Non-racemic metabolic biomaterials for HFpEF

用于 HFpEF 的非外消旋代谢生物材料

• 批准号: 10677638
• 负责人: Andrei Maiseyeu
• 金额: $ 40.25万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677638
• 关键词: Activated Lymphocyte; Adaptive Immune System; Allogenic; Animals; Antigens; Apoptosis; Biocompatible Materials; Biological Assay; Blood; Brain natriuretic peptide; CD28 gene; CD3 Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cardiac; Cardiotoxicity; Cells; Chronic; Clinical Trials; Coculture Techniques; Collagen; Collection; Congestive Heart Failure; Deterioration; Devices; Dexamethasone; Diagnosis; Disease; Drug Delivery Systems; Drug usage; EFRAC; Eating; Echocardiography; Engineering; Evaluation; Exclusion; Fibrosis; Flow Cytometry; Formulation; Genetic; Genus Hippocampus; Glycolysis; Goals; Grant; Heart; Heart Function Tests; Heart failure; Hepatotoxicity; Histology; Immune; Immune Targeting; Immunization; Immunize; Immunomodulators; Immunosuppression; Immunotherapy; In Vitro; Incidence; Infiltration; Inflammatory; Interferon Type II; Investigational Therapies; Lead; Left ventricular structure; Length; Leucocytic infiltrate; Ligands; Lipids; Liver; Lymphocyte Activation; Macrophage; Maintenance; Measurement; Measures; Medical; Metabolic; Metabolism; Modeling; Morbidity - disease rate; Mus; Myelogenous; Myocardial; Myocardium; Myofibroblast; NG-Nitroarginine Methyl Ester; Organ; Oxidative Phosphorylation; Pathogenesis; Pathway interactions; Patients; Phenotype; Pilot Projects; Polymers; Prevalence; Probability; Proteins; Public Health; Reporter; Safety; Signal Transduction; Site; Spleen; Surface; Syndrome; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Thymidine; Toxic effect; Treatment Failure; Work; aorta constriction; arginase; cell motility; cell type; clinically relevant; coronary fibrosis; cytokine; draining lymph node; drug efficacy; enantiomer; experience; fluorescence imaging; heart function; immune activation; immunoregulation; improved; in vivo; in vivo Model; in vivo evaluation; inhibitor; monocyte; mortality; mouse model; nanoparticle; novel therapeutic intervention; preservation; pressure; prevent; rational design; response; success; therapeutic nanoparticles; treatment guidelines; uptake

Heart failure with preserved ejection fraction (НFpEF) is a syndrome that manifests in approximately 50% of all heart failure patients. The incidence and prevalence of НFpEF is sharply rising in the last years, however most patients remain unaddressed. One of the main reasons is the lack of efficacy of drugs, but the other is that historically HFpEF patients were excluded from many heart failure clinical trials. As a result, current treatment guidelines exist for other heart failure types, but completely lack for HFpEF. This proposal will develop a new class of biomaterial-based immunomodulators which work via targeted modulation of specific immune cells in HFpEF. These cells, namely monocytes and T-lymphocytes, are known to be responsible for HFpEF pathogenesis and their targeting is hypothesized to delay the onset of HFpEF and, possibly, alleviate its common consequence - cardiac fibrosis. We propose to develop such biomaterials and test them in mouse models of HFpEF through consecutive execution of the following Specific Aims: 1) We will synthesize and test these polymeric materials with the goal of developing lead formulations that will effectively tune activation of the immune cells in vitro; 2) We will test lead formulations in in vivo models of immune cell activation and further optimize our lead formulations; 3) We will thoroughly investigate best-performing materials in clinically-relevant mouse models of HFpEF. In addition, we will thoroughly investigate safety, including evaluation of systemic immunosuppression of these materials. Therefore, this proposal is significant, because targeting inflammatory and immune pathways proposed here could provide a promising approach for developing therapeutic options in HFpEF patients who have not yet responded adequately to approved and late-stage investigational treatments.

射血分数保留性心力衰竭（LVEF）是一种综合征， 心力衰竭患者。在过去的几年里，ERFpEF的发病率和患病率急剧上升，但大多数 患者仍然没有得到治疗。主要原因之一是药物疗效不足，但另一个原因是， 历史上HFpEF患者被排除在许多心力衰竭临床试验之外。因此，目前的治疗 对于其他类型的心力衰竭，存在指南，但完全缺乏HFpEF。 该提案将开发一类新的基于生物材料的免疫调节剂，其通过靶向的免疫调节剂发挥作用。 HFpEF中特异性免疫细胞的调节。这些细胞，即单核细胞和T淋巴细胞，是已知的。 负责HFpEF的发病机制，并且假设它们的靶向可以延迟HFpEF的发作 并可能减轻其常见后果-心脏纤维化。 我们建议开发这样的生物材料，并通过连续的HFpEF小鼠模型对其进行测试。 具体目标如下：1）我们将合成和测试这些聚合物材料， 开发出能够有效调节体外免疫细胞激活的先导制剂; 2）我们将测试 在体内免疫细胞活化模型中的领先配方，并进一步优化我们的领先配方; 3）我们 将彻底研究临床相关HFpEF小鼠模型中表现最佳的材料。此外，本发明还提供了一种方法， 我们将彻底研究安全性，包括评价这些材料的全身免疫抑制作用。 因此，这个提议意义重大，因为这里提出的靶向炎症和免疫途径 可以为尚未接受HFpEF治疗的HFpEF患者提供一种有前途的治疗方法。 对批准的和后期研究治疗有充分反应。

项目成果

Plaque-targeted, proteolysis-resistant, activatable and MRI-visible nano-GLP-1 receptor agonist targets smooth muscle cell differentiation in atherosclerosis.

• DOI: 10.7150/thno.66456
• 发表时间: 2022
• 期刊: Theranostics
• 影响因子: 12.4
• 作者: Maiseyeu A;Di L;Ravodina A;Barajas-Espinosa A;Sakamoto A;Chaplin A;Zhong J;Gao H;Mignery M;Narula N;Finn AV;Rajagopalan S
• 通讯作者: Rajagopalan S