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：
10295348
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/10295348
关键词：
Allogenic Animals Antigens Apoptosis Biocompatible Materials Biological Assay Blood Brain natriuretic peptide CD28 gene CD3 Antigens CD8-Positive T-Lymphocytes Cells Chronic Clinical Trials Collagen Collection Congestive Deterioration Dexamethasone Diagnosis Disease Drug Delivery Systems Drug usage EFRAC Eating Engineering Evaluation Fibrosis Flow Cytometry Formulation Genetic Genus Hippocampus Glycolysis Goals Grant Heart Heart failure Hepatotoxicity Histology Immune Immune Targeting Immune system Immunization Immunize Immunomodulators Immunosuppression Immunotherapy In Vitro Incidence Infiltration Inflammatory Interferon Type II Investigational Therapies Lead Left ventricular structure Length Ligands Lipids Liver Maintenance Measurement Measures Medical Device Metabolic Metabolism Modeling Morbidity - disease rate Mus Muscle Myelogenous Myocardial Myocardium 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 Work arginase base cell motility cell type clinically relevant constriction coronary fibrosis cytokine design draining lymph node drug efficacy experience fluorescence imaging immune activation immunoregulation improved in vivo in vivo Model in vivo evaluation inhibitor/antagonist macrophage monocyte mortality mouse model novel therapeutic intervention preservation pressure prevent response success 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.

心力衰竭，保留的射血分数（γFPEF）是一种综合征，大约50％心力衰竭患者。在过去的几年中，事件和患病率急剧上升，但是大多数患者仍然没有解决。主要原因之一是缺乏药物的效率，但另一个是从历史上看，HFPEF患者被排除在许多心力衰竭临床试验之外。结果，当前的治疗存在其他心力衰竭类型的指南，但HFPEF完全缺乏。该建议将开发一类新的基于生物材料的免疫调节剂调节HFPEF中特定免疫细胞。这些细胞，即单核细胞和T淋巴细胞，已知假设负责HFPEF发病机理及其靶向以延迟HFPEF的发作而且，可能会减轻其共同的后果 - 心脏纤维化。我们建议开发此类生物材料并通过连续的HFPEF小鼠模型进行测试执行以下特定目的：1）我们将综合并测试这些聚合物材料开发铅公式，这些公式将有效地调节体外的免疫细胞激活； 2）我们将测试免疫细胞激活体内模型中的铅公式，并进一步优化我们的铅配方； 3）我们将彻底研究与HFPEF的临床相关小鼠模型中最出色的材料。此外，我们将彻底研究安全性，包括评估这些材料的全身免疫抑制。因此，该提议很重要，因为此处提出的针对炎症和免疫途径可以为在尚未的HFPEF患者中开发治疗选择的有前途的方法对批准和晚期研究治疗做出了适当的反应。