慢性持续炎症反应可导致造血干细胞（hematopoietic stem cell，HSC）功能衰竭, 然而保护HSC免受炎性伤害的分子机制依然所知甚少。申请人近期阐明了STAT3通过抑制E2泛素化结合酶Ubc13保护HSC免受炎性损伤的分子机制，成果提示Ubc13高表达是诱导HSC内源性炎性损伤的关键环节。申请人通过RNA测序发现Ubc13敲除后，多个调控HSC线粒体关键功能的蛋白表达失调。基于上述工作基础，申请人拟通过Ubc13敲除和过表达两种小鼠模型，分别探究生理稳态和炎症刺激下，Ubc13对HSC功能，转录组和蛋白组的调控，以及对线粒体功能和关键蛋白表达水平的影响。验证Ubc13通过调控线粒体关键蛋白和线粒体功能，影响HSC干性，分化和生存的中心科学假说。通过实施上述计划，预期获得Ubc13调控HSC和线粒体功能细胞和分子机制，为拮抗HSC炎症反应提供治疗新策略和潜在药物靶点。

Chronic exposure to pro-inflammatory signals damages hematopoietic stem cells (HSCs) and results in bone marrow failure, yet anti-inflammatory mechanisms that protect HSCs are understudied. Our previous study revealed STAT3 restrains pro-inflammatory responses and preserve HSC function by inhibiting expression of Ubc13, an E2 ubiquitin-conjugating enzyme involved in inflammatory responses. Therefore, it collectively suggested hyperactivation of Ubc13 might directly contribute to endogenous proinflammatory damages in hematopoietic stem and progenitor cells (HSPCs). We identified multiple proteins, which involved in modulating mitochondria function and were proved to be critical for HSC stemness or differentiation, were deregulated in absence of Ubc13 through RNAseq. Therefore, we propose a crucial role for Ubc13 in HSCs preservation through regulating critical mitochondrial proteins. We will explore the cell intrinsic function of Ubc13 in HSCs and their mitochondria under both homeostasis and inflammatory settings, and reveal transcriptome and proteomics changes in the presence or absence of Ubc13 in HSC. We expect to reveal novel cellular and molecular mechanism of how Ubc13 regulates HSC functions, and provide fundamental new insight to identify potential therapeutic targets to protect HSC from inflammatory insults.