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.

项目总结/摘要 急性心肌梗死（MI）并发于随后的瘢痕组织发展， 慢性心功能不全不幸的是，缺乏这种适应不良的纤维化反应的治疗往往 导致预后不良。干细胞输送和生物疗法的早期尝试解决了这一问题 问题是有希望的，但不一致。为了应对这一挑战，德赛实验室与合作者， 开发了一种独特的随机分散的聚合物微结构系统，称为微棒， 已发现在体外降低成纤维细胞增殖并促进心肌细胞肥大。客观 本研究的目的是在体外研究微棒与心脏成纤维细胞的相互作用机制 以及在梗塞的动物模型中。我们还将研究微结构对心脏重塑的影响。 这将使设计更有效的治疗方法，以防止心脏瘢痕组织的发展， 促进MI后心脏功能的恢复。根据以往的研究和最近的研究， 机械微环境，假设原代成人心室成纤维细胞将响应于机械微环境。 微棒的存在与一组独特的转录变化相关的途径， 机械转导、微环境相互作用和细胞外基质（ECM）沉积。在目标1中， 基因表达变化的定量分析和免疫荧光显微镜将用于 在3D培养中检查细胞与微棒的相互作用。具体地，ECM下调的定量 和机械力传递的相互作用将阐明微结构对成纤维细胞的作用机制。 此外，将开发HepIII结合的微棒，以增强血管化，这是另一个关键。 心脏再生的元素。目标2将使用定量生化和免疫组织化学技术 在已建立的MI大鼠模型中，以检验向梗塞区注射微棒将产生 在体外通过与纤维化反应的标记物的相互作用观察到类似的转录变化， 心脏成纤维细胞群，以及加入HepIII的微棒产生的血管生成。 最后，目标3将评价注射微棒在慢性缺血性心脏病（CHD）中的治疗获益。 初步体内结果提示心肌病。微棒注射后的治疗效果 通过连续超声心动图测量，以评估与梗死相关的射血分数和心脏解剖结构 瘢痕和血管生成。通过减少纤维化瘢痕形成，诱导血管生成和促进心肌 再生，可注射微棒将有助于改善MI后的结果。了解这些 机制将导致补充疗法和药物输送的设计和优化 这将进一步推进NHLBI治疗心脏病的使命，以提高所有人的健康 使他们能够活得更长、更充实。

项目成果

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

脂质信号传导会影响刚度和显微照片的一级成纤维细胞集体迁移和锚定。

• 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