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

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.


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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Michael Seth Kapiloff其他文献

Michael Seth Kapiloff的其他文献

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{{ 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:

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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
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Synemin is an A-Kinase Anchoring Protein in the Heart
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蛋白激酶 A 与激酶锚定蛋白相互作用的分析
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