Modulation of signaling from damage-associated molecular patterns to improve radiation-induced thymic dysfunction

调节损伤相关分子模式的信号传导以改善辐射引起的胸腺功能障碍

• 批准号: 10474884
• 负责人: Jarrod Dudakov
• 金额: $ 59.92万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-18 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10474884
• 关键词: Acute; Age; Agonist; Apoptosis; BMP4; Cell Death; Cell physiology; Cells; Complex; Data; Dose; Endothelial Cells; Equilibrium; Functional disorder; G-Protein-Coupled Receptors; GPR39 gene; Generations; Goals; Immune; Immune Targeting; Immunity; Immunocompetence; Immunologics; Individual; Infection; Injury; Ionizing radiation; Ions; Kinetics; Life; Longevity; Lymphoid Cell; Lymphopenia; Mediating; Molecular; Morbidity - disease rate; Mus; Natural regeneration; Outcome; Pathway interactions; Pattern; Pharmacology; Population Heterogeneity; Process; Production; Purinergic P2 Receptors; Purinoceptor; Radiation; Radiation Accidents; Radiation Dose Unit; Radiation Injuries; Radiation induced damage; Recovery; Recovery of Function; Regenerative capacity; Regenerative pathway; Regenerative response; Rejuvenation; Signal Transduction; Site; Stress; T cell reconstitution; T-Cell Depletion; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Thymic epithelial cell; Thymus Gland; Tissues; Whole-Body Irradiation; Zinc; adaptive immunity; aged; base; cell regeneration; conditioning; experience; hematopoietic cell transplantation; immune function; immunogenic cell death; improved; innovation; interleukin-22; interleukin-23; medical countermeasure; preclinical study; programs; receptor; regenerative; repaired; response; restoration; severe injury; sex; therapeutic target; thymic regeneration; thymocyte; tissue regeneration

PROJECT SUMMARY The thymus, which is the primary site of T cell generation, is extremely sensitive to insult, but also has a remarkable capacity for endogenous repair. Even though there is likely continual thymic involution and regeneration in response to everyday insults like stress and infection, profound thymic damage caused by radiation injury leads to prolonged T cell lymphopenia. Consequently, identification of therapies that can boost T cell reconstitution in recipients after a dose of radiation is a clear priority. We have previously identified two distinct pathways of endogenous thymic regeneration, centered on the production of the regeneration factors IL-22 by innate lymphoid cells (ILCs), and BMP4 by endothelial cells (ECs); both of which mediate their regenerative effects by targeting thymic epithelial cells. More recently we have found that the trigger for these distinct regenerative pathways hinge on the balance between forms of cell death, with immunologically silent apoptosis (which is abundant in thymocytes during steady-state) suppressive to the regenerative program. On the other hand, after thymic damage caused by radiation injury, we found a switch toward immunogenic cell death, with the resulting release of damage-associated molecular patterns (DAMPs) sufficient to promote regeneration. Specifically, we identified that intracellular Zn was released after radiation injury, where it could signal through the G-protein coupled receptor 39 (GPR39) to stimulate production of BMP4 and IL-23, a key upstream regulator of IL-22 production. Separately, we also found that the release of the prototypical DAMP, ATP, was able to signal directly on thymic epithelial cells through purinergic (P2) receptors and promote their expression of Foxn1, key microenvironmental drivers of T cell development. Importantly, our preliminary data also suggests that each of these pathways can be therapeutically targeted to improve thymic recovery following radiation damage in young mice. Based on our preliminary data, we hypothesize that modulation of pathways associated with these DAMPs can be used as a countermeasure to improve immune function after radiation injury by stimulating the generation of new T cells in the thymus. Specifically, our proposal has the following aims: (1) To validate and optimize the targeting of GPR39 or P2 receptors to improve the production of new T cells and immune function after radiation injury; (2) to examine the ability of the thymus to respond to regenerative signals across mouse lifespan and sex; and (3) to comprehensively evaluate the potential for targeting GPR39 or P2 receptors to improve thymic function after radiation damage across mouse lifespan and sex. The studies outlined in this proposal not only have the potential to define important pathways underlying tissue regeneration across lifespan but could also result in innovative approaches to enhance T cell recovery after radiation damage.

项目摘要 胸腺是T细胞产生的主要部位，对损伤极其敏感，但也具有免疫抑制作用。 具有非凡的内源性修复能力。即使有可能持续的胸腺退化， 再生反应日常侮辱，如压力和感染，深刻的胸腺损伤所造成的 辐射损伤导致延长的T细胞淋巴细胞减少症。因此，确定可以提高T细胞的治疗方法， 接受者在接受一剂辐射后的细胞重建是一个明确的优先事项。 我们以前已经确定了两种不同的内源性胸腺再生途径， 先天性淋巴样细胞（ILC）产生再生因子IL-22，内皮细胞（EC）产生BMP 4; 两者都通过靶向胸腺上皮细胞介导其再生作用。最近我们发现 这些不同再生途径的触发因素取决于细胞死亡形式之间的平衡， 免疫沉默的细胞凋亡（在稳态期间在胸腺细胞中丰富）抑制免疫应答。 再生程序另一方面，在辐射损伤导致胸腺损伤后， 导致免疫原性细胞死亡，从而释放损伤相关分子模式（DAMP） 足以促进再生。具体地说，我们发现，细胞内锌释放后，辐射 损伤，其中它可以通过G蛋白偶联受体39（GPR 39）发出信号以刺激BMP 4的产生 和IL-23，IL-22产生的关键上游调节因子。另外，我们还发现， 原型DAMP，ATP，能够通过嘌呤能（P2）受体直接在胸腺上皮细胞上发出信号 并促进其Foxn 1的表达，Foxn 1是T细胞发育的关键微环境驱动因素。重要的是我们的 初步数据还表明，这些途径中的每一种都可以在治疗上靶向改善胸腺功能， 在年轻的小鼠辐射损伤后的恢复。根据我们的初步数据，我们假设， 调节与这些DAMP相关的途径可用作改善免疫应答的对策。 在辐射损伤后通过刺激胸腺中新T细胞的产生来发挥功能。具体来说，我们的建议 目的：（1）验证和优化GPR 39或P2受体的靶向作用，以提高肿瘤细胞的增殖能力。 放射损伤后新T细胞的产生和免疫功能;（2）检查胸腺的能力， 对小鼠寿命和性别的再生信号作出反应;以及（3）全面评估 靶向GPR 39或P2受体改善小鼠辐射损伤后胸腺功能的潜力 寿命和性别 该提案中概述的研究不仅有可能确定潜在的重要途径， 组织再生，但也可能导致创新的方法，以提高T细胞的恢复 辐射损伤后。