Investigating CD56 signaling in multiple myeloma growth and immune escape

研究多发性骨髓瘤生长和免疫逃逸中的 CD56 信号传导

• 批准号: 10449807
• 负责人: Francesca Cottini
• 金额: $ 25.32万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-09 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449807
• 关键词: Adult; Advisory Committees; Affect; American; Animal Model; Biology; CREB1 gene; Cell Adhesion; Cell Line; Cell physiology; Cell-Mediated Cytolysis; Cells; Characteristics; Clinical; Clinical Sciences; Clinical Trials; Committee Members; Complement; Comprehensive Cancer Center; Cyclic AMP-Responsive DNA-Binding Protein; Cytotoxic T-Lymphocytes; Data; Deubiquitinating Enzyme; Deubiquitination; Development Plans; Diagnosis; Dialysis procedure; Disease; Doctor of Philosophy; Elderly; Gene Expression; Genetic; Genomics; Goals; Grant; Growth; Health Care Costs; Hematology; Hospital Costs; Human; Immune; Immune response; Immune system; In Vitro; Internal Medicine; Knowledge; Leadership; Learning Skill; Length of Stay; MEKs; Malignant Neoplasms; Mediating; Mentors; Minority; Modeling; Molecular Abnormality; Morbidity - disease rate; Multiple Myeloma; Mus; NCAM1 gene; Names; Natural Killer Cells; Neurons; Ohio; Outcome; Oxidative Regulation; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physicians; Prognosis; Proteins; Quality of life; Recurrence; Recycling; Rehabilitation therapy; Reporting; Research; Resistance; Role; Science; Scientist; Signal Transduction; Surface; Testing; Therapeutic; Toxic effect; Translational Research; Tumor Escape; UCHL1 gene; Universities; Writing; Yang; base; career; career development; cell growth; cell type; cytotoxicity; design; drug development; experience; genomic data; high risk; improved; improved outcome; in vivo Model; individualized medicine; loss of function; overexpression; predictive marker; professor; programs; protein degradation; response biomarker; skills; therapeutically effective; transcription factor; treatment response; tumor; tumor immunology; tumor microenvironment; ubiquitin C-terminal hydrolase

PROJECT SUMMARY/ABSTRACT Francesca Cottini, MD, is a Tenure-eligible Assistant Professor in the Division of Hematology, Department of Internal Medicine (70% research, 30% clinical) at The Ohio State University Comprehensive Cancer Center. Dr. Cottini’s career goal is to become an independent and productive physician scientist whose research will combine aspects of multiple myeloma (MM) pathogenesis and tumor immunology to develop tailored therapies for MM patients. MM is an incurable disease that affects vulnerable adults causing high healthcare costs and poor quality of life. No tailored therapies exist to treat patients with MM, despite major differences in terms of genetic abnormalities, gene expression profiles, or immune signatures. To fill this gap, Dr. Cottini has identified a surface marker, named CD56, which is present in 70 percent of patients and is associated with poor prognosis. Thus far, Dr. Cottini has demonstrated the feasibility of her project with strong preliminary data, showing that CD56 promotes MM growth and tumor escape from the immune system. The main objective of Dr. Cottini’s K08 proposal is to characterize the mechanisms associated with CD56 protumoral phenotype in terms of: 1. MM growth; 2. resistance to anti-MM therapies; 3. regulation of oxidative stress; and 4. escape from natural killer (NK) cell-mediated cytotoxicity. The final step of Dr. Cottini’s proposal is to find strategies to promote CD56 degradation in MM and induce tumor regression. This knowledge will lead to science-driven clinical trials and improve outcomes in high-risk CD56 positive MM patients. To support her pathway to independence, Dr. Cottini has established a mentoring committee consisting of: Drs. Don Benson MD, PhD (Primary Mentor: expertise in MM biology, tumor immunology, and translational and clinical science), Yiping Yang MD, PhD (co-Mentor: expertise in tumor immunology, grant writing, and leadership skills), Bei Liu, PhD (Advisory Committee Member: expertise in MM murine animal models), and Natarajan Muthusamy, DVM, PhD (Advisory Committee Member: expertise in signaling and translational science). She will also take advantages of two additional collaborators, with experience in genomics (Dr. Pearlly Yan) and drug development (Dr. Gerard Hilinski). She formulated a career development plan with objectives of (1) learning skills in tumor immunology, drug development, and animal models; (2) developing knowledge in the analysis and interpretation of genomic data and design of correlatives for clinical trials; (3) improving expertise in leadership, grant writing, and team management. These objectives will complement Dr. Cottini’s current knowledge to help achieving independence as a physician scientist in the field of MM. To conclude, Dr. Cottini’s studies have the potential to identify therapeutic options based on disease characteristics and hence improve outcomes and reduce toxicities in patients.

项目总结/摘要 Francesca Cottini，医学博士，是血液学系的终身助理教授， 俄亥俄州州立大学综合内科（70%研究，30%临床） 癌症中心Cottini博士的职业目标是成为一名独立和富有成效的医生科学家， 研究将结合多发性骨髓瘤（MM）发病机制和肿瘤免疫学方面的联合收割机， 为MM患者量身定制的治疗方案。 MM是一种不治之症，影响脆弱的成年人，导致医疗保健成本高，质量差 生命尽管在遗传学方面存在重大差异，但没有定制的治疗方法来治疗MM患者。 异常、基因表达谱或免疫特征。为了填补这一空白，科提尼博士发现了一种表面 一种名为CD 56的标记物，存在于70%的患者中，与预后不良相关。因此 到目前为止，Cottini博士已经用强有力的初步数据证明了她的项目的可行性，表明CD 56 促进MM生长和肿瘤从免疫系统逃逸。科蒂尼博士的K 08的主要目标是 建议是表征与CD 56促肿瘤表型相关的机制：1. MM 增长; 2.对抗MM疗法的抗性; 3.氧化应激的调节;和4.逃离自然杀手 (NK)细胞介导的细胞毒性。Cottini博士建议的最后一步是找到促进CD 56的策略。 在MM中降解并诱导肿瘤消退。这些知识将导致科学驱动的临床试验， 改善高危CD 56阳性MM患者的预后。 为了支持她的独立之路，Cottini博士成立了一个指导委员会， Don Benson博士（主要导师：MM生物学，肿瘤免疫学和翻译 Yiping Yang MD，PhD（共同导师：肿瘤免疫学专业知识，基金撰写， 领导技能），Bei Liu，PhD（顾问委员会成员：MM鼠动物模型的专业知识），以及 Natarajan Muthusamy，DVM，PhD（咨询委员会成员：信号和翻译专业知识 科学）。她还将利用另外两名具有基因组学经验的合作者（Pearlly博士 Yan）和药物开发（Gerard Hilinski博士）。她制定了职业发展计划，目标是 (1)学习肿瘤免疫学、药物开发和动物模型方面的技能;（2）发展肿瘤免疫学、药物开发和动物模型方面的知识。 基因组数据的分析和解释以及临床试验相关物的设计;（3）提高专业知识 在领导力、基金撰写和团队管理方面。这些目标将补充科蒂尼博士目前的 知识，以帮助实现独立作为一个医生科学家在该领域的MM。 研究有可能根据疾病特征确定治疗方案， 减少患者的不良反应。