Immunomodulation of Galectin-3 to Prevent Radiation-Induced Myocardial Fibrogenesis

Galectin-3对放射性心肌纤维化的免疫调节作用 本申请旨在实现FOA-PA-19-112的科学目标。半数以上危及生命 胸部癌症用重复剂量的电离辐射治疗。不幸的是， 电离辐射的促纤维化特性增加了心脏损伤的累积风险。半乳糖凝集素-3（gal 3）是一种 独特的碳水化合物和肽结合分子，广泛参与心肌炎症和纤维化。 据报道，在心脏照射模型中，心肌gal 3表达增加，但gal 3 直接导致了辐射诱发的心脏纤维化我们的目的是确定gal 3在介导 辐射的炎症和纤维化效应。我们建议检验gal 3介导 辐射诱导的心肌炎症和纤维化，以及遗传或免疫调节 Gal 3表达或功能的降低中和了这些作用，因此是心脏保护性的。特异特征 辐射暴露激活心肌细胞和巨噬细胞释放 gal 3，然后与高亲和力肥大细胞表面受体结合，诱导炎症和纤维化的释放。 调解员此外，我们设计了一种新的gal 3免疫调节疫苗， 在小鼠模型中单剂量肌内给药。为了验证这个假设，我们提出了三个 具体目标。 在目的I中，我们将确定gal 3调节对炎症、纤维化和心脏功能的影响。 在反复暴露于胸部辐射之后。我们将使用基因工程心肌细胞选择性gal 3 功能获得小鼠研究gal 3-肌细胞-成纤维细胞途径，骨髓移植小鼠研究 gal 3-巨噬细胞-成纤维细胞途径。在目标II中，我们将确定由以下物质释放的gal 3的贡献： 心肌细胞和巨噬细胞激活肥大细胞后，在体外照射，以及下游 对心脏成纤维细胞生长和胶原合成的影响，使用最先进的微室系统。在Aim中 第三，我们将比较一种新的gal 3免疫调节疫苗对辐射的预防和治疗作用。 诱发心脏纤维化和功能障碍。该项目的可行性得到了以下方面的证实：a） 用于gal 3功能丧失研究的gal 3敲除小鼠，B）心脏选择性和整体gal 3过表达小鼠 用于心脏和全身性功能获得研究，和c）用gal 3-缺失或gal 3-缺失移植的骨髓清除小鼠， 过表达祖细胞用于巨噬细胞靶向的Gal 3功能丧失和获得研究。一个安全和 本实验室设计了一种高效的gal 3抑制剂疫苗，以研究gal 3的治疗潜力 抑制作用预期的项目成果包括gal 3介导心脏纤维化和功能障碍的证据 累积辐射暴露后，以及早期Gal 3保护作用的临床前数据 免疫调节这些研究对及时和有针对性的干预具有重要的治疗意义 易受放射治疗诱导的心肌纤维化和心功能丧失影响的癌症患者。

Immunomodulation of Galectin-3 to Prevent Radiation-Induced Myocardial Fibrogenesis This application addresses the scientific goals of FOA-PA-19-112. More than half of life-threatening thoracic cancers are treated with repeated doses of ionizing radiation. Unfortunately, the pro-inflammatory and pro-fibrotic properties of ionizing radiation increase the cumulative risk of cardiac damage. Galectin-3 (gal3) is a unique carbohydrate and peptide-binding molecule widely implicated in myocardial inflammation and fibrosis. Increased myocardial gal3 expression is reported in models of cardiac irradiation, but it is unclear whether gal3 directly contributes to radiation-induced cardiac fibrosis. We aim to determine the function of gal3 in mediating the inflammatory and fibrotic effects of radiation. We propose to test the hypothesis that gal3 mediates radiation-induced myocardial inflammation and fibrosis, and that genetic or immunological modulation of gal3 expression or function neutralizes these effects and is thus cardioprotective. The unique features of this hypothesis are the concept that radiation exposure activates cardiomyocytes and macrophages to release gal3, which then binds to high-affinity mast cell surface receptors inducing the release of inflammatory and fibrotic mediators. Moreover, we have designed a new gal3 immunomodulatory vaccine that neutralizes gal3 after single-dose intramuscular administration in a mouse model. To test the general hypothesis, we propose three specific aims. In Aim I, we will determine the effects of gal3 modulation on inflammation, fibrosis, and cardiac function after repeated exposure to thoracic radiation. We will use genetically engineered cardiomyocyte-selective gal3 gain-of-function mice to study gal3-myocyte-fibroblast pathways, and bone marrow transplanted mice to study gal3-macrophage-fibroblast pathways. In Aim II, we will determine the contribution of gal3 released by cardiomyocytes and macrophages to activate mast cells after in vitro irradiation, as well as the downstream effects on cardiac fibroblast growth and collagen synthesis using a state-of-the art microchamber system. In Aim III, we will compare the preventive and therapeutic effects of a new gal3-immunomodulatory vaccine on radiation- induced cardiac fibrogenesis and dysfunction. The feasibility of this project is confirmed by the a) availability of gal3 knockout mice for gal3 loss-of-function studies, b) cardio-selective and global gal3 overexpression mice for cardiac and systemic gain-of-function studies, and c) Myeloablated mice engrafted with gal3-null or gal3- overexpressing progenitor cells for macrophage-targeted gal3 loss-and gain-of-function studies. A safe and highly potent gal3 inhibitor vaccine has been designed in our laboratory to study the therapeutic potential of gal3 inhibition. Expected project outcomes include the evidence that gal3 mediates cardiac fibrosis and dysfunction after cumulative radiation exposure, and pre-clinical data on the protective effects of early gal3 immunomodulation. These studies have important therapeutic implications for timely and targeted interventions in cancer patients susceptible to radiotherapy-induced myocardial fibrogenesis and loss of cardiac function.