Decoupling Bidirectional EphB/ephrinB2 in Multiple Myeloma

多发性骨髓瘤中双向 EphB/ephrinB2 的解偶联

• 批准号: 10611460
• 负责人: Joshua P Sasine
• 金额: $ 25.69万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611460
• 关键词: Angiogenesis Inhibitors; Animals; Antibodies; Award; Binding Sites; Biology; Blood Cells; Blood Vessels; Bone Marrow; Bone Marrow Cells; Cancer Biology; Cancer Model; Cell Surface Receptors; Cell Therapy; Cells; Clinical; Collaborations; Data; Dedications; Dependence; Development; Development Plans; Disease; Disease Progression; Doctor of Philosophy; Drug resistance; Education; Endothelial Cells; Eph Family Receptors; Ephrin B Receptor; Ephrins; Event; Family; Family member; Foundations; Genetic Transcription; Goals; Growth; Hematologic Neoplasms; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; Immunoglobulin Fragments; Immunologics; Impairment; Intervention; K-Series Research Career Programs; Knowledge; Laboratories; Life Expectancy; Ligands; Malignant - descriptor; Malignant Neoplasms; Mediating; Mediator; Medical; Membrane; Mentors; Mentorship; Multiple Myeloma; Mus; Outcome; PTK2 gene; Pathogenesis; Pathologic; Pathology; Patients; Phenotype; Plasma Cells; Population; Process; Proliferating; Proteins; Receptor Protein-Tyrosine Kinases; Recurrence; Relapse; Research; Research Training; Role; STAT3 gene; Scientist; Signal Pathway; Signal Transduction; Site-Directed Mutagenesis; Stimulus; Techniques; Testing; Therapeutic; Training; Vascular Endothelial Cell; Work; angiogenesis; arm; bioluminescence imaging; burden of illness; cancer cell; career; career development; cell behavior; cell motility; clinical care; clinical training; design; experimental study; in vivo; in vivo evaluation; insight; knowledge base; novel therapeutics; pharmacologic; preservation; programs; protective effect; receptor; skills; small hairpin RNA; stem cell biology; success; targeted treatment; tool; transcriptome sequencing; tumor progression

Project Summary/Abstract My research objectives are to study the impact of decoupling the EphB4/ephrinB2 axis in multiple myeloma (MM), a cancer of antibody-secreting plasma cells, and the mechanisms through which outcomes of decoupling occur. The Eph/ephrin family is the largest family of receptor tyrosine kinases. Eph/ephrin interactions mediate bidirectional signaling events in juxtaposed cells. Our preliminary studies suggest that Eph/ephrin interactions between MM and bone marrow endothelial cells (BMECs) are required for MM pathogenesis. MM is the most common primary bone marrow malignancy and although recent advances in treatment have prolonged the life expectancy of patients suffering with this disease, it remains incurable and inexorably fatal. Understanding of the biology of MM will reveal vulnerabilities that will lead to the development of targeted therapies for malignant plasma cells. Additionally, our preliminary studies regarding Eph/ephrin signaling provide important new insights into the pathological reciprocity of cancer cells and their microenvironmental neighbors. Here, we will use new tools to decouple the partnership of the Eph receptor/ephrin interaction. Historically, separating influences of such signaling events was less feasible. Now armed with advanced tools, we propose to dissect the bidirectionality inherent in this signaling pathway and provide a new insight into the pathological basis of MM. My primary short-term goals are to combine my scientific research and clinical care into a medically relevant and scientifically rigorous endeavor, while expanding my scientific skillset and progressing toward an independent research program. This award, training plan, and scientific aims are a critical step in the merger of my clinical and research training. I plan to lead a laboratory program dedicated to furthering the understanding of hematopoietic cancer pathology and discovering new therapeutic avenues. Long-term, I plan to become a leader in hematopoietic malignancies and cellular therapy. My training outline, mentorship plan, and scientific strategy are constructed to best reach my goals. This plan builds on my strong foundation in hematopoietic stem cell biology to transition into cancer biology. The career development plan includes expanding my skillset to include 1) building relevant in vivo cancer models; 2) didactic and hands-on training in developing an expanded knowledge base, scientific research tools, and techniques relevant to cancer biology; 3) transition to independence, supported by the completion of the aims of this award. This proposed track has already been initiated and the strong preliminary results, I believe, predict a high likelihood of success.

项目概要/摘要 我的研究目标是研究 EphB4/ephrinB2 轴解耦对多发性骨髓瘤的影响 （MM），一种分泌抗体的浆细胞癌症，以及解耦结果的机制 发生。 Eph/ephrin 家族是最大的受体酪氨酸激酶家族。 Eph/肝配蛋白相互作用介导 并列细胞中的双向信号传导事件。我们的初步研究表明 Eph/ephrin 相互作用 MM 发病机制需要 MM 和骨髓内皮细胞 (BMEC) 之间的相互作用。 MM 是最常见的原发性骨髓恶性肿瘤，尽管最近治疗方法取得了进展 延长了患有这种疾病的患者的预期寿命，但它仍然无法治愈且不可阻挡 致命的。了解 MM 的生物学将揭示其弱点，从而导致靶向药物的开发 恶性浆细胞的治疗。此外，我们关于 Eph/ephrin 信号传导的初步研究提供了 关于癌细胞及其微环境邻居的病理相互作用的重要新见解。 在这里，我们将使用新工具来解耦 Eph 受体/肝配蛋白相互作用的伙伴关系。从历史上看， 分离此类信号事件的影响不太可行。现在配备了先进的工具，我们建议 剖析该信号通路固有的双向性，并为病理学提供新的见解 MM的基础。 我的主要短期目标是将我的科学研究和临床护理结合起来 相关且科学严谨的努力，同时扩展我的科学技能并朝着 独立研究计划。该奖项、培训计划和科学目标是合并的关键一步 我的临床和研究培训。我计划领导一个实验室项目，致力于加深理解 造血系统癌症病理学的研究并发现新的治疗途径。从长远来看，我计划成为一名 造血系统恶性肿瘤和细胞治疗领域的领导者。 我的培训大纲、指导计划和科学策略都是为了最好地实现我的目标而制定的。这 该计划建立在我在造血干细胞生物学方面的坚实基础上，以过渡到癌症生物学。这 职业发展计划包括扩展我的技能，包括1）建立相关的体内癌症模型； 2） 开发扩展知识库、科学研究工具和知识的教学和实践培训 与癌症生物学相关的技术； 3）在完成目标的支持下过渡到独立 这个奖项。这条拟议的轨道已经启动，我相信，强有力的初步结果预示着 成功的可能性很高。