Non-racemic metabolic biomaterials for HFpEF

射血分数保留的心力衰竭(Н)是一种综合征，大约50%的患者表现为心力衰竭 心力衰竭患者。Н的发病率和患病率在过去几年中急剧上升，但大多数 患者仍然没有得到解决。其中一个主要原因是药物缺乏疗效，但另一个原因是 从历史上看，HFpEF患者被排除在许多心力衰竭临床试验之外。因此，目前的治疗 有针对其他心力衰竭类型的指南，但完全缺乏针对HFpEF的指南。 这项提议将开发一类新的基于生物材料的免疫调节剂，它通过靶向作用 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 对HFpEF的发病负有责任，其靶向被假设为延迟HFpEF的发病 并有可能缓解其常见的后果--心脏纤维化。 我们建议开发这种生物材料，并通过连续的方法在HFpEF小鼠模型上进行测试 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 开发能够在体外有效调节免疫细胞激活的铅配方；2)我们将测试 体内免疫细胞激活模型中的铅配方，并进一步优化我们的铅配方；3)我们 将深入研究与临床相关的HFpEF小鼠模型中表现最好的材料。此外, 我们将彻底调查安全性，包括对这些材料的全身免疫抑制的评估。 因此，这项建议意义重大，因为这里提出了针对炎症和免疫途径的建议 可以为尚未治疗HFpEF的患者提供一种有希望的治疗方法 对已批准的和后期研究治疗作出了充分反应。

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.