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: 10469629
• 负责人: PETER X MA
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10469629
• 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微球 心血管疾病（CVD）是当今世界导致死亡的主要原因。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伤或死亡，并且是 心脏病人的头号杀手。心肌梗死后心脏功能恢复的一大挑战是严酷的环境 梗塞区域的环境，阻止内源细胞的重新增殖或/和 移植细胞的保留/整合。我们开发了可注射的纳米纤维自凝胶微球 作为一种新型细胞载体，发现它们可以显着增加梗塞心脏中的细胞植入。我们还有 开发了控制释放生物分子以增强心脏再生的新技术。此外， 我们发现表观遗传药物丙戊酸 (VPA) 可减少约 50% 的梗塞面积 在大鼠心肌梗死模型中，缺血再灌注（IR）后给药并保留心脏的泵血功能。 因此，我们假设移植细胞的高度保留和恢复的表观遗传微环境 因为它们可以协同梗塞心脏中的心肌再生，显着改善功能 恢复。提出以下具体目标来检验我们的假设并开发新型再生心脏 治疗： 目的1.确定VPA增强梗塞心脏细胞存活的分子机制。目标2。 开发纳米纤维自凝胶微球作为细胞和生物分子的载体。目标 3. 重生 使用 VPA 和携带细胞的纳米纤维自胶凝微球对免疫缺陷大鼠的梗塞心脏进行治疗。经过 实现这些具体目标，我们将获得实质性的新的机制理解，并将 开发心脏再生的新颖和先进技术。

项目成果

Acetyl-CoA production by specific metabolites promotes cardiac repair after myocardial infarction via histone acetylation.

• DOI: 10.7554/elife.60311
• 发表时间: 2021-12-23
• 期刊: eLife
• 影响因子: 7.7
• 作者: Lei I;Tian S;Gao W;Liu L;Guo Y;Tang P;Chen E;Wang Z
• 通讯作者: Wang Z

ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription.

• DOI: 10.7554/elife.53550
• 发表时间: 2020-10-21
• 期刊: eLife
• 影响因子: 7.7
• 作者: Riou R;Ladli M;Gerbal-Chaloin S;Bossard P;Gougelet A;Godard C;Loesch R;Lagoutte I;Lager F;Calderaro J;Dos Santos A;Wang Z;Verdier F;Colnot S
• 通讯作者: Colnot S

Improving Cardiac Reprogramming for Heart Regeneration in Translational Medicine.

• DOI: 10.3390/cells10123297
• 发表时间: 2021-11-25
• 期刊: Cells
• 影响因子: 6
• 作者: Liu L;Guo Y;Li Z;Wang Z
• 通讯作者: Wang Z

Peptidylarginine Deiminase 2 Knockout Improves Survival in Hemorrhagic Shock.

• DOI: 10.1097/shk.0000000000001489
• 发表时间: 2019-11
• 期刊: Shock
• 影响因子: 3.1
• 作者: Jing Zhou;Ben E. Biesterveld;Yongqing Li;Zhenyu Wu;Yuzi Tian;Aaron M Williams;Shuo Tian;Wenbin Gao