Determine the molecular and metabolic mechanisms by which A-FABP links dysregulated lipid metabolism-induced obesity/breast cancer risk

确定 A-FABP 与脂质代谢失调引起的肥胖/乳腺癌风险相关的分子和代谢机制

基本信息

批准号：
10683379
负责人：
Bing Li
金额：
$ 115.28万
依托单位：
UNIVERSITY OF IOWA
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

来源：
https://reporter.nih.gov/project-details/10683379
关键词：
Address Adipocytes Adipose tissue Affect Basic Science Breast Breast Cancer Cell Breast Cancer Patient Breast Cancer Risk Factor Cellular Metabolic Process Chronic Clinical Collaborations Consumption Data Development FABP4 gene Fatty acid glycerol esters Fish Oils Funding Opportunities Health High Fat Diet Holden Comprehensive Cancer Center at the University of Iowa Human Immune Immunosuppression Immunotherapy Inflammation Insulin Interleukin-6 Knockout Mice Leptin Link Linoleic Acids Lipids Macrophage Mammary Neoplasms Measures Mediating Metabolic Modeling Molecular Molecular Chaperones Monoclonal Antibodies Mus Obesity Oleic Acids Olive oil preparation Omega-3 Fatty Acids PDL1 pathway Palmitic Acids Pathway interactions Peripheral Phenotype Physician Executives Postmenopause Prevention Prevention strategy Regulation Research Risk Role Sampling Serum Shapes Source Specimen Therapeutic antibodies Thinness Tissues Treatment Efficacy Tumor-associated macrophages Unsaturated Fats Woman Xenograft procedure adiponectin cancer clinical trial cancer immunotherapy cancer risk cocoa butter conditional knockout design diet-induced obesity epidemiology study extracellular fatty acid-binding proteins humanized antibody improved insight lipid metabolism malignant breast neoplasm metabolic profile monocyte mortality mouse model new therapeutic target novel novel strategies novel therapeutic intervention obesity biomarkers oxidation programs response saturated fat therapeutic biomarker tumor tumor growth tumorigenic

项目摘要

The objective of this proposal is to determine how high fat diet (HFD)-induced lipid dysregulation links obesity with increased breast cancer (BC) risk. Epidemiologic studies have confirmed that obesity increases the risk and mortality of BC, but the molecular mechanisms of obesity/breast cancer associations remain largely unknown. Our recent studies demonstrate that lipid chaperone A-FABP (adipose fatty acid binding protein, also known as FABP4) promotes obesity-associated BC by intracellular regulating pro-tumor activity in tumor associated macrophages (TAMs) and extracellular enhancing aggressive phenotype of BC cells. Thus, A- FABP might represent a new factor linking dysregulated lipid metabolism with obesity/BC risk. Moreover, we observed that obesity can be induced by consumption of different types of HFDs, including saturated fats (e.g. cocoa butter) or unsaturated fats (e.g. olive oil, fish oil). However, only cocoa butter HFD-induced obesity was associated with increased A-FABP expression and mammary tumor growth. These observations suggest a novel concept that not all HFD-induced obesity is tumorigenic. Given the undefined links underlying obesity- induced BC risk, we hypothesized that HFDs rich in saturated fats promote BC risk through A-FABP-mediated immune and metabolic regulations. As such, A-FABP offers a novel therapeutic target and biomarker for obesity-associated BC risk. Three complementary but independent specific aims are designed to address our central hypothesis. Aim 1 is to determine the molecular mechanisms by which different HFDs upregulate A- FABP for BC risk. We will identify which HFDs promote mammary tumor risk and further dissect how the “bad” fat drives intracellular A-FABP expression in TAMs and promotes extracellular A-FABP secretion from adipocytes. Aim 2 is to delineate the downstream metabolic mechanisms of HFD-upregulated A-FABP in BC risk and immunotherapy. We will delineate how intracellular A-FABP in TAMs regulates the FA oxidation (FAO)/HIF2α/PD-L1 pathway for immune suppressive function, followed by delineation of how extracellular A- FABP reprograms lipid metabolic profile in BC cells to enhance their aggressive phenotype. We will further evaluate if blocking A-FABP activity with our unique humanized antibodies improves A-FABP-induced metabolic dysregulation and reduces obesity/BC risk. Aim 3 is to evaluate A-FABP as a biomarker for obesity- associated BC in humans. We will determine the function of A-FABP in peripheral monocytes and measure the levels of soluble A-FABP in serum and A-FABP expression in tumor stroma using specimens collected from lean and obese women with or without BC. Successful completion of this proposal will determine the “bad HFDs” in promoting BC risk and identify the molecular and metabolic mechanisms by which A-FABP mediates the pro-tumorigenic activities in HFD-induced obesity/BC risk.

该提案的目的是确定高脂肪饮食（HFD）诱导的脂质失调的程度乳腺癌（BC）风险增加。流行病学研究证实，肥胖会增加风险卑诗省的死亡率，但肥胖/乳腺癌关联的分子机制在很大程度上仍然存在未知。我们最近的研究表明，脂质伴侣A-FABP（脂肪脂肪酸结合蛋白，也被称为Fabp4）通过细胞内调节性肿瘤活性促进与肥胖相关的BC 相关的巨噬细胞（TAM）和细胞外增强BC细胞的攻击表型。那，A- FABP可能代表了将失调的脂质代谢与肥胖/BC风险联系起来的新因素。而且，我们观察到可以通过消耗不同类型的HFD（包括饱和脂肪）来诱导肥胖症（例如可可黄油）或不饱和脂肪（例如橄榄油，鱼油）。但是，只有可可黄油HFD引起的肥胖是与A-FABP表达增加和乳腺肿瘤生长有关。这些观察表明并非所有HFD诱导的肥胖症都是肿瘤的新颖概念。鉴于肥胖的潜在链接 - 诱发BC风险，我们假设富含饱和脂肪的HFD通过A-FABP介导的促进BC风险免疫和代谢法规。因此，A-FABP提供了一种新颖的治疗靶标和生物标志物肥胖相关的卑诗省风险。三个完整但独立的特定目标旨在解决我们的中央假设。目的1是确定不同HFD上调A-的分子机制 BC风险的FABP。我们将确定哪种HFD促进乳腺肿瘤风险，并进一步剖析“不良” 脂肪在TAM中驱动细胞内A-FABP表达，并促进细胞外A-FABP分泌脂肪细胞。 AIM 2是描述BC中HFD upped A-FABP的下游代谢机制风险和免疫疗法。我们将描述TAM中细胞内A-FABP如何调节FA氧化（粮农组织）/HIF2α/PD-L1途径用于免疫抑制功能，然后描述细胞外A-如何 FABP在BC细胞中重新编程脂质代谢谱，以增强其侵袭性表型。我们将进一步评估使用我们独特的人源化抗体阻止A-FABP活性改善A-FABP诱导的代谢失调和降低肥胖/BC风险。 AIM 3是评估A-FABP作为肥胖症的生物标志物与人类相关的卑诗省。我们将确定A-FABP在外周单核细胞中的功能，并测量使用从有或没有卑诗省有或没有肥胖的妇女。该提案的成功完成将决定“不好 HFD”在促进BC风险并确定A-FABP培养物的分子和代谢机制中 HFD诱导的肥胖/BC风险中的亲肿瘤活动。