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:10501614
- 负责人:
- 金额:$ 117.85万
- 依托单位:
- 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:
- 关键词:AddressAdipocytesAdipose tissueAffectBasic ScienceBreastBreast Cancer CellBreast Cancer PatientBreast Cancer Risk FactorCellular Metabolic ProcessChronicClinicalComprehensive Cancer CenterConsumptionDataDevelopmentFABP4 geneFatty acid glycerol estersFish OilsFunding OpportunitiesHealthHigh Fat DietHumanImmuneImmunosuppressionImmunotherapyInflammationInsulinInterleukin-6IowaKnockout MiceLeptinLinkLinoleic AcidsLipidsMammary NeoplasmsMeasuresMediatingMetabolicMolecularMolecular ChaperonesMonoclonal AntibodiesMusObesityOleic AcidsOlive oil preparationOmega-3 Fatty AcidsPDL1 pathwayPalmitic AcidsPathway interactionsPeripheralPhenotypePhysician ExecutivesPostmenopausePreventionPrevention strategyRegulationResearchRiskRoleSamplingSerumShapesSourceSpecimenTherapeutic antibodiesThinnessTissuesTreatment EfficacyTumor-DerivedTumor-associated macrophagesUniversitiesUnsaturated FatsWomanXenograft Modeladiponectinbasecancer clinical trialcancer immunotherapycancer riskcocoa butterconditional knockoutdesigndiet-induced obesityepidemiology studyextracellularfatty acid-binding proteinshumanized antibodyimprovedinsightlipid metabolismmacrophagemalignant breast neoplasmmetabolic profilemonocytemortalitymouse modelnew therapeutic targetnovelnovel strategiesnovel therapeutic interventionobesity biomarkersoxidationprogramsresponsesaturated fattargeted biomarkertumortumor growthtumorigenic
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.
本提案的目的是确定高脂饮食(HFD)诱导的脂质失调与肥胖的联系
乳腺癌(BC)风险增加。流行病学研究证实,肥胖会增加
和死亡率,但肥胖/乳腺癌关联的分子机制仍然主要是
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
称为FABP 4)通过调节肿瘤细胞内的促肿瘤活性来促进肥胖相关的BC
相关巨噬细胞(TAM)和细胞外增强BC细胞的侵袭性表型。因此,A-
FABP可能是一个新的因素,将脂质代谢失调与肥胖/BC风险联系起来。而且我们
观察到肥胖可以通过消耗不同类型的HFD来诱导,包括饱和脂肪(例如,
可可脂)或不饱和脂肪(例如橄榄油、鱼油)。然而,只有可可脂HFD诱导的肥胖,
与A-FABP表达增加和乳腺肿瘤生长相关。这些观察表明,
新概念,即并非所有HFD诱导的肥胖都是致瘤性的。考虑到肥胖背后的不确定联系-
诱导BC风险,我们假设富含饱和脂肪的HFD通过A-FABP介导
免疫和代谢调节。因此,A-FABP提供了一种新的治疗靶点和生物标志物,
与肥胖相关的BC风险。三个互补但独立的具体目标旨在解决我们的
中心假设目的1是确定不同HFD上调A-
用于BC风险的FABP。我们将确定哪些HFD会增加乳腺肿瘤的风险,并进一步分析HFD如何“坏”。
脂肪驱动TAM中的细胞内A-FABP表达,并促进细胞外A-FABP分泌,
脂肪细胞目的二是阐明HFD上调A-FABP在BC中的下游代谢机制
风险和免疫治疗。我们将描述TAMs细胞内A-FABP如何调节FA氧化
(FAO)/HIF 2 α/PD-L1通路的免疫抑制功能,然后描绘细胞外A-
FABP重编程BC细胞中的脂质代谢谱以增强其侵袭性表型。我们将进一步
评估用我们独特的人源化抗体阻断A-FABP活性是否改善A-FABP诱导的
代谢失调和降低肥胖/BC风险。目的3是评估A-FABP作为肥胖的生物标志物-
人类的BC。我们将确定外周血单核细胞中A-FABP的功能,并测量A-FABP在外周血单核细胞中的表达。
血清中可溶性A-FABP水平和肿瘤间质中A-FABP表达,
有或没有BC的瘦和肥胖妇女。成功完成这一建议将确定“坏
HFDs”在促进BC风险中的作用,并确定A-FABP介导的分子和代谢机制
HFD诱导的肥胖/BC风险中的促肿瘤活性。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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{{ truncateString('Bing Li', 18)}}的其他基金
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
- 批准号:
10683379 - 财政年份:2022
- 资助金额:
$ 117.85万 - 项目类别:
E-FABP mediates n-3 fatty acid-induced tumor prevention through epigenetic control of immune cell differentiation and function
E-FABP 通过免疫细胞分化和功能的表观遗传控制介导 n-3 脂肪酸诱导的肿瘤预防
- 批准号:
10320058 - 财政年份:2021
- 资助金额:
$ 117.85万 - 项目类别:
E-FABP mediates n-3 fatty acid-induced tumor prevention through epigenetic control of immune cell differentiation and function
E-FABP 通过免疫细胞分化和功能的表观遗传控制介导 n-3 脂肪酸诱导的肿瘤预防
- 批准号:
10544533 - 财政年份:2021
- 资助金额:
$ 117.85万 - 项目类别:
E-FABP mediates n-3 fatty acid-induced tumor prevention through epigenetic control of immune cell differentiation and function
E-FABP 通过免疫细胞分化和功能的表观遗传控制介导 n-3 脂肪酸诱导的肿瘤预防
- 批准号:
10459794 - 财政年份:2021
- 资助金额:
$ 117.85万 - 项目类别:
Immunomodulatory mechanisms of E-FABP in psoriasis pathogenesis
E-FABP在银屑病发病机制中的免疫调节机制
- 批准号:
10459902 - 财政年份:2021
- 资助金额:
$ 117.85万 - 项目类别:
Immunomodulatory mechanisms of E-FABP in psoriasis pathogenesis
E-FABP在银屑病发病机制中的免疫调节机制
- 批准号:
10478125 - 财政年份:2021
- 资助金额:
$ 117.85万 - 项目类别:
Immunomodulatory mechanisms of E-FABP in psoriasis pathogenesis
E-FABP在银屑病发病机制中的免疫调节机制
- 批准号:
9790920 - 财政年份:2018
- 资助金额:
$ 117.85万 - 项目类别:
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