Targeted inhibition of fibrosis for the prevention of heart failure

靶向抑制纤维化以预防心力衰竭

• 批准号: 9449362
• 负责人: JASON R. McCARTHY
• 金额: $ 79.7万
• 依托单位: MASONIC MEDICAL RESEARCH LABORATORY, INC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9449362
• 关键词: Actins; Affinity; Agonist; Binding; Blood Circulation; Calcium; Cardiac; Cardiac Myocytes; Cell Survival; Cells; Cellular Morphology; Chronic; Collagen; Cytoskeleton; Data; Deposition; Development; Disease; Dose; Echocardiography; Encapsulated; Endothelial Cells; Fibroblasts; Fibrosis; Fluorescent Probes; GTP-Binding Proteins; Gene Activation; Genes; Heart; Heart Hypertrophy; Heart Injuries; Heart failure; Hydrophobicity; Immunosuppressive Agents; In Vitro; Infarction; Injury; Investigation; Ligands; MAPK3 gene; MG132; Mediating; Molecular; Molecular Analysis; Monomeric GTP-Binding Proteins; Mus; Myocardial; Myocardial Infarction; Myocardium; Nodal; Pathologic; Pathology; Pathway interactions; Peptides; Phagocytes; Pharmaceutical Preparations; Polymers; Preparation; Prevention; Property; Protein Analysis; Protein Biosynthesis; Proto-Oncogene Proteins c-akt; Regulation; Role; Serum Response Factor; Signal Pathway; Signal Transduction; Site; Steroids; Stimulus; Stress; Technology; Therapeutic; Therapeutic Effect; Time; Tissues; Toxic effect; Transcriptional Activation; Treatment Efficacy; Up-Regulation; Ventricular Remodeling; analog; base; cardioprotection; cell type; cohort; constriction; coronary fibrosis; design; drug release profile; efficacy testing; fetal; in vivo; inhibitor/antagonist; interest; macrophage; monocyte; mouse model; multicatalytic endopeptidase complex; myocardin; nanomaterials; nanoparticle; nanoparticulate; novel; particle; preservation; prevent; public health relevance; response; rho; rhoA GTP-Binding Protein; systemic toxicity; targeted delivery; transcription factor; uptake; zeta potential

 DESCRIPTION (provided by applicant): Cardiomyocytes undergo remodeling in response to pathological stimuli, causing altered cell morphology, increased protein synthesis and upregulation of fetal genes. While initially compensatory, ultimately, these changes prove maladaptive, inducing fibrosis and adverse ventricular remodeling. In response to cardiac stress and/or injury, activation of the Ras-related small G protein RhoA was previously shown to mediate deleterious in vivo pathological responses. However, more recently, RhoA has also been shown to promote cell survival and be cardio-protective after myocardial infarct (MI) injury. To determine the molecular mechanisms that underlie these opposing roles for RhoA in the myocardium, we generated mice with a cardiomyocyte-specific deletion of RhoA (RhoAfl/fl-aMHC-Cre). In response to chronic injury (transverse aortic constriction, TAC), we found that hearts from RhoAfl/fl-aMHC-Cre mice developed an accelerated dilation, with significant loss of contractile function. Despite this, and in parallel, hearts from these mice also showed significantly decreased cardiac fibrosis, with a demonstrated decrease in transcriptional activation of genes involved in the fibrotic response, including the serum response factor (SRF) and the myocardin related transcription factor (MRTF). Taken together, our data suggest that RhoA serves as a critical bi-nodal point in response to cardiac injury, whereby a component of the downstream signaling is required to preserve contractility, while the other mediates activation of maladaptive responses due to activation of profibrotic genes. Therefore, we hypothesize that targeted inhibition of downstream RhoA-mediated pro-fibrotic genes (SRF and MRTF) will not only prevent onset of fibrosis and subsequent maladaptive responses associated with MI injury, but will also allow for the preservation of the upstream cardio-protective effects n contractility exerted by RhoA parallel signaling pathways. Nanomaterials have found wide applicability in the treatment of disease, as they possess the ability to modulate the properties o drugs, including circulation times and localization to tissues of interest. Importantly, the incorporation of therapeutic moieties within targeted nanoparticles allows for their site-specific delivery, minimizing the dose required to bring about a therapeutic effect, while concomitantly decreasing systemic repercussions. Using this technology, we will investigate novel targeting ligands for the cell specific delivery of inhibitors of cardiac fibrosis following myocardial injur. Using in-vivo, ex-vivo and in-vitro analyses, we will 1) generate and fully characterize targeted nanoagents incorporating inhibitors chosen to prevent the deposition of collagen after MI; 2) examine the in vitro and in vivo binding and inhibitory efficacy of the synthesized nanoagents; and 3) longitudinally assess the therapeutic efficacy of the targeted delivery of inhibitors in murine models of MI. Importantly, we expect that the efficacy of this technology to extend beyond MI, and be applicable to more chronic conditions, such as fibrosis caused by cardiac hypertrophy and/or valvular disease.



项目成果

Microwave-assisted chemical ligation of S-acyl peptides containing non-terminal cysteine residues.

含有非末端半胱氨酸残基的 S-酰基肽的微波辅助化学连接。

• DOI: 10.1039/c1ob05740e
• 发表时间: 2011
• 期刊: Organic & biomolecular chemistry
• 影响因子: 3.2
• 作者: Hansen,FinnK;Ha,Khanh;Todadze,Ekaterina;Lillicotch,Aaron;Frey,Alexander;Katritzky,AlanR
• 通讯作者: Katritzky,AlanR

A benzotriazole-mediated route to protected marine-derived hetero-2,5-diketopiperazines containing proline.

苯并三唑介导的含有脯氨酸的受保护海洋来源的杂-2,5-二酮哌嗪的路线。

• DOI: 10.1039/c5ob00023h
• 发表时间: 2015
• 期刊: Organic & biomolecular chemistry
• 影响因子: 3.2
• 作者: Nsengiyumva,Olivier;Hamedzadeh,Sadra;McDaniel,James;Macho,Jocelyn;Simpson,Grant;Panda,SivaS;Ha,Khanh;Lebedyeva,Iryna;Faidallah,HassanM;Al-Mohammadi,ManalMetgen;Hall,CDennis;Katritzky,AlanR
• 通讯作者: Katritzky,AlanR