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

基本信息

批准号：
10683321
负责人：
Heather F Campbell
金额：
$ 9.96万
依托单位：
MAINEHEALTH
依托单位国家：
美国
项目类别：
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

项目摘要

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.

项目概要由于肿瘤细胞本身的性质以及肿瘤细胞的性质，癌症的发展并最终蓬勃发展肿瘤生长的微环境或“土壤” 多发性骨髓瘤是一种由多发性骨髓瘤引起的血癌。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。老年人和体重指数高的人患骨髓瘤的几率更高，他们通常也与年轻或较瘦的人相比，骨髓脂肪组织或脂肪更多，但是，这种关系。骨髓脂肪细胞（脂肪细胞）和骨髓瘤细胞之间的关系，以及具体机制骨髓脂肪细胞调节骨髓瘤疾病进展尚不清楚，因此，我们的目标是。通过解锁新的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特有的脆弱性，这可以我们的细胞培养研究表明骨髓是脂肪酸和促骨髓瘤细胞因子的来源。脂肪细胞诱导骨髓瘤细胞产生耐药性——这是骨髓瘤患者的一个常见问题。我们发现连接脂肪细胞和骨髓瘤细胞的一种机制是通过蛋白质称为脂肪酸结合蛋白 4 和 5（FABP4 和 FABP5），我们将分析骨髓脂肪细胞的作用。通过使用新颖的三维 (3D) 组织工程癌症模型来促进骨髓瘤由骨髓脂肪细胞和骨髓瘤细胞在丝支架上生长而成。通过观察这些 3D 微型骨骼环境中的细胞，我们可以确定骨髓瘤细胞如何响应变化脂肪细胞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来进行研究。通过增加或去除小鼠骨髓脂肪细胞来研究骨髓脂肪细胞-骨髓瘤串扰并量化对肿瘤生长和耐药性的影响。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驱动多发性骨髓瘤生长的分子和机制骨髓，以及癌症如何劫持这一利基以达到其自身目的。该提案支持这一努力。为研究专家进一步开发、领导和执行实验提供支持描述了询问细胞“土壤”（骨髓脂肪细胞）的一个新部分，其中肿瘤细胞或“种子”落地并生长。