Non-racemic metabolic biomaterials for HFpEF

用于 HFpEF 的非外消旋代谢生物材料

基本信息

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
项目类别：
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

项目摘要

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.

射血分数保留的心力衰竭 (НFpEF) 是一种综合征，约 50% 的患者有此症状过去几年，心力衰竭患者的发病率和患病率急剧上升，但大多数患者仍未得到解决的主要原因之一是药物缺乏疗效，但另一个原因是因此，历史上的 HFpEF 患者被排除在许多心力衰竭临床试验之外。存在针对其他心力衰竭类型的指南，但完全缺乏针对 HFpEF 的指南。该提案将开发一类基于生物材料的新型免疫调节剂，其通过靶向作用发挥作用 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 发病机制，并捕获其靶向以延迟 HFpEF 的发作并且可能减轻其常见后果——心脏纤维化。我们建议开发此类生物材料，并通过连续的 HFpEF 小鼠模型对其进行测试执行以下具体目标： 1）我们将合成和测试这些聚合物材料，目标是开发可有效调节体外免疫细胞激活的先导制剂 2) 我们将进行测试； 3) 我们在免疫细胞激活的体内模型中主导配方，并进一步优化我们的主导配方；3) 我们此外，还将在临床相关的 HFpEF 小鼠模型中彻底研究表现最佳的材料。我们将彻底调查安全性，包括评估这些材料的全身免疫抑制。因此，这个提议很重要，因为这里提出的针对炎症和免疫途径可以为尚未治疗的 HFpEF 患者开发治疗方案提供一种有前景的方法对已批准的后期研究治疗做出充分反应。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

斑块靶向、抗蛋白水解、可激活且 MRI 可见的纳米 GLP-1 受体激动剂以动脉粥样硬化中的平滑肌细胞分化为目标。

DOI：
发表时间：
2022
期刊：
影响因子：
12.4
作者：
Maiseyeu, Andrei;Di, Lin;Ravodina, Anastasia;Barajas;Sakamoto, Atsushi;Chaplin, Alice;Zhong, Jixin;Gao, Huiyun;Mignery, Matthew;Narula, Navneet;Finn, Aloke V;Rajagopalan, Sanjay
通讯作者：
Rajagopalan, Sanjay