Functional Landscape of Glycosylation in Skin Cancer

皮肤癌中糖基化的功能景观

• 批准号: 10581094
• 负责人: Matthew Robert Kudelka
• 金额: $ 18.26万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581094
• 关键词: 3-Dimensional; ATAC-seq; Address; Animals; Antibodies; Binding Proteins; Biological Models; Biology; CRISPR screen; Carbohydrates; Cause of Death; Cells; Complementary DNA; Data; Development; Disease; Environment; Epidermis; Foundations; Genetic; Genetic Models; Genome; Glycobiology; Glycoproteins; Glycoside Hydrolases; Grant; Heterogeneity; Histologic; Human Cell Line; Image; Incidence; Individual; Injections; Knowledge; Label; Leadership; Learning; Lentivirus; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Medical Oncologist; Medical Oncology; Memorial Sloan-Kettering Cancer Center; Mentorship; Metabolic; Methods; Microscopy; Modeling; Modification; Monosaccharides; Mus; Neoplasm Metastasis; Oncoproteins; Papilloma; Pathway interactions; Phase; Physicians; Polysaccharides; Positioning Attribute; Post-Translational Protein Processing; Post-Translational Regulation; Postdoctoral Fellow; Protein Glycosylation; Proteins; Recurrence; Regulation; Research; Research Personnel; Role; Scientist; Signal Transduction; Site; Skin; Skin Cancer; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Squamous cell carcinoma; Structure; Techniques; Technology; Testing; Time; Tissues; Training; Tumor Biology; Tumor Suppressor Proteins; Universities; Visualization; Work; cancer genetics; career; chemotherapy; clinical translation; drug candidate; first-in-human; functional genomics; glycoproteomics; glycosylation; high-throughput drug screening; improved; in utero; in vivo; insight; keratinocyte; mortality; mouse model; multimodality; mutant; nanobodies; new therapeutic target; novel; novel therapeutics; skin squamous cell carcinoma; small molecule; therapeutic candidate; transcriptome sequencing; transcriptomics; tumor; tumorigenesis

PROJECT SUMMARY/ABSTRACT Squamous cell carcinoma is a major cause of death worldwide. Despite advances in cancer genetics, alterations in post-translational modifications are poorly understood. Protein glycosylation is the most abundant PTM and altered in cancer. Glycans are not directly encoded in the genome but rather are comprised of up to ten monosaccharides in various linkages to form thousands of structures, making their structural and functional characterization challenging and largely unknown in SCC. To address this, I propose to use murine skin as a highly tractable model system to study altered glycosylation, downstream consequences, and identify novel therapies. In the K99, I will use glycan binding proteins, metabolic labeling, advanced microscopy, MALDI imaging, glycomics, glycoproteomics, and single cell transcriptomics to spatially map glycosylation and identify specific glycan and glycoprotein changes in a genetic, multi-hit, histologically progressive model of SCC from papilloma to SCC, before chemotherapy, and after recurrence (Aim I). Next in the K99, I will use our in utero lentivirus technology to transduce epidermis and perform a large-scale, unbiased, in vivo, functional genomics screen of the ~700 glycogenes to define the role of glycosylation in SCC (Aim II). Lastly in the R00, I will combine glycoproteomics, single cell transcriptomics of the tumor and microenvironment, protein-specific glycan editing, and high-throughput drug screens to identify mechanisms of glycan-driven tumorigenesis and novel therapeutic candidates (Aim III). My background in glycobiology, medical oncology, and mentorship from leading skin and cancer biologist Dr. Elaine Fuchs at the outstanding training environments at Rockefeller University and Memorial Sloan Kettering Cancer Center, as a postdoctoral and medical oncology fellow, will position me to tackle these important questions and learn techniques, knowledge, and leadership to establish a career as a leading independent investigator and physician-scientist in cancer glycobiology.

项目摘要/摘要 鳞状细胞癌是世界范围内的主要死亡原因。尽管癌症遗传学取得了进展，但基因突变 在翻译后修饰中，人们对此知之甚少。蛋白质糖基化是最丰富的PTM和 在癌症中发生了改变。糖链并不直接编码在基因组中，而是由多达10个糖链组成。 单糖在不同的连接中形成数千种结构，使它们具有结构和功能 在鳞状细胞癌中具有挑战性和鲜为人知的特征。为了解决这个问题，我建议用小鼠皮肤作为 高度易处理的模型系统，用于研究糖基化改变、下游后果，并确定新的 治疗。在K99中，我将使用葡聚糖结合蛋白、代谢标记、高级显微镜、MALDI 成像、糖组学、糖蛋白组学和单细胞转录组学，以空间定位糖基化和识别 遗传性、多发作性、组织学进展性鳞癌模型中特定糖链和糖蛋白的变化 从乳头状瘤到鳞癌，化疗前和复发后(目标I)。接下来在K99中，我将使用我们的宫内 慢病毒技术转导表皮并进行大规模、无偏见的在体功能基因组学 筛选~700个糖基因以确定糖基化在鳞癌中的作用(AIM II)。最后，在R00中，我将结合 糖蛋白组学，肿瘤和微环境的单细胞转录组学，蛋白质特异的糖链编辑， 和高通量药物筛选，以确定多糖驱动的肿瘤发生机制和新的治疗方法 候选人(目标III)。我在糖生物学、内科肿瘤学方面的背景，以及从领先的皮肤和 癌症生物学家Elaine Fuchs博士在洛克菲勒大学杰出的培训环境中 纪念斯隆·凯特琳癌症中心，作为博士后和肿瘤学内科研究员，将把我定位为 解决这些重要问题，学习技术、知识和领导力，以建立自己的职业生涯 癌症糖生物学领域领先的独立研究员和内科科学家。