Targeting Diabetes With Novel SERCA Allosteric Activators
利用新型 SERCA 变构激活剂治疗糖尿病
基本信息
- 批准号:10573471
- 负责人:
- 金额:$ 34.65万
- 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:2022-02-16 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAgonistAnimal ModelAnimalsApoptosisBeta CellBiological AssayBlood GlucoseCa(2+)-Transporting ATPaseCalciumCell DeathCell SurvivalCell physiologyCellsChemicalsClinicalCultured CellsDataDefectDevelopmentDiabetes MellitusDiseaseEndoplasmic ReticulumEnzymesEpidemicEquilibriumFatty LiverFunctional disorderGenetic ModelsGlucoseGoalsHealthHepatocyteHigh Fat DietHomeostasisHumanHyperglycemiaHypoglycemiaImpairmentIn VitroIncidenceInsulinInsulin ResistanceKnockout MiceKnowledgeLeadMediatingMedicalMetabolicMetabolic DiseasesMetabolic PathwayMetabolismMitochondriaModalityModelingMusNon-Insulin-Dependent Diabetes MellitusObese MiceObesityOutcomePharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPhysiologicalPropertyPumpSeriesSocietiesSpecificityTestingTherapeuticThinnessToxic effectanaloganimal databasebiological adaptation to stresscell injurydesigndiabetes mellitus therapydiabeticendoplasmic reticulum stressexperimental studyglucose metabolismglucose toleranceimprovedin vitro Assayin vivoinnovationinsulin secretioninsulin sensitivitylead seriesliver metabolismloss of functionnovelnovel strategiespreservationscaffoldsmall moleculetherapy developmenttranslational applicationstranslational potentialuptake
项目摘要
Obesity and insulin resistance are major causes of type 2 diabetes, representing an enormous
health burden to societies worldwide. Major perturbations associated with diabetes are
abnormalities in calcium homeostasis and substrate metabolism, and induction of insulin
resistance. Interestingly, disruption of endoplasmic reticulum (ER) Ca2+ levels caused primarily
by impaired function of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) has been
demonstrated to trigger ER stress in liver and β cell leading to the development of insulin
resistance in obesity and diabetes conditions. Thus, targeting dysfunctional SERCA2 will
alleviate aberrant ER stress and associated disorders in diabetes. We pharmacologically
activated SERCA2b in a genetic model of insulin resistance and type 2 diabetes (ob/ob mice)
with a novel class of small molecules that allosterically activate SERCA enzyme and rescue ER
stress-induced cell death. These compounds are amenable to optimization for potency, and
have enormous potential to treat diabetes. Studies in animal models of diabetes show
significant improvement in glucose tolerance, hepatic steatosis and metabolism, and
preservation of β-cell function and survival. Through medicinal chemistry and analoging
strategies, we aim in this proposal to conduct compound optimization of these novel series of
SERCA activators and profile them more extensively in vitro and in vivo for further development
as SERCA-based therapeutic modalities to treat diabetes and its complications.
肥胖和胰岛素抵抗是2型糖尿病的主要原因,代表了巨大的风险。
给全世界社会带来健康负担。与糖尿病相关的主要扰动是
钙稳态和底物代谢异常,以及胰岛素诱导
阻力有趣的是,内质网(ER)Ca 2+水平的破坏主要引起
由于肌浆网/内质网Ca 2 +-ATP酶(SERCA)功能受损,
证实可触发肝脏和β细胞中的ER应激,导致胰岛素的产生
抵抗肥胖和糖尿病。因此,靶向功能失调的SERCA 2将
减轻糖尿病中异常的ER应激和相关疾病。我们
在胰岛素抵抗和2型糖尿病的遗传模型(ob/ob小鼠)中激活SERCA 2b
用一类新型的小分子,变构激活SERCA酶并拯救ER,
应激诱导的细胞死亡这些化合物适合于优化效力,并且
在治疗糖尿病方面有巨大的潜力。对糖尿病动物模型的研究表明,
显著改善葡萄糖耐量、肝脂肪变性和代谢,以及
保持β细胞功能和存活。通过药物化学和类比
战略,我们的目的是在这个建议进行复合优化这些新的系列,
SERCA激活剂,并在体外和体内对其进行更广泛的分析,以进一步开发
作为基于SERCA的治疗方式来治疗糖尿病及其并发症。
项目成果
期刊论文数量(0)
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{{ truncateString('DJAMEL LEBECHE', 18)}}的其他基金
Molecular and Metabolic phenotype of Impaired AdipoR1 in the Heart
心脏中 AdipoR1 受损的分子和代谢表型
- 批准号:
9902515 - 财政年份:2017
- 资助金额:
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Genes and miRNAs controlled by ORAI3 in cardiovascular remodeling
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Genes and miRNAs controlled by ORAI3 in cardiovascular remodeling
ORAI3在心血管重塑中控制的基因和miRNA
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9334046 - 财政年份:2016
- 资助金额:
$ 34.65万 - 项目类别:
Targeting Diabetes With Novel Small Molecule Therapeutics
用新型小分子疗法治疗糖尿病
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9001399 - 财政年份:2015
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$ 34.65万 - 项目类别:
Genetic Analysis of microRNAs Function in Diabetic Cardiomyopathy
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8495395 - 财政年份:2010
- 资助金额:
$ 34.65万 - 项目类别:
Genetic Analysis of microRNAs Function in Diabetic Cardiomyopathy
糖尿病心肌病中 microRNA 功能的遗传分析
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8107677 - 财政年份:2010
- 资助金额:
$ 34.65万 - 项目类别:
Genetic Analysis of microRNAs Function in Diabetic Cardiomyopathy
糖尿病心肌病中 microRNA 功能的遗传分析
- 批准号:
8284424 - 财政年份:2010
- 资助金额:
$ 34.65万 - 项目类别:
Genetic Analysis of microRNAs Function in Diabetic Cardiomyopathy
糖尿病心肌病中 microRNA 功能的遗传分析
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7983115 - 财政年份:2010
- 资助金额:
$ 34.65万 - 项目类别:
Electrical Remodeling and Cardiac Hypertrophy and Signa*
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$ 34.65万 - 项目类别:
Electrical Remodeling and Cardiac Hypertrophy and Signa*
电重塑和心脏肥大及信号*
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6886754 - 财政年份:2004
- 资助金额:
$ 34.65万 - 项目类别:
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