Microstructural Cues for the Treatment of Heart Failure

治疗心力衰竭的微观结构线索

• 批准号: 10078623
• 负责人: Tejal A. Desai
• 金额: $ 39.97万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078623
• 关键词: Acute; Acute myocardial infarction; Address; Adult; Affect; Alginates; American; Americas; Anatomy; Animal Model; Animals; Biochemical; Biocompatible Materials; Biological Response Modifier Therapy; Biopolymers; Cardiac; Cardiac Myocytes; Cardiac development; Cardiomyopathies; Cardiovascular system; Catheters; Cause of Death; Cell Communication; Cell Culture Techniques; Cells; Chronic; Cicatrix; Clinical; Clinical Research; Collagen; Complementary therapies; Coronary heart disease; Cues; Deposition; Development; Diagnosis; Dose; Down-Regulation; Drug Delivery Systems; EFRAC; Echocardiography; Elements; Engineering; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Formulation; Gel; Gene Expression; Genetic Transcription; Geometry; Goals; Health; Heart; Heart Diseases; Heart Injuries; Heart failure; Hypertrophy; Immunofluorescence Microscopy; In Situ; In Vitro; Individual; Infarction; Injectable; Injections; Measures; Mechanics; Medical; Medicine; Microfabrication; Mission; Modeling; Myocardial; Myocardial Infarction; Myocardium; National Heart, Lung, and Blood Institute; Natural regeneration; Pathogenicity; Pathway interactions; Patients; Peptides; Play; Polymers; Population; Pre-Clinical Model; Prognosis; Property; Rattus; Recovery; Regenerative capacity; Research; Rodent Model; Role; Shapes; Structure; Support System; System; Techniques; Testing; Therapeutic; Therapeutic Effect; Thick; Tissues; Vascular blood supply; Vascularization; Ventricular; angiogenesis; base; cardiac regeneration; cardiac repair; clinical application; design; disability; effective therapy; heart function; improved; improved outcome; in vivo; in vivo regeneration; injured; insight; ischemic cardiomyopathy; ischemic injury; mechanotransduction; mortality; myocardial injury; prevent; repaired; response; stem cell delivery; three dimensional cell culture; translational approach; vascular bed

Project Summary/Abstract Acute myocardial infarction (MI) is complicated by the subsequent development of scar tissue leading to chronic cardiac insufficiency. Unfortunately, the lack of treatments for this maladaptive fibrotic response often leads to a poor prognosis. Early attempts at stem cell delivery and biological therapeutics to address this problem have been promising, but inconsistent. To meet this challenge, the Desai lab, with collaborators, has developed a unique system of randomly dispersed polymeric microstructures, termed microrods, that have been found to decrease fibroblast proliferation and promote cardiomyocyte hypertrophy in vitro. The objective of this proposal is to study the mechanisms of interaction between microrods and cardiac fibroblasts in vitro and in an animal models of infarct. We will also examine the effect of microstructures on cardiac remodeling. This will enable the design of more effective therapies to prevent the development of cardiac scar tissue and encourage recovery of heart function after MI. Based on previous studies and recent research on the mechanical microenvironment, it is hypothesized that primary adult ventricular fibroblasts will respond to the presence of microrods with a unique set of transcriptional changes in pathways relevant to mechanotransduction, micro-environmental interaction, and extracellular matrix (ECM) deposition. In Aim 1, quantitative analyses of changes in gene expression and immunofluorescence microscopy will be used to examine cellular interactions with microrods in 3D culture. Specifically, quantification of ECM down-regulation and mechanotransductive interactions will elucidate the mechanisms of effect of microstructures on fibroblasts. In addition, HepIII conjugated microrods will be developed in order to augment vascularization, another key element of cardiac regeneration. Aim 2 will use quantitative biochemical and immunohistochemical techniques in an established rat model of MI to test the hypothesis that microrod injection into the infarct zone will produce similar transcriptional changes in markers of the fibrotic response as seen in vitro through interaction with the cardiac fibroblast population, as well as angiogenesis produced with the addition of HepIII to the microrods. Finally, Aim 3 will evaluate the therapeutic benefit of injected microrods in the setting of chronic ischemic cardiomyopathy as suggested by preliminary in vivo results. Therapeutic effect after microrod injection will be measured by serial echocardiograms to assess ejection fraction and cardiac anatomy in relation to the infarct scar and angiogenesis. By decreasing fibrotic scarring, inducing angiogenesis and promoting myocardial regeneration, injectable microrods will contribute to improving outcomes after MI. Understanding these mechanisms will lead to the design and optimization of complementary therapies and drug delivery possibilities, which will further the NHLBI's mission of treating heart disease to enhance the health of all individuals so that they can live longer and more fulfilling lives.

项目摘要/摘要 急性心肌梗塞（MI）随后发生疤痕组织的发展使 慢性心脏不足。不幸的是，这种不良适应性纤维化反应缺乏治疗方法 导致预后不佳。早期尝试干细胞输送和生物疗法解决这一问题 问题一直很有希望，但不一致。为了应对这一挑战，Desai实验室与合作者有 开发了一种独特的系统，该系统是随机分散的聚合微结构，称为微脚架，具有 发现在体外降低成纤维细胞增殖并促进心肌细胞肥大。目标 该建议是研究微棒与心脏成纤维细胞之间相互作用的机制 并在梗塞动物模型中。我们还将检查微结构对心脏重塑的影响。 这将使设计更有效的疗法的设计，以防止心脏疤痕组织的发展和 鼓励在MI后恢复心脏功能。基于以前的研究和最近的研究 机械微环境，假设原发性成人心室成纤维细胞会对 存在与与途径相关的唯一转录变化的微型模型的存在 机械转导，微环境相互作用和细胞外基质（ECM）沉积。在AIM 1中， 基因表达和免疫荧光显微镜变化的定量分析将用于 检查3D培养中与微棒的细胞相互作用。具体而言，ECM下调的定量 机械转移的相互作用将阐明微观结构对成纤维细胞的作用机理。 此外，将开发HEPIII共轭微码以增强血管化，这是另一个关键 心脏再生元素。 AIM 2将使用定量的生化和免疫组织化学技术 在已建立的MI大鼠模型中，以检验以下假设，即在 通过与与纤维化反应的标记的标记相似的转录变化，如通过与 心脏成纤维细胞种群以及在微脚架上添加HEPIII产生的血管生成。 最后，AIM 3将在慢性缺血的情况下评估注射微型棒的治疗益处 体内初步结果所建议的心肌病。微型注射后的治疗作用将是 通过连续超声心动图测量，以评估相对于梗死的射血分数和心脏解剖学 疤痕和血管生成。通过减少纤维化疤痕，诱导血管生成并促进心肌 再生，可注射的微脚架将有助于改善MI后的结局。了解这些 机制将导致互补疗法和药物输送的设计和优化 可能性，这将进一步促进NHLBI治疗心脏病的使命，以增强所有人的健康 个人，以便他们可以生活更长，更充实的生活。

项目成果

Lipid signaling affects primary fibroblast collective migration and anchorage in response to stiffness and microtopography.

• DOI: 10.1002/jcp.26236
• 发表时间: 2018-04
• 期刊: Journal of cellular physiology
• 影响因子: 5.6
• 作者: Mkrtschjan MA;Gaikwad SB;Kappenman KJ;Solís C;Dommaraju S;Le LV;Desai TA;Russell B
• 通讯作者: Russell B

Injectable hyaluronic acid based microrods provide local micromechanical and biochemical cues to attenuate cardiac fibrosis after myocardial infarction.

• DOI: 10.1016/j.biomaterials.2018.03.042
• 发表时间: 2018-07
• 期刊: Biomaterials
• 影响因子: 14
• 作者: Le LV;Mohindra P;Fang Q;Sievers RE;Mkrtschjan MA;Solis C;Safranek CW;Russell B;Lee RJ;Desai TA
• 通讯作者: Desai TA