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Nanofibrous self-gelling microspheres for heart regeneration

用于心脏再生的纳米纤维自凝胶微球

基本信息

批准号：
10229376
负责人：
Zhong Wang
金额：
$ 39万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229376
关键词：
3-Dimensional Acetylation Address American Area Biological Assay Biomimetics Body Temperature Cardiac Myocytes Cardiac development Cardiovascular Diseases Cause of Death Cell Proliferation Cell Survival Cell Transplantation Cells Cessation of life Chromatin Coupling Data Devices Disease Drug Delivery Systems Engraftment Ensure Environment Epigenetic Process Extracellular Matrix Extracellular Matrix Proteins FOXM1 gene Gel Gene Expression Genes Heart Heart failure Human Hydrogels Hypoxia In Vitro Infarction Injectable Ischemia Length Luciferases Mechanics Mediating Mediator of activation protein Methylation Microspheres Modeling Modulus Molecular Myocardial Infarction Myocardium Nanosphere Natural regeneration Oxygen Patients Pharmacology Phenotype Property Proteoglycan Pump RNA Interference Rattus Recovery Recovery of Function Recurrence Reperfusion Therapy Role Source Structure System Technology Temperature Testing Tissue Engineering Tissues Transplantation Valproic Acid Weight base cardiac regeneration controlled release copolymer design epigenetic drug experimental study heart cell heart function high throughput screening improved in vivo knock-down muscle regeneration nanofiber new technology novel overexpression preservation prevent regenerative regenerative biology scaffold small molecule sudden cardiac death

项目摘要

Nanofibrous self-gelling microspheres for heart regeneration Cardiovascular disease (CVD) is the leading cause of death in the world today. In particular, myocardial infarction (MI), commonly known as heart attack, results in permanent heart muscle damage or death, and is the number one killer of heart patients. One major challenge to heart functional recovery after MI is the harsh environment of infarcted areas, which prevents either repopulation of endogenous cells or/and retention/integration of transplanted cells. We have developed injectable nanofibrous self-gelling microspheres as a novel cell carrier and found they dramatically increase cell engraftment in infarcted hearts. We have also developed novel technology for controlled release of biomolecules to enhance heart regeneration. In addition, we have discovered that an epigenetic drug valproic acid (VPA) reduces ~50% of the infarct size when administrated after ischemia reperfusion (IR) and preserves the pumping function of heart in a rat MI model. We therefore hypothesize that high retention of transplanted cells and a reviving epigenetic microenvironment for them can synergize cardiac muscle regeneration in infarcted heart, substantially improving functional recovery. The following specific aims are proposed to test our hypothesis and develop novel regenerative heart therapy: Aim 1. Determine the molecular mechanism of VPA in enhancing cell survival in infarcted heart. Aim 2. Develop nanofibrous self-gelling microspheres as a carrier for cells and biomolecules. Aim 3. Regenerate infarcted heart using VPA and cell-carrying nanofibrous self-gelling microspheres in immunodeficient rats. By accomplishing these specific aims, we will achieve substantial new mechanistic understandings and will develop novel and advanced technologies for heart regeneration.

用于心脏再生的纳米纤维自胶凝微球心血管疾病（CVD）是当今世界上导致死亡的主要原因。特别是心肌心肌梗塞（MI），通常称为心脏病发作，导致永久性心肌损伤或死亡，心脏病患者的头号杀手心肌梗死后心脏功能恢复的一个主要挑战是梗塞区域的环境，其阻止内源性细胞的再增殖或/和移植细胞的保留/整合。我们已经开发出可注射的纳米纤维自凝胶微球作为一种新的细胞载体，并发现它们显著增加了梗死心脏中的细胞移植。我们还开发了一种新技术，用于控制生物分子的释放，以增强心脏再生。此外，本发明还提供了一种方法，我们已经发现，一种表观遗传药物丙戊酸（VPA）可以减少约50%的梗死面积，在大鼠MI模型中，在缺血再灌注（IR）后给药并保留心脏的泵送功能。因此，我们假设，移植细胞的高保留和再生的表观遗传微环境因为它们可以协同梗死心脏的心肌再生，复苏提出以下具体目标来验证我们的假设并开发新型再生心脏治疗：目的1.确定VPA增强梗死心脏细胞存活的分子机制。目标2. 开发纳米纤维自胶凝微球作为细胞和生物分子的载体。目标3.再生在免疫缺陷大鼠中使用VPA和携带细胞的纳米纤维自胶凝微球的梗死心脏。通过实现这些具体目标，我们将获得实质性的新的机械理解，开发新的和先进的心脏再生技术。