Functional Landscape of Glycosylation in Skin Cancer

皮肤癌中糖基化的功能景观

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要鳞状细胞癌是全世界死亡的主要原因。尽管癌症遗传学取得了进展，但变化人们对翻译后修饰知之甚少。蛋白质糖基化是最丰富的 PTM 和在癌症中发生改变。聚糖并不直接在基因组中编码，而是由多达十个组成单糖通过各种连接形成数千个结构，使其结构和功能 SCC 中的表征具有挑战性且很大程度上未知。为了解决这个问题，我建议使用小鼠皮肤作为高度易于处理的模型系统，用于研究改变的糖基化、下游后果并识别新的疗法。在 K99 中，我将使用聚糖结合蛋白、代谢标记、高级显微镜、MALDI 成像、糖组学、糖蛋白质组学和单细胞转录组学，以空间映射糖基化并识别遗传性、多次打击、组织学进展的鳞状细胞癌模型中的特异性聚糖和糖蛋白变化乳头状瘤至鳞状细胞癌、化疗前和复发后（目标 I）。接下来在 K99 中，我将使用我们的子宫内慢病毒技术可转导表皮并进行大规模、公正的体内功能基因组学研究筛选约 700 个糖原以确定糖基化在 SCC 中的作用（目标 II）。最后在R00中，我将结合糖蛋白质组学、肿瘤和微环境的单细胞转录组学、蛋白质特异性聚糖编辑、和高通量药物筛选，以确定聚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、医学肿瘤学方面的背景，以及来自领先的皮肤和肿瘤学专家的指导癌症生物学家 Elaine Fuchs 博士在洛克菲勒大学出色的培训环境中纪念斯隆凯特琳癌症中心作为一名博士后和肿瘤内科研究员，将使我能够解决这些重要问题并学习技术、知识和领导力，以建立职业生涯癌症糖生物学领域的领先独立研究者和医师科学家。