Kinase Anchoring Protein
Duplin:一种新型 A 激酶锚定蛋白
- 批准号:
7484816 - 财政年份:2008
- 资助金额:
$ 29.9万 - 项目类别:
Duplin: A Novel A-Kinase Anchoring Protein
Duplin:一种新型 A 激酶锚定蛋白
- 批准号:
7676742 - 财政年份:2008
- 资助金额:
$ 29.9万 - 项目类别:
Synemin is an A-Kinase Anchoring Protein in the Heart
Synemin 是心脏中的一种 A 激酶锚定蛋白
- 批准号:
7169231 - 财政年份:2004
- 资助金额:
$ 29.9万 - 项目类别:
Synemin is an A-Kinase Anchoring Protein in the Heart
Synemin 是心脏中的一种 A 激酶锚定蛋白
- 批准号:
6857635 - 财政年份:2004
- 资助金额:
$ 29.9万 - 项目类别:
Synemin is an A-Kinase Anchoring Protein in the Heart
Synemin 是心脏中的一种 A 激酶锚定蛋白
- 批准号:
6994379 - 财政年份:2004
- 资助金额:
$ 29.9万 - 项目类别:
Synemin is an A-Kinase Anchoring Protein in the Heart
Synemin 是心脏中的一种 A 激酶锚定蛋白
- 批准号:
7326774 - 财政年份:2004
- 资助金额:
$ 29.9万 - 项目类别:
ANALYSIS OF PROTEIN KINASE A A KINASE ANCHORING PROTEIN INTERACTIONS
蛋白激酶 A 与激酶锚定蛋白相互作用的分析
- 批准号:
6470644 - 财政年份:2001
- 资助金额:
$ 29.9万 - 项目类别: