Nanofibrous self-gelling microspheres for heart regeneration

用于心脏再生的纳米纤维自凝胶微球

• 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
• 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

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凝胶型微球 心血管疾病(CVD)是当今世界主要的死亡原因。尤其是心肌梗塞 心肌梗死(MI)，俗称心脏病发作，会导致永久性的心肌损伤或死亡， 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严酷的 梗死区的环境，防止内源性细胞或/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型微球 作为一种新的细胞载体，他们发现它们极大地增加了梗塞心脏中的细胞植入率。我们还有 开发了生物分子控制释放的新技术，以促进心脏再生。此外, 我们发现，表观遗传药物丙戊酸(VPA)在以下情况下可减少~50%的梗塞面积 在缺血再灌流(IR)后给药，并在大鼠心肌梗死模型上保留心脏的泵血功能。 因此，我们假设移植细胞的高保留率和复苏的表观遗传微环境 因为它们可以协同梗死心脏的心肌再生，显著改善功能 恢复。为了验证我们的假设和开发新的再生心脏，我们提出了以下具体目标 治疗：目的1.确定丙戊酸促进心肌梗死后细胞存活的分子机制。目标2. 开发纳米纤维自凝胶型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凝胶微球进行心肌梗死。通过 实现这些具体目标，我们将获得实质性的新的机械性认识和意愿 开发新的和先进的心脏再生技术。