HMGB1 in EB-Associated Squamous Cell Carcinoma
HMGB1 in EB-Associated Squamous Cell Carcinoma
批准号:
10676346
负责人:
Kacey Linnea Guenther Bui
金额:
$4.16万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-08-01 至 2027-07-31
关键词:
AccelerationAddressAgeAllelesAttenuatedBasal cell carcinomaBasement membraneBindingBiological MarkersBiological ProcessCOL7A1Cause of DeathCell LineCell NucleusChildhoodChromatinCicatrixClinicalCodeCollagen Type VIIComplexCutaneousDNADNA BindingDNA DamageDNA RepairDNA Repair EnzymesDNA Repair PathwayDNA biosynthesisDefectDevelopmentDiagnosisDiseaseEpidermolysis BullosaEpidermolysis Bullosa DystrophicaEpithelial CellsExposure toExtracellular MatrixExtracellular SpaceFellowshipFibrosisFoundationsGenesGenetic DiseasesGenetic Skin DiseasesGenetic TranscriptionGenomeGenome StabilityGenomic InstabilityGoalsHMGB1 geneHumanIn VitroIncidenceInflammationInflammatoryInflammatory ResponseInnate Immune ResponseKnowledgeLifeLocationLongevityMaintenanceMalignant Epithelial CellMalignant NeoplasmsMelanoma CellMembrane ProteinsMentorshipMinnesotaMolecularMusMutagensMutationNatureNuclearNuclear ProteinOncologistOxidation-ReductionPathogenesisPathway interactionsPatientsPatternPediatric HematologistPediatric OncologistPhysiciansPlayPositioning AttributePost-Translational Protein ProcessingPreventionProductionProductivityProteinsResearchRoleScientistSerumSeverity of illnessSignal PathwaySignal TransductionSiteSkinSquamous cell carcinomaStimulator of Interferon GenesTLR4 geneTP53 geneTestingTimeTrainingTumor Suppressor ProteinsUniversitiesattenuationcancer initiationcarcinogenesiscareercareer developmentcell injurycell transformationchemical carcinogenesischronic woundcytokinedisease-causing mutationearly onseteffective therapyhealingimprovedin vivoin vivo Modelinflammatory milieuinhibitorkeratinocytemouse modelmutantnew therapeutic targetpatient populationpediatric patientspreventprimary endpointprotein functionprotein protein interactionpublic health relevancerare genetic disorderreceptor for advanced glycation endproductsrecruitresponseskin squamous cell carcinomasmall molecule inhibitortumortumor progressiontumorigenesiswoundwound healing
中文摘要
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。
英文摘要
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.
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