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.

项目概要/摘要 急性心肌梗死 (MI) 因疤痕组织的后续发展而变得复杂，导致 慢性心功能不全。不幸的是，这种适应不良的纤维化反应通常缺乏治疗方法 导致预后不良。干细胞输送和生物疗法的早期尝试来解决这个问题 问题一直很有希望，但不一致。为了应对这一挑战，德赛实验室与合作者一起， 开发了一种独特的随机分散聚合物微结构系统，称为微棒， 在体外发现可减少成纤维细胞增殖并促进心肌细胞肥大。目标 该提案的目的是在体外研究微棒与心脏成纤维细胞之间的相互作用机制 以及梗塞动物模型。我们还将研究微观结构对心脏重塑的影响。 这将使设计更有效的疗法来预防心脏疤痕组织的发展和 促进 MI 后心脏功能的恢复。基于之前的研究和最近的研究 机械微环境中，假设初级成体心室成纤维细胞会对机械微环境做出反应 微棒的存在，在相关途径中具有一组独特的转录变化 力转导、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 检查 3D 培养中细胞与微棒的相互作用。具体来说，ECM 下调的量化 机械传导相互作用将阐明微结构对成纤维细胞的影响机制。 此外，将开发 HepIII 结合微棒以增强血管化，这是另一个关键 心脏再生的要素。目标 2 将使用定量生化和免疫组织化学技术 在已建立的心肌梗塞大鼠模型中测试微棒注射到梗塞区会产生的假设 通过与纤维化反应标记物的相互作用在体外观察到类似的转录变化 心脏成纤维细胞群，以及在微棒中添加 HepIII 时产生的血管生成。 最后，目标 3 将评估注射微棒在慢性缺血性疾病中的治疗效果 初步体内结果表明心肌病。微棒注射后的治疗效果 通过连续超声心动图进行测量，以评估与梗塞相关的射血分数和心脏解剖结构 疤痕和血管生成。通过减少纤维化疤痕、诱导血管生成和促进心肌 再生，可注射微棒将有助于改善心肌梗死后的结果。了解这些 机制将导致补充疗法和药物输送的设计和优化 的可能性，这将进一步推进 NHLBI 治疗心脏病以增强所有人健康的使命 个人，以便他们能够活得更长久、更充实的生活。

项目成果

Local delivery of decorin via hyaluronic acid microrods improves cardiac performance and ventricular remodeling after myocardial infarction.

通过透明质酸微棒局部递送核心蛋白聚糖可改善心肌梗塞后的心脏功能和心室重塑。

• 发表时间: 2023-02-08
• 作者: Desai, Tejal;Mohindra, Priya;Zhong, Justin;Fang, Qizhi;Huynh, Cindy;Cuylear, Darnell;Qiu, Huiliang;Gao, Dongwei;Kharbikar, Bhushan;Huang, Xiao;Springer, Matt;Lee, Randall
• 通讯作者: Lee, Randall

Networks of High Aspect Ratio Particles to Direct Colloidal Assembly Dynamics and Cellular Interactions.

高纵横比粒子网络指导胶体组装动力学和细胞相互作用。

• 发表时间: 2020-11-25
• 影响因子: 19
• 作者: Finbloom, Joel A;Demaree, Benjamin;Abate, Adam R;Desai, Tejal A
• 通讯作者: Desai, Tejal A

Transthyretin amyloid fibrils alter primary fibroblast structure, function, and inflammatory gene expression.

运甲状腺素蛋白淀粉样原纤维改变初级成纤维细胞结构、功能和炎症基因表达。

• 发表时间: 2021
• 作者: Dittloff, Kyle T;Iezzi, Antonio;Zhong, Justin X;Mohindra, Priya;Desai, Tejal A;Russell, Brenda
• 通讯作者: Russell, Brenda

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

脂质信号传导影响原代成纤维细胞对硬度和微形貌的集体迁移和锚定。

• 发表时间: 2018
• 影响因子: 5.6
• 作者: Mkrtschjan, Michael A;Gaikwad, Snehal B;Kappenman, Kevin J;Solís, Christopher;Dommaraju, Sagar;Le, Long V;Desai, Tejal A;Russell, Brenda
• 通讯作者: Russell, Brenda

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

基于可注射透明质酸的微棒提供局部微机械和生化线索，以减轻心肌梗塞后的心脏纤维化。

• 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