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

项目总结 病毒感染引起的心肌炎是猝死的主要原因，并可发展为扩张性心肌炎。 心肌病(DCM)和心脏移植的需要。目前，还没有针对疾病的治疗方法。 以减少心肌炎或防止进展为DCM。已知Toll样受体4(TLR4)可促进病毒 心肌炎，触发促炎性级联反应，促进急性心力衰竭和进展为扩张型心肌炎。 因此，需要开发抑制TLR4驱动的炎症以改善的新疗法 心肌炎。最近的研究表明，脂肪干细胞(ADSCs)具有抗炎作用 由细胞分泌的生物纳米颗粒(BiNPs)介导的效应。然而，免疫调节剂 异质脂肪组织衍生的BiNPs的特性还没有被探索。我们的初步结果 提示脂肪组织来源的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的炎症和TLR4的表达，(Iii)服用 与细胞培养衍生的BiNPs相比，加工时间更短，获得成本更低，并且含量更丰富 (Iv)可装载可进一步增强抗炎效果的常规药物。我们假设 脂肪衍生的BiNPs可减少TLR4诱导的心脏炎症激活，可用于治疗 心肌炎和扩张型心肌炎。为了验证这一假设，我们将确定患者来源的吸脂剂的机制- 在心肌炎/扩张性心肌炎小鼠模型(目标1)中衍生的BiNPs(Lipo-NPs)，并评估 患者来源的脂纳米粒作为抗炎化合物的药物载体在小鼠模型中的作用 心肌炎(目标2)，测量脂纳米粒在健康和雌雄小鼠中的生物分布 心肌炎及抗炎脂纳米粒对心肌炎的影响 性。我们将利用我们实验室在BiNP分离方面的专业知识以及一种具有良好特征的小鼠病毒 心肌炎/DCM模型。我们预计这项研究将描述脂肪BiNPs在心肌炎/ DCM，并可能导致新的临床相关治疗策略。

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.