Latexin function in the maintenance and regeneration of the hematopoietic system

摘要 造血系统对各种压力非常敏感。放射治疗通常会导致便秘 不仅急性造血抑制，而且长期骨髓(BM)损伤会增加BM的风险 失败或恶毒。老化过程中损伤的积累是对HSCs的另一种压力。 提高HSC的存活率和在应激状态下保持其基因组的完整性是HSC保存的关键 自我更新功能和对应激诱导的骨髓损伤的保护。然而，潜在的分子 机制没有得到很好的定义。还没有开发出有效的治疗方法来预防或治疗压力引起的 HSC损伤及相关病理后果。这个项目的主要目标是识别小说 针对HSC应激调节蛋白Latexin的药物化合物和转录机制 (LXN)，并揭示抑制LXN导致辐射防护和HSC年轻化的机制。 我们已经确定了一种新的LXN抑制剂小化合物，并发现它通过以下方式显著提高存活率 通过一种新发现的典型的羧基肽酶A抑制辐射机制来保护HSCs。 LXN缺失还可缓解与衰老相关的HSCs功能衰退。我们假设药物和 LXN转录抑制对应激(辐射和衰老)诱导的HSC和血液系统的保护作用 通过典型的CPA3途径上调而导致的功能衰退。目标1是确定分子 LXN失活对放射性骨髓损伤的保护机制 CPA3途径。目的2确定LXN铅抑制剂在辐射防护中的作用机制。 造血系统。目标3是确定LXN抑制在恢复旧的HSC中的作用。调查结果将 提高我们对LXN如何调节应激性造血的新机制的认识。结果将提供一个 针对LXN的令人信服的起点和新药发现的基础，这将使患者受益 接受放射治疗的老年人和肝星状细胞功能障碍和免疫老化。

ABSTRACT The hematopoietic system is very sensitive to a variety of stresses. Radiation therapy commonly results in not only acute hematopoietic suppression but also long-term bone marrow (BM) injury with increased risk of BM failure or malignancy. Accumulation of damages during aging process is another type of stress on HSCs. Enhancing HSC survival and maintaining their genomic integrity upon stress are crucial for preservation of HSC self-renewal function and for protection against stress-induced BM injury. However, the underlying molecular mechanisms are not well defined. No effective treatment has been developed to prevent or treat stress-induced HSC damages and related pathological consequences. The primary goal of this project is to identify novel pharmaceutical compounds and transcriptional mechanism that target a HSC stress regulatory protein, latexin (Lxn), and to uncover the mechanisms that Lxn suppression results in radiation protection and HSC rejuvenation. We have identified a novel Lxn inhibitor small compound and found that it significantly increases survival by protecting HSCs via a newly identified canonical mechanism of carboxypeptidase A inhibition upon radiation. Lxn deletion also mitigates aging-related functional decline of HSCs. We hypothesize that pharmaceutical and transcriptional suppression of Lxn protects HSCs and blood system from stress (radiation and aging)-induced functional decline via the upregulation of canonical CPA3 pathway. Aim 1 is to determine the molecular mechanisms by which Lxn inactivation protects against radiation-induced BM injury via up-regulation of canonical CPA3 pathway. Aim 2 is to identify the mechanism of action of Lxn lead inhibitor in radiation protection of hematopoietic system. Aim 3 is to define the role of Lxn suppression in rejuvenating old HSCs. Findings will advance our knowledge of novel mechanisms how Lxn regulates stress hematopoiesis. Results will provide a compelling starting point and lay grounds for the novel drug discovery by targeting Lxn, which will benefit patients subject to radiation treatment and old people with dysfunctional HSC and immune aging.