Endoplasmic Reticulum Stress, Brain and Obesity
内质网应激、大脑和肥胖
基本信息
- 批准号:10000892
- 负责人:
- 金额:$ 62.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-06-18 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdipocytesAdipose tissueAffectAlgorithmsAllelesAntidiabetic DrugsAppetite DepressantsAwardBody WeightBody Weight decreasedBrainCardiovascular DiseasesCellsChemicalsChronicDNADependovirusDesire for foodDevelopmentDietDiseaseDistalDrug ScreeningEnergy MetabolismEngineeringEnterobacteria phage P1 Cre recombinaseExposure toExpression ProfilingFDA approvedGene Expression ProfilingGoalsHormonesHumanHypertensionHypothalamic structureIndividualInjectionsInsulinInterleukin-1 ReceptorsKidney DiseasesKnockout MiceLaboratoriesLeadLeptinLeptin resistanceLongevityMediatingMediator of activation proteinMedicalMedicineMethodologyModelingMolecularMolecular BiologyMolecular ChaperonesMolecular Mechanisms of ActionMolecular TargetMusNatureNeuronsNon-Insulin-Dependent Diabetes MellitusObese MiceObesityPeripheralPharmaceutical PreparationsPhasePhenotypePlayPopulationProcessProteinsPublishingQuality of lifeResearchResistanceResistance developmentRoleSF1Signal TransductionStructure of nucleus infundibularis hypothalamiSystems BiologyTechniquesTherapeuticTherapeutic AgentsThinnessTimeTranslatingTranslationsUp-Regulationbariatric surgerybasedb/db mousediabeticendoplasmic reticulum stressenergy balanceexperimental studyimprovedin silicoinsulin sensitivityleptin receptormathematical algorithmmouse modelmutantneural networknonalcoholic steatohepatitisnovelobesity developmentobesity treatmentpreventprogramsresponserestorationside effecttime usetripterine
项目摘要
Obesity is a major cause for the development of debilitating diseases such as type-2 diabetes, cardiovascular
disease, hypertension, renal diseases, non-alcoholic steatohepatitis (NASH), all of which reduce life quality as
well as lifespan. Despite enormous efforts to develop anti-obesity medications, the drugs that are currently
available have had only marginal effects (in the range of 3–10%) on body weight, and most have been
withdrawn from the market owing to their side effects. Therefore, there is an urgent need for safe and effective
medical treatments for obesity
Leptin, an adipose tissue-derived hormone that communicates the status of peripheral energy reserves
to the brain has robust influence on appetite suppression and on increasing energy expenditure. These
features of leptin initially created great excitement for the treatment of obesity; however the development of
leptin resistance in the brains of obese individuals has prevented its use as an effective anti-obesity
therapeutic. We and others have previously shown that increased Endoplasmic Reticulum (ER) stress in leptin-
responsive neurons in the brain plays a central role in the development of leptin resistance, and consequently
of obesity. To translate our molecular biology discoveries into treatment, we used systems biology approaches
and unconventional in-silico drug screens powered with mathematical algorithms, to target ER stress. We have
discovered Celastrol and Withaferin A as powerful chemical chaperones that alleviate ER stress, restore
insulin and leptin sensitivity, and reduce the bodyweight of obese mice to lean levels. The effect of Celastrol on
bodyweight (~45-50% reduction) is stronger than that which follows bariatric surgery.
We have subsequently focused on the molecular mechanisms of action of Celastrol in increasing leptin
sensitivity. These efforts revealed interleukin 1 receptor 1 (IL1R1) as an intermediate mediator of Celastrol's
action: we have shown that IL1R1 KO mice are completely resistant to Celastrol's leptin sensitizing and anti-
obesity effect.
Our proposal is based on these previous observations and has three Specific Aims. Aim 1 and
Aim 2 focus on identification of hypothalamic neuron populations that mediate Celastrol's anti-obesity and anti-
diabetic effects. Furthermore, these aims plan to determine the contribution of each identified neuron
population to the different aspects of Celastrol's anti-obesity and anti-diabetic effects. Aim3 proposes to
determine the molecular mechanisms of Celastrol action and utilizes state-of-art techniques to identify
molecular networks affected by Celastrol. The ultimate goal of this aim is to determine the exact target of
Celastrol in mediating leptin sensitization and consequently its anti-obesity and anti-diabetic effects.
肥胖是导致衰弱性疾病如2型糖尿病、心血管疾病和糖尿病的主要原因。
疾病,高血压,肾脏疾病,非酒精性脂肪性肝炎(NASH),所有这些都会降低生活质量,
以及寿命。尽管在开发抗肥胖药物方面做出了巨大努力,但目前
现有的药物对体重只有轻微的影响(在3-10%的范围内),并且大多数药物
由于其副作用而退出市场。因此,迫切需要安全有效的
肥胖症的药物治疗
瘦素,一种脂肪组织来源的激素,可传达外周能量储备的状态
对抑制食欲和增加能量消耗有强大的影响。这些
瘦素的特性最初为肥胖的治疗创造了巨大的兴奋;然而,
肥胖者大脑中的瘦素抵抗阻止了它作为有效的减肥药的使用
有治疗作用的我们和其他人以前已经表明,增加内质网(ER)的压力,在瘦素-
大脑中的反应神经元在瘦素抵抗的发展中起着重要作用,因此,
肥胖症。为了将我们的分子生物学发现转化为治疗,我们使用了系统生物学方法
和非传统的计算机药物筛选,以数学算法为动力,以靶向ER应激。我们有
发现雷公藤红素和Withaferin A作为强大的化学伴侣,可以缓解ER应激,
胰岛素和瘦素敏感性,并将肥胖小鼠的体重降低至瘦水平。雷公藤红素对
体重(约45-50%减少)比减肥手术后更强。
我们随后集中在雷公藤红素增加瘦素的分子作用机制
灵敏度这些努力揭示了白细胞介素1受体1(IL 1 R1)作为南蛇藤酚的中间介体
作用:我们已经表明,IL 1 R1基因敲除小鼠对雷公藤红素的瘦素致敏和抗-
肥胖效应
我们的建议是基于这些以前的意见,并有三个具体目标。目标1和
目的2:鉴定雷公藤红素抗肥胖和抗肥胖作用的下丘脑神经元群。
糖尿病的影响此外,这些目标计划确定每个已识别神经元的贡献
在不同的人群中,雷公藤红素的抗肥胖和抗糖尿病作用的不同方面。AIM 3建议
确定雷公藤红素作用的分子机制,并利用最先进的技术来鉴定
分子网络受到雷公藤红素的影响。这一目标的最终目标是确定
雷公藤红素介导瘦素致敏作用及其抗肥胖和抗糖尿病作用。
项目成果
期刊论文数量(0)
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Umut Ozcan其他文献
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{{ truncateString('Umut Ozcan', 18)}}的其他基金
The In Vivo Role of JNK-1 and IRS-1 Ser307 Phosphorylation In Development of Insu
JNK-1 和 IRS-1 Ser307 磷酸化在 Insu 发育中的体内作用
- 批准号:
8003722 - 财政年份:2010
- 资助金额:
$ 62.98万 - 项目类别:
The In Vivo Role of JNK-1 and IRS-1 Ser307 Phosphorylation In Development of Insu
JNK-1 和 IRS-1 Ser307 磷酸化在 Insu 发育中的体内作用
- 批准号:
8210936 - 财政年份:2008
- 资助金额:
$ 62.98万 - 项目类别:
The In Vivo Role of JNK-1 and IRS-1 Ser307 Phosphorylation In Development of Insu
JNK-1 和 IRS-1 Ser307 磷酸化在 Insu 发育中的体内作用
- 批准号:
7572946 - 财政年份:2008
- 资助金额:
$ 62.98万 - 项目类别:
The In Vivo Role of JNK-1 and IRS-1 Ser307 Phosphorylation In Development of Insu
JNK-1 和 IRS-1 Ser307 磷酸化在 Insu 发育中的体内作用
- 批准号:
7751212 - 财政年份:2008
- 资助金额:
$ 62.98万 - 项目类别:
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