Spatial patterning modulates tissue revascularization and regeneration

空间模式调节组织血运重建和再生

基本信息

批准号：
10368134
负责人：
Karina Nakayama
金额：
$ 24.47万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-20 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10368134
关键词：
3-Dimensional Amputation Anastomosis - action Angioplasty Architecture Arteriographies Autologous Award Balloon Angioplasty Biological Biological Assay Blood Vessels Blood capillaries Blood flow Cardiovascular system Cell Culture Techniques Cells Cellular Morphology Computer Interface Coupled Cues Data Science Deterioration Diagnosis Differentiation Antigens Disease Endothelial Cells Endothelium Engineering Ensure Enzyme-Linked Immunosorbent Assay Extracellular Matrix FGF2 gene First Independent Research Support and Transition Awards Focal Adhesion Kinase 1 Foundations Future Gene Silencing Generations Genes Genetic Transcription Goals Grant Growth Factor Histologic Image In Vitro Individual Injury Insulin-Like Growth Factor I Integrins Intervention Ischemia Isolated limb perfusion Isolectin Lasers Lead Limb structure Link MAPK7 gene Mediating Medicine Methodology Mitogen-Activated Protein Kinases Molecular Monitor Morbidity - disease rate Motor Activity Mus Muscle Muscle Fibers Muscle function Myoblasts Natural regeneration Operative Surgical Procedures PECAM1 gene Pathway interactions Pattern Peripheral arterial disease Persons Phenotype Physiological Platelet-Derived Growth Factor Play Process Property Public Health Reconstructive Surgical Procedures Recovery of Function Regenerative engineering Reperfusion Therapy Research Role Running Sampling Series Signal Transduction Site Skeletal Muscle Skeletal Muscle Myosins Stains Stents Structure Therapeutic Therapeutic Intervention Tissue Engineering Tissues Training Transplantation Treatment Efficacy Tube United States United States National Institutes of Health Vascular Diseases Vascular Endothelial Cell Vascular Endothelial Growth Factors Vascularization Vein graft Work angiogenesis artery occlusion base bioluminescence imaging blood perfusion cadherin 5 career critical limb Ischemia cytokine density disability efficacy evaluation externship functional genomics gene network health goals implantation improved injured innovation insight loss of function mechanical properties medical schools mortality mouse model muscle physiology muscle regeneration myogenesis nanofibrillar nanoscale neutralizing antibody novel paracrine regenerative regenerative approach repaired restoration scaffold therapeutic evaluation tissue injury tissue regeneration transcriptome sequencing vascular injury von Willebrand Factor

项目摘要

PROJECT SUMMARY 8.5 million people in the United States suffer from peripheral arterial disease (PAD). As the disease progresses, it can lead to severe obstruction of arterial blood flow to the extremities causing critical limb ischemia, and is associated with devastatingly high mortality rates of up to 20% just 6 months from initial diagnosis. This condition requires immediate endovascular treatment to re-establish blood flow, commonly through the use of stents, balloon angioplasty, or autologous vein grafts; however, these treatments require multiple interventions and do not conclusively lower the amputation rates. Therapeutic interventions aimed at long-term functional recovery must augmenting tissue angiogenesis concomitant with restoring physiological tissue architecture. This K99/R00 Pathway to Independence Award builds on previous work that demonstrates that spatial patterning cues from nanoscale extracellular matrices modulate endothelial cell (EC) morphology and angiogenic function. The objective of the current study is to use nanoscale cell guidance from aligned 3D scaffolds to enhance the angiogenic potential of vascular ECs, with the regenerative goal of restoring blood flow to ischemic regions and enabling functional repair of severely damaged tissue, an important public health goal that has been challenging to attain. First, this award will provide the opportunity to examine the role of spatial patterning using aligned versus non-patterned scaffolds, in the enhancement of EC angiogenic function as well as the modulation of muscle myoblasts phenotype and mechanical properties. In parallel with this aim, the therapeutic efficacy of EC-seeded aligned scaffolds in comparison to non-patterned scaffolds, will be assessed for tissue revascularization and muscle regeneration in a mouse model of volumetric muscle and vascular injury. Through these studies, the challenge of restoring both vascular and muscular function to injured tissues is tackled on multiple fronts by using spatial cell patterning to induce an EC phenotype concomitant with angiogenesis that will in turn enhance muscle myofiber differentiation and maturation. Finally, to gain a deeper understanding of the mechanisms by which gene networks and pathways work in concert to promote angiogenesis through spatial patterning, methodologies in gene silencing and functional genomics will be employed to reveal novel cell patterning pathways. The proposed training will include courses offered through the Stanford School of Medicine and externships with leading experts in the fields of cardiovascular medicine, data science, and muscle regeneration. The proposed series of studies will deepen the understanding of the biological mechanisms through which spatial cell patterning confers enhancement of EC angiogenesis and muscle myoblast function. Findings from these studies will provide insights that will inform future regenerative strategies and engineered therapeutics for revascularization of severely damaged and ischemic tissues, and will serve as an innovative platform and important step in the treatment of a broad range of vascular diseases.

项目摘要美国有850万人患有周围动脉疾病（PAD）。作为疾病进步，可能导致严重阻塞动脉血流到肢体导致临界肢体的肢体缺血，并且与最初仅6个月的毁灭性高死亡率高达20％有关诊断。这种情况需要立即进行血管内治疗以重新建立血液，通常通过使用支架，气球血管成形术或自体静脉移植；但是，这些治疗需要多次干预措施，不会最终降低截肢率。针对的治疗干预措施长期功能恢复必须增强组织血管生成与恢复生理组织结构。这项K99/R00独立奖的奖项是基于以前的作品建立的来自纳米级细胞外矩阵的空间图案提示调节内皮细胞（EC）形态和血管生成功能。当前研究的目的是使用对齐3D的纳米级细胞指导脚手架以增强血管EC的血管生成潜力，其再生目标是恢复血液流向缺血区域并实现严重损坏的组织的功能修复，这是一个重要的公共卫生实现挑战的目标。首先，该奖项将提供机会，以检查使用Alimed的空间图案的作用在增强EC血管生成功能以及调制方面，肌肉成肌细胞表型和机械性能。与这个目标并联，治疗功效与非图案脚手架相比，将评估组织的ec种子对准支架体积肌肉和血管损伤的小鼠模型中的血运重建和肌肉再生。通过这些研究，恢复受伤组织的血管和肌肉功能的挑战是通过使用空间细胞模式在多个方面进行处理，以诱导与血管生成会增强肌肉肌纤维的分化和成熟。最后，更深入了解基因网络和途径协同促进的机制通过空间模式，基因沉默的方法论和功能基因组学中的方法论是被用来揭示新颖的细胞模式途径。拟议的培训将包括通过斯坦福大学医学院和企业与心血管医学领域的领先专家数据科学和肌肉再生。拟议的一系列研究将加深对空间细胞模式的生物学机制赋予EC血管生成的增强和肌肉成肌细胞功能。这些研究的发现将提供见解，这些见解将为未来的再生提供信息严重受损和缺血组织血运重建的策略和工程疗法，以及将作为一个创新平台，也将在治疗广泛的血管疾病方面进行重要一步。