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动微球心血管疾病（CVD）是当今世界上死亡的主要原因。特别是心肌梗塞（MI），通常称为心脏病发作，会导致永久性心肌损害或死亡，并且是心脏病患者的第一杀手。 MI后心脏功能恢复的一个主要挑战是苛刻梗塞区域的环境，可防止内源性细胞的重生或/和/和保留/整合移植细胞。我们已经开发了可注射的纳米纤维自动微球作为一种新型的细胞载体，发现它们会大大增加梗塞心脏中的细胞植入。我们也有开发了用于控制生物分子释放的新型技术，以增强心脏再生。此外，我们已经发现，当表观遗传药物丙戊酸（VPA）减少了梗塞大小的约50％缺血再灌注（IR）后管理，并保留大鼠MI模型中心脏的抽水功能。因此，我们假设移植细胞的高度保留和复兴的表观遗传微环境对于他们来说，可以在梗塞心脏中协同性心肌再生，从而显着提高功能恢复。提出了以下特定目的来检验我们的假设并发展新的再生心脏治疗：目标1。确定VPA的分子机制在增强梗塞心脏中的细胞存活中。目标2。开发纳米纤维的自芯微球作为细胞和生物分子的载体。目标3。再生使用VPA和携带细胞的纳米纤维自粘膜微球中的梗塞心脏梗塞心脏。经过实现这些特定目标，我们将实现大量的新机械理解，并将为心脏再生开发新颖和先进的技术。