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 本申请解决了FOA-PA-19-112的科学目标。超过一半的危及生命的 胸癌是用反复剂量的电离辐射治疗的。不幸的是，亲炎症和 电离辐射的促纤维化特性增加了心脏损伤的累积风险。半乳凝素-3(Galectin-3，Gal3)是一种 独特的碳水化合物和多肽结合分子广泛参与心肌炎症和纤维化。 心脏照射模型中心肌Gal3表达增加的报道，但尚不清楚Gal3是否 直接导致辐射引起的心脏纤维化。我们的目标是确定Gal3在中介中的功能 辐射的炎症和纤维化作用。我们建议检验Gal3中介的假设 辐射诱导的心肌炎症和纤维化，以及遗传或免疫调节 Gal3表达或功能的改变可中和这些影响，因此具有心脏保护作用。独有的特点 这一假说的主要观点是，辐射照射能激活心肌细胞和巨噬细胞释放 Gal3，然后与高亲和力的肥大细胞表面受体结合，诱导炎症和纤维化的释放 调解人。此外，我们还设计了一种新的Gal3免疫调节疫苗，在 在小鼠模型上进行单次肌肉注射。为了检验一般假设，我们提出了三个假设 明确的目标。 在目标I中，我们将确定Gal3调节对炎症、纤维化和心功能的影响。 在反复暴露于胸部辐射后。我们将使用基因工程的心肌细胞选择性Gal3 功能获得小鼠研究Gal3-肌细胞-成纤维细胞通路，骨髓移植小鼠研究 Gal3-巨噬细胞-成纤维细胞通路。在AIM II中，我们将确定由 心肌细胞和巨噬细胞体外照射后激活肥大细胞以及下游 使用最先进的微室系统对心脏成纤维细胞生长和胶原合成的影响。在AIM 我们将比较一种新的Gal3免疫调节疫苗对辐射的预防和治疗效果。 诱导的心脏纤维化和功能障碍。该项目的可行性从a)可获得性得到证实。 用于Gal3功能丧失研究的Gal3基因敲除小鼠，b)心脏选择性和全局Gal3过表达小鼠 用于心脏和系统功能获得的研究，以及c)移植了gal3缺失或gal3缺失的去髓小鼠。 巨噬细胞靶向的Gal3功能丧失和功能获得研究中的过表达前体细胞。一个保险箱和 为了研究Gal3的治疗潜力，我们实验室设计了高效的Gal3抑制剂疫苗。 抑制力。预期的项目结果包括Gal3介导心脏纤维化和功能障碍的证据 在累积辐射暴露后，以及临床前数据关于早期Gal3的保护作用 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。 在癌症患者中，易受放射治疗引起的心肌纤维化和心脏功能丧失的影响。

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.