HMGB1 in EB-Associated Squamous Cell Carcinoma

EB 相关鳞状细胞癌中的 HMGB1

• 批准号: 10676346
• 负责人: Kacey Linnea Guenther Bui
• 金额: $ 4.16万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676346
• 关键词: Acceleration; Address; Age; Alleles; Attenuated; Basal cell carcinoma; Basement membrane; Binding; Biological Markers; Biological Process; COL7A1; Cause of Death; Cell Line; Cell Nucleus; Childhood; Chromatin; Cicatrix; Clinical; Code; Collagen Type VII; Complex; Cutaneous; DNA; DNA Binding; DNA Damage; DNA Repair; DNA Repair Enzymes; DNA Repair Pathway; DNA biosynthesis; Defect; Development; Diagnosis; Disease; Epidermolysis Bullosa; Epidermolysis Bullosa Dystrophica; Epithelial Cells; Exposure to; Extracellular Matrix; Extracellular Space; Fellowship; Fibrosis; Foundations; Genes; Genetic Diseases; Genetic Skin Diseases; Genetic Transcription; Genome; Genome Stability; Genomic Instability; Goals; HMGB1 gene; Human; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Knowledge; Life; Location; Longevity; Maintenance; Malignant Epithelial Cell; Malignant Neoplasms; Melanoma Cell; Membrane Proteins; Mentorship; Minnesota; Molecular; Mus; Mutagens; Mutation; Nature; Nuclear; Nuclear Protein; Oncologist; Oxidation-Reduction; Pathogenesis; Pathway interactions; Patients; Pattern; Pediatric Hematologist; Pediatric Oncologist; Physicians; Play; Positioning Attribute; Post-Translational Protein Processing; Prevention; Production; Productivity; Proteins; Research; Role; Scientist; Serum; Severity of illness; Signal Pathway; Signal Transduction; Site; Skin; Squamous cell carcinoma; Stimulator of Interferon Genes; TLR4 gene; TP53 gene; Testing; Time; Training; Tumor Suppressor Proteins; Universities; attenuation; cancer initiation; carcinogenesis; career; career development; cell injury; cell transformation; chemical carcinogenesis; chronic wound; cytokine; disease-causing mutation; early onset; effective therapy; healing; improved; in vivo; in vivo Model; inflammatory milieu; inhibitor; keratinocyte; mouse model; mutant; new therapeutic target; patient population; pediatric patients; prevent; primary endpoint; protein function; protein protein interaction; public health relevance; rare genetic disorder; receptor for advanced glycation endproducts; recruit; response; skin squamous cell carcinoma; small molecule inhibitor; tumor; tumor progression; tumorigenesis; wound; wound healing

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.

项目概要/摘要 隐性营养不良性大疱性表皮松解症（RDEB）是一种罕见的遗传性疾病，其特征是慢性伤口 由于早发性鳞状细胞癌（SCC）的高发病率，寿命缩短。高度 RDEB 患者 SCC 的侵袭性值得进一步的机制研究。高机动组箱1 (HMGB1) 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 尚未得到彻底调查。 HMGB1 是一种染色质相关蛋白，在细胞核中发挥作用 DNA复制和修复的调节剂。为了响应炎症信号，HMGB1 由 细胞核并作为损伤相关分子模式发挥作用，刺激先天免疫反应。 该提案的中心假设是角质形成细胞中核 HMGB1 的耗竭会导致癌变 通过促进炎症和加速基因组不稳定来治疗 RDEB。该假设将通过以下方式进行检验 研究将 HMGB1 隔离在细胞核中的影响的两个具体目标。第一个目标是探索 HMGB1 定位改变对 RDEB 角质形成细胞炎症反应和基因组不稳定性的影响。 第二个目标是评估 HMGB1 分泌的小分子抑制剂在预防肿瘤方面的有效性 使用 RDEB 体内小鼠模型形成。这些目标的成功完成将提供新的 RDEB SCC 患者中 HMGB1 生物学功能的信息。本研究的结果有 为迫切需要安全有效的脆弱患者群体揭示新药物靶点的潜力 治疗方案。 该提案将在明尼苏达大学 Jakub Tolar 博士（Jakub Tolar 博士）的共同指导下完成。 Anja-Katrin Bielinsky 博士是 RDEB 领域的医师科学家和儿科肿瘤学家，也是该领域的专家 癌症发生过程中的基因组维护和 DNA 修复缺陷。共同的互补专业知识 赞助商为候选人提供独特的定位，以完成本提案中描述的目标并实现她的目标 成为一名学术儿科血液学家-肿瘤学家，领导一个专注于检查的研究实验室 罕见遗传病和癌症的潜在机制。职业发展和奖学金培训计划 本申请中概述的内容为研究更好的治疗方法奠定了长期而富有成效的职业生涯的基础 适用于患有复杂且难以治疗的遗传性疾病的儿科患者。