HMGB1 in EB-Associated Squamous Cell Carcinoma

项目概要/摘要 隐性营养不良性大疱性表皮病（RDEB）是一种罕见的以慢性创伤为特征的遗传性疾病 以及由于早发性鳞状细胞癌（SCC）的高发病率而缩短的寿命。高度 RDEB患者中SCC的侵袭性需要进一步的机制研究。高迁移率族蛋白b1 HMGB 1是RDEB疾病严重程度的血清生物标志物，但其在RDEB患者肿瘤发生中的作用 还没有被彻底调查。HMGB 1是一种染色质相关蛋白，在细胞核中起作用， DNA复制和修复的调节器。在炎症信号的反应中，HMGB 1从细胞分泌， 细胞核和功能作为损伤相关的分子模式，刺激先天免疫反应。 该建议的中心假设是角质形成细胞中核HMGB 1的耗竭驱动癌发生 通过促进炎症和加速基因组的不稳定性。这一假设将通过 两个具体的目的是研究在细胞核中隔离HMGB 1的效果。第一个目标探讨了 改变HMGB 1定位对RDEB角质形成细胞炎症反应和基因组不稳定性的影响 第二个目的是评估HMGB 1分泌的小分子抑制剂在预防肿瘤中的有用性。 使用RDEB的体内小鼠模型来形成。这些目标的成功实现将提供新的 HMGB 1在RDEB SCC患者中的生物学功能信息。这项研究的结果有 有可能为迫切需要安全有效的药物的脆弱患者群体揭示新的药物靶点。 治疗方案。 该提案将在明尼苏达大学的Jakub Tolar博士的共同指导下完成， 医学科学家和儿科肿瘤学家，专门从事RDEB，和博士Anja-Katrin Bielinsky，专家在 基因组维持和DNA修复缺陷在癌症发生中的作用。联合国的互补性专门知识- 赞助商使候选人处于独特的位置，以完成本提案中描述的目标并实现其目标 成为一名学术儿科血液肿瘤学家，领导一个研究实验室， 罕见遗传疾病和癌症的潜在机制。职业发展和研究金培训计划 在此应用程序中概述了建立一个长期和富有成效的职业生涯研究更好的治疗基础 用于患有复杂和难以治疗的遗传疾病的儿科患者。

Project Summary/Abstract Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disease characterized by chronic wounds and shortened lifespan due to a high incidence of early-onset squamous cell carcinoma (SCC). The highly aggressive nature of SCC in RDEB patients warrants further mechanistic study. High mobility group box 1 (HMGB1) is a serum biomarker of disease severity in RDEB, but its role in tumorigenesis in patients with RDEB has not been thoroughly investigated. HMGB1 is a chromatin-associated protein that functions in the nucleus as a regulator of DNA replication and repair. In response to inflammatory signals, HMGB1 is secreted from the nucleus and functions as a damage associated molecular pattern that stimulates the innate immune response. The central hypothesis of this proposal is that depletion of nuclear HMGB1 in keratinocytes drives carcinogenesis in RDEB by promoting inflammation and accelerating genome instability. This hypothesis will be tested through two specific aims investigating the effects of sequestering HMGB1 in the nucleus. The first aim explores the impact of altered HMGB1 localization on inflammatory response and genomic instability in RDEB keratinocytes. The second aim evaluates the usefulness of small molecule inhibitors of HMGB1 secretion in preventing tumor formation using an in vivo mouse model of RDEB. Successful completion of these aims will provide new information on the biological function of HMGB1 in patients with RDEB SCC. The results of this study have the potential to reveal new drug targets for a fragile patient population in desperate need of safe and effective treatment options. This proposal will be completed at the University of Minnesota under the co-mentorship of Dr. Jakub Tolar, a physician-scientist and pediatric oncologist specializing in RDEB, and Dr. Anja-Katrin Bielinsky, an expert in genome maintenance and DNA repair defects in the initiation of cancer. The complementary expertise of the co- sponsors uniquely positions the candidate to complete the aims described in this proposal and achieve her goal of becoming an academic pediatric hematologist-oncologist leading a research lab focused on examining mechanisms underlying rare genetic diseases and cancer. The career development and fellowship training plans outlined in this application build the foundation for a long and productive career investigating better treatments for pediatric patients with complex and difficult-to-treat genetic conditions.