Research Specialist Support for Defining the Roles of Bone Marrow Adipocytes and FABP4/5 Signaling in Multiple Myeloma

研究专家支持定义骨髓脂肪细胞和 FABP4/5 信号转导在多发性骨髓瘤中的作用

• 批准号: 10516510
• 负责人: Heather F Campbell
• 金额: $ 9.96万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-12 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10516510
• 关键词: 3-Dimensional; Adipocytes; Adipose tissue; Automobile Driving; Bone Marrow; Cancer Model; Cell Culture Techniques; Cells; Disease Progression; Drug resistance; Environment; FABP4 gene; FABP5 gene; Fatty Acids; Fatty acid glycerol esters; Goals; Growth; Hematopoietic Neoplasms; In Vitro; Individual; Intervention; Lead; Link; Malignant Neoplasms; Multiple Myeloma; Mus; Mutate; Nature; Patients; Persons; Plasma Cells; Proteins; Quality of life; Research; Risk; Role; Seeds; Signal Transduction; Silk; Soil; Source; Specialist; Testing; Thinness; Tissue Engineering; Work; bone; cancer drug resistance; cytokine; experimental study; fatty acid-binding proteins; high body mass index; improved; in vivo Model; mouse model; neoplastic cell; novel; novel therapeutics; response; scaffold; tumor; tumor growth; tumor progression

Project Summary Cancer develops and ultimately flourishes due to both the nature of the tumor cells themselves as well as the microenvironment or ‘soil’ in which the tumor thrives. Multiple myeloma, a blood cancer that results from mutated plasma cells, grows in the rich soil of the bone marrow causing breakdown of the bone. The risk of developing myeloma is greater in older individuals and people with high body mass index who also typically have more bone marrow adipose tissue, or fat, than younger or leaner individuals. However, the relationship between bone marrow adipocytes (fat cells) and myeloma cells, as well as the specific mechanisms by which bone marrow adipocytes modulate myeloma disease progression are not well understood. Therefore, we aim to identify novel therapeutic avenues for the treatment of multiple myeloma patients by unlocking new vulnerabilities specific to the interactions between myeloma cells and bone marrow adipocytes, which can serve as a source of fatty acids and pro-myeloma cytokines. Our cell culture studies suggest bone marrow adipocytes induce drug resistance in myeloma cells- recapitulating a common problem for myeloma patients. We have found that one mechanism of cross-talk linking adipocytes with myeloma cells is through proteins called fatty acid-binding proteins 4 and 5 (FABP4 and FABP5). We will analyze how bone marrow adipocytes contribute to myeloma by using novel, three-dimensional (3D), tissue engineered cancer models which consist of bone marrow adipocytes and myeloma cells grown together on silk scaffolds. By growing myeloma cells in these 3D mini-bone environments, we can determine how myeloma cells change in response to adipocytes and discover new ways to target this interaction. We will also use our novel mouse models to study bone marrow adipocyte- myeloma crosstalk by increasing or removing bone marrow adipocytes in mice and quantifying effects on tumor growth and drug resistance. We will use these in vitro and in vivo models to specifically test the role of FABP4 and FABP5 in tumor progression and drug resistance, and work toward our long-term goal to better understand the molecules and mechanisms driving multiple myeloma growth in the bone marrow, and how cancer hijacks this niche for its own purposes. This proposal supports this endeavor by providing support for a Research Specialist to further develop, lead, and execute the experiments described which interrogate a novel part of the cellular “soil” (the bone marrow adipocyte), in which tumor cells, or “seeds” land and grow.

项目摘要 由于肿瘤细胞本身的性质以及肿瘤细胞的增殖， 肿瘤生长的微环境或“土壤”。多发性骨髓瘤是一种血液癌症， 突变的浆细胞，生长在骨髓的肥沃土壤中，导致骨骼破裂。的风险 发生骨髓瘤在老年人和高体重指数的人中更常见， 比年轻或较瘦的人有更多的骨髓脂肪组织。然而， 骨髓脂肪细胞（脂肪细胞）和骨髓瘤细胞之间的关系，以及 骨髓脂肪细胞调节骨髓瘤疾病进展的机制还不清楚。因此，我们旨在 通过解锁新的治疗方法来确定治疗多发性骨髓瘤患者的新治疗途径， 骨髓瘤细胞和骨髓脂肪细胞之间相互作用的特异性弱点， 作为脂肪酸和促骨髓瘤细胞因子的来源。我们的细胞培养研究表明骨髓 脂肪细胞诱导骨髓瘤细胞的耐药性--这是骨髓瘤患者的一个常见问题。 我们发现脂肪细胞与骨髓瘤细胞之间的一种交联机制是通过蛋白质 脂肪酸结合蛋白4和5（FABP4和FABP5）。我们将分析骨髓脂肪细胞 通过使用新的三维（3D）组织工程癌症模型， 由骨髓脂肪细胞和骨髓瘤细胞组成，它们一起生长在丝支架上。通过骨髓瘤的生长 细胞在这些3D迷你骨环境中，我们可以确定骨髓瘤细胞如何响应 并发现针对这种相互作用的新方法。我们还将使用我们的新型小鼠模型， 通过增加或去除小鼠骨髓脂肪细胞来研究骨髓脂肪细胞-骨髓瘤串扰 以及量化对肿瘤生长和耐药性的影响。我们将使用这些体外和体内模型， 专门测试FABP4和FABP5在肿瘤进展和耐药性中的作用，并致力于我们的研究。 长期目标是更好地了解在多发性骨髓瘤中驱动多发性骨髓瘤生长的分子和机制。 以及癌症如何劫持这个利基为自己的目的。本提案支持这一努力 为研究专家提供支持，以进一步开发、领导和执行实验 描述了询问细胞“土壤”（骨髓脂肪细胞）的新部分，其中肿瘤 细胞或"种子"降落并生长。