Branched chain amino acids and pancreatic cancer
支链氨基酸与胰腺癌
基本信息
- 批准号:10688001
- 负责人:
- 金额:$ 45.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:ATP Citrate (pro-S)-LyaseAcetyl Coenzyme AAcetylationAcinar CellAllograftingBiological MarkersBranched-Chain Amino AcidsCatabolismCell ProliferationCell SurvivalCellsCholesterolCitratesCitric Acid CycleClinicalClinical TrialsConsumptionCytoplasmDairy ProductsDataDevelopmentDiabetes MellitusDiagnosisDietDiseaseDuct (organ) structureEnvironmentEpigenetic ProcessEvaluationFatty AcidsFatty acid glycerol estersFeedbackFibroblastsGeneticGenetic ModelsGoalsGrantGrowthGrowth FactorHistonesHumanHyperinsulinismIn VitroIncidenceInsulinInsulin ResistanceIslets of LangerhansIsotopesKRAS2 geneKRASG12DLinkLocationMalignant NeoplasmsMalignant neoplasm of pancreasMeat ProductsMediatingMetabolicMetabolismMetaplasiaMitochondriaMusNuclearNutritionalObesityPancreasPancreatic Ductal AdenocarcinomaPancreatic Intraepithelial NeoplasiaPancreatic ductPatientsPlasmaPlayPrognosisRiskRisk FactorsRoleSignal TransductionSourceSurvival RateTestingTracerTumor PromotionUnresectableWorkamino acid metabolismcancer typechemotherapycurative treatmentsdietarygain of functionimprovedin vivoinhibitorinsightinsulin secretioninsulin signalingloss of functionmouse modelmutantnovelnovel strategiesnovel therapeutic interventionnutritionobese personpancreatic ductal adenocarcinoma cellpancreatic ductal adenocarcinoma modelpancreatic neoplasmpancreatic tumorigenesispharmacologicresponsestandard of caretreatment responsetumortumor growthtumor initiationtumor progressiontumorigenesiswound healingyoung adult
项目摘要
PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDA) remains one of the most intractable types of cancer,
with a 5-year survival rate below 9%. Alarmingly, the incidence of pancreatic cancer is on the
rise over the past 20 years, with particularly sharp increases in incidence among young adults.
Poor nutrition and obesity are likely culprits, with obesity and diabetes independently conferring
increased risk of PDA, but the mechanisms remain unclear.
Branched chain amino acids (BCAAs) have emerged as one potentially important link between
diet, systemic metabolism, and PDA. We have demonstrated in previous work and preliminary
data that BCAAs are avidly consumed by the pancreas, where they contribute prominently to
the TCA cycle and to acetyl-CoA pools. We have also recently shown that acetyl-CoA
metabolism plays a key role in facilitating pancreatic tumor initiation, leading to the hypothesis
that BCAA metabolism is required for efficient pancreatic tumorigenesis. Thus, one major goal
of this grant will be to test the role of BCAA catabolism in the pancreas in facilitating acinar cell
plasticity and tumor formation. We will use state-of-the-art in vivo isotope tracer approaches to
elucidate the fates of BCAAs in the pancreas. We will also employ nutritional, genetic (using
two novel mouse models), and pharmacological approaches to define the roles of BCAA
catabolism in pancreatic function and tumorigenesis.
In contrast to normal pancreatic cells, use of BCAAs as a fuel source is thought to be
suppressed as pancreatic cancer develops. Nevertheless, BCAAs are an important biomarker
of PDA, with circulating levels elevated years prior to PDA diagnosis, indicating a risk that likely
mechanistically differs from that of tumor initiation. BCAAs are also elevated in obesity and
diabetes, where they promote insulin secretion and insulin resistance, promoting a
hyperinsulinemic state. Insulin itself acts as a growth factor to promote anabolic signaling and
metabolism in PDA cells. Our second major goal is thus to evaluate the contribution of systemic
BCAA levels and hyperinsulinemia to PDA tumor growth. We will manipulate systemic BCAA
levels through nutritional, genetic, and pharmacological approaches to test the impact on tumor
growth. We will then query the impact of insulin directly on PDA cells and on cancer-associated
fibroblasts (CAFs), along with the impact of reducing hyperinsulinemia on tumor growth. Finally,
we will test the potential to target BCAA metabolism through mouse clinical trials.
These studies will provide deep insight into the roles of BCAAs in multi-step PDA tumorigenesis
and could lead to novel therapeutic strategies for this deadly disease.
项目总结
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Whole-body metabolic fate of branched-chain amino acids.
- DOI:10.1042/bcj20200686
- 发表时间:2021-02-26
- 期刊:
- 影响因子:4.1
- 作者:Blair, Megan C.;Neinast, Michael D.;Arany, Zoltan
- 通讯作者:Arany, Zoltan
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Zoltan P Arany其他文献
Zoltan P Arany的其他文献
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{{ truncateString('Zoltan P Arany', 18)}}的其他基金
Comprehensive quantification of fuel use in cold-induced thermogenesis in vivo
体内冷诱导生热过程中燃料使用的综合量化
- 批准号:
10637680 - 财政年份:2023
- 资助金额:
$ 45.59万 - 项目类别:
High-throughput screening for modulators of vascular fat transport to treat and prevent diabetes
高通量筛选血管脂肪转运调节剂以治疗和预防糖尿病
- 批准号:
10343859 - 财政年份:2021
- 资助金额:
$ 45.59万 - 项目类别:
High-throughput screening for modulators of vascular fat transport to treat and prevent diabetes
高通量筛选血管脂肪转运调节剂以治疗和预防糖尿病
- 批准号:
10331230 - 财政年份:2021
- 资助金额:
$ 45.59万 - 项目类别:
Keeping fat out of muscle - Role of Branched Amino Acids
保持肌肉中的脂肪——支链氨基酸的作用
- 批准号:
10186735 - 财政年份:2018
- 资助金额:
$ 45.59万 - 项目类别:
Keeping fat out of muscle - Role of Branched Amino AcidsAmino Acids in Insulin Resistance
保持肌肉中的脂肪 - 支链氨基酸氨基酸在胰岛素抵抗中的作用
- 批准号:
10736605 - 财政年份:2018
- 资助金额:
$ 45.59万 - 项目类别:
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