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首页> 外文学位 >Cell-taught gene therapy for the preservation and regeneration of cardiac tissue following chronic heart failure.
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Cell-taught gene therapy for the preservation and regeneration of cardiac tissue following chronic heart failure.

机译：用于慢性心力衰竭后心脏组织的保存和再生的细胞传授基因疗法。

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摘要

Heart failure is the primary cause of mortality and morbidity in the Western world. Although cell therapy has demonstrated improvement in cardiac function, these benefits are being attributed to the activation of paracrine factors, rather than the differentiation and integration of the transplanted cells into the host tissue. Based on this knowledge the focus of this thesis work was to deliver paracrine factors, and evaluate its effect on cardiac function.;Gene therapy has evolved as a promising option to deliver pro-angiogenic proteins to infarct zones, thus providing cardiac benefit. This study has identified a gene design without the use of viral vectors, to deliver transient, yet therapeutic levels of an angiogenic chemokine, Stromal-Derived-Cell-Factor-1 (SDF-1) in rodents with chronic heart failure, and has reported significant improvement in cardiac function. The use of Kozak sequences and translational enhancers helped boost gene expressions which could be accurately measured using bio-fluorescence imaging techniques. This improvement in gene expression was directly proportional to the improvement in cardiac function in rodents with chronic heart failure.;However effective plasmid delivery, via the systemic route, requires the encapsulation and targeting of the plasmid to infarct zones. An infarct-specific peptide was identified with the help of phage panning techniques and nanoparticles, formulated with poly lactide-co-glycolide (PLGA), were employed to encapsulate a fluorescent dye, 6-Coumarin (6C). Targeted and efficient delivery was achieved by tagging the surface of the nanoparticles with the targeting peptide. Another aspect of this study was to identify novel paracrine factors responsible for reverse ventricular remodeling, following the treatment of chronic heart failure with mesenchymal stem cell (MSC) therapy, using microarray analysis.;Overall, this study has identified the design and delivery technique for a therapeutic, cardiac-benefiting gene to the infarct zone, in rodents with heart failure. These results can be translated to a clinical setting, providing relief to patients with chronic heart failure. This study has also paved the way for future research in developing novel cardiac drugs, by identifying cardiac specific genes, responsible for reverse ventricular remodeling.
机译：心力衰竭是西方世界死亡率和发病率的主要原因。尽管细胞疗法已证明可改善心脏功能，但这些益处归因于旁分泌因子的激活，而不是移植细胞分化为宿主组织后的整合。基于此知识，本论文的工作重点是传递旁分泌因子并评估其对心脏功能的影响。基因治疗已发展成为将促血管生成蛋白传递至梗塞区域的有前途的选择，从而为心脏带来益处。这项研究已经确定了不使用病毒载体的基因设计，该基因设计可在患有慢性心力衰竭的啮齿动物中提供瞬态的，但仍具有治疗水平的血管生成趋化因子基质细胞衍生细胞因子-1（SDF-1）。心功能显着改善。使用Kozak序列和翻译增强子有助于增强基因表达，可以使用生物荧光成像技术对其进行精确测量。基因表达的这种改善与患有慢性心力衰竭的啮齿动物的心脏功能的改善成正比。然而，通过全身途径有效递送质粒需要将质粒包封和靶向至梗塞区域。借助于噬菌体淘选技术鉴定了梗塞特异性肽，并且将由聚丙交酯-共-乙交酯（PLGA）配制的纳米颗粒用于封装荧光染料6-香豆素（6C）。通过用靶向肽标记纳米颗粒的表面来实现靶向和有效的递送。这项研究的另一个方面是使用微阵列分析法鉴定间充质干细胞（MSC）疗法治疗慢性心力衰竭后引起反向心室重构的新型旁分泌因子。患有心力衰竭的啮齿动物的梗塞区的一种有益心脏的治疗性基因。这些结果可以转化为临床结果，为患有慢性心力衰竭的患者提供缓解。这项研究还通过鉴定负责逆心室重构的心脏特异性基因，为开发新型心脏药物的未来研究铺平了道路。

著录项

  • 作者

    Sundararaman, Srividya.;

  • 作者单位

    Cleveland State University.;

  • 授予单位 Cleveland State University.;
  • 学科 Engineering Biomedical.
  • 学位 D.Eng.
  • 年度 2010
  • 页码 209 p.
  • 总页数 209
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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