Adipose-derived biogenic nanoparticles for treatment of myocarditis/DCM(MPDPI)

脂肪源性生物纳米颗粒治疗心肌炎/扩张型心肌病（MPDPI）

基本信息

批准号：
10089412
负责人：
DeLisa Fairweather
金额：
$ 19.56万
依托单位：
MAYO CLINIC JACKSONVILLE
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：
2020-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10089412
关键词：
Acute Acute Myocarditis Adipose tissue Adverse reactions Allogenic Animal Model Anti-Inflammatory Agents Antiinflammatory Effect Autologous Automobile Driving Biocompatible Materials Biodistribution Biological Biological Markers Biopsy Blood Circulation Cardiac Cardiomyopathies Cell Culture Techniques Cells Clinical Congestive Heart Failure Coxsackie Viruses Diagnosis Dilated Cardiomyopathy Disease Disease model Drug Delivery Systems Ensure Enterovirus Female Future Goals Heart Heart Transplantation Heart failure Histology Hour ITGAM gene Immune response Individual Inflammation Inflammatory Inflammatory Response Innate Immune Response Interleukin-1 Interleukin-6 Laboratories Lead Lipids Measures Mediating Modeling Mus Myocarditis Pathologic Processes Pathway interactions Patients Performance Pharmaceutical Preparations Physiological Processes Plasma Prevention strategy Process Property Proteins RNA Risk Role Sex Differences Sex Ratio Signal Transduction Site Source Sudden Death Supportive care TLR2 gene TLR4 gene TNF gene Testing Testosterone Therapeutic Therapeutic Agents Therapeutic Effect Time Toll-like receptor 11 Transfusion Viral Virus Diseases Virus Replication Woman clinically relevant cost cytokine extracellular vesicles heart function immunoregulation mRNA Expression macrophage male men mouse model nanoparticle novel therapeutics prevent sex side effect stem cells success therapy development treatment response treatment strategy viral myocarditis

项目摘要

PROJECT SUMMARY Myocarditis caused by viral infections is a leading cause of sudden death and can progress to dilated cardiomyopathy (DCM) and the need for a heart transplant. Currently, there are no disease-specific therapies to reduce myocarditis or prevent progression to DCM. Toll like receptor 4 (TLR4) is known to promote viral myocarditis, triggering proinflammatory cascades that promote acute heart failure and progression to DCM. Thus, there is a need to develop novel therapies that suppress TLR4-driven inflammation to ameliorate myocarditis. Recent studies have indicated that adipose-derived stem cells (ADSCs) have anti-inflammatory effects that are mediated by cell-secreted biogenic nanoparticles (BiNPs). However, the immunomodulatory properties of heterogeneous adipose tissue-derived BiNPs have not been explored. Our preliminary results indicate that adipose tissue-derived BiNPs: (i) suppress TLR4-induced inflammatory responses in macrophages, (ii) reduce inflammation and TLR4 expression in a mouse model of viral myocarditis, (iii) take less time to process, cost less to obtain, and are more abundant compared to cell culture-derived BiNPs, and (iv) can be loaded with conventional drugs that further enhance anti-inflammatory effects. We hypothesize that adipose-derived BiNPs reduce TLR4-induced activation of inflammation in the heart and can be used to treat myocarditis and DCM. To test this hypothesis, we will determine the mechanism of patient-derived lipoaspirate- derived BiNPs (Lipo-NPs) in a mouse model of myocarditis/ DCM (Aim 1), and assess the performance of patient-derived Lipo-NPs as drug delivery vehicles for anti-inflammatory compounds in a mouse model of myocarditis (Aim 2), measuring the biodistribution of Lipo-NPs in healthy and male and female mice with myocarditis and determining the effect of Lipo-NPs loaded with anti-inflammatory agents on myocarditis by sex. We will utilize our laboratory's expertise in BiNP isolation along with a well-characterized murine viral myocarditis/ DCM model. We anticipate that this study will delineate the role of adipose BiNPs in myocarditis/ DCM and potentially lead to new clinically relevant therapeutic strategies.

项目概要病毒感染引起的心肌炎是猝死的主要原因，并可进展为扩张型心肌炎心肌病（DCM）和心脏移植的需要。目前尚无针对疾病的特效疗法减少心肌炎或防止进展为 DCM。 Toll 样受体 4 (TLR4) 已知可促进病毒传播心肌炎，引发促炎级联反应，促进急性心力衰竭并进展为 DCM。因此，需要开发新的疗法来抑制 TLR4 驱动的炎症以改善心肌炎。最近的研究表明，脂肪源性干细胞（ADSC）具有抗炎作用由细胞分泌的生物纳米颗粒（BiNP）介导的效应。然而，免疫调节异质脂肪组织衍生的 BiNP 的特性尚未被探索。我们的初步结果表明脂肪组织衍生的 BiNPs：（i）抑制 TLR4 诱导的炎症反应巨噬细胞，(ii) 减少病毒性心肌炎小鼠模型中的炎症和 TLR4 表达，(iii) 与细胞培养物衍生的 BiNP 相比，处理时间更短，获得成本更低，并且含量更丰富，并且 (iv)可负载常规药物，进一步增强抗炎作用。我们假设脂肪来源的 BiNP 可减少 TLR4 诱导的心脏炎症激活，可用于治疗心肌炎和 DCM。为了检验这一假设，我们将确定患者来源的脂肪抽吸物的机制- 在心肌炎/ DCM 小鼠模型中衍生 BiNP（Lipo-NP）（目标 1），并评估其性能患者来源的脂质纳米粒子作为小鼠模型中抗炎化合物的药物输送载体心肌炎（目标 2），测量健康雄性和雌性小鼠中 Lipo-NP 的生物分布心肌炎并确定负载抗炎剂的脂质纳米粒对心肌炎的影响性别。我们将利用我们实验室在 BiNP 分离方面的专业知识以及充分表征的鼠病毒心肌炎/DCM模型。我们预计这项研究将描述脂肪 BiNP 在心肌炎中的作用/ DCM 并有可能带来新的临床相关治疗策略。