The Role of Ceramides in the Pancreatic Beta Cell
神经酰胺在胰腺β细胞中的作用
基本信息
- 批准号:10592412
- 负责人:
- 金额:$ 55万
- 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:2022-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:Adipose tissueAnabolismAnimal ModelApoptosisApoptoticAutoimmuneBeta CellBiological AssayBiological MarkersBiotechnologyBlood GlucoseCarbohydratesCell SurvivalCell physiologyCellsCeramidesCessation of lifeConsumptionCytoprotectionDataDetergentsDevelopmentDiabetes MellitusDiseaseDrug KineticsEnzymesFailureFamilyFatty AcidsGenesGlucoseGrowthHormonesHumanHyperglycemiaImmunologicsImpairmentInbred NOD MiceInduction of ApoptosisInflammationInflammatoryInsulinIntestinal permeabilityIslets of LangerhansIsotopesLinkLipidsLiverMacronutrients NutritionMembraneMetabolicMetabolismMitochondriaModelingMolecularMusMuscleNatural regenerationNon-Insulin-Dependent Diabetes MellitusNutrientNutritionalOrganismPancreasPathway interactionsPharmaceutical PreparationsPharmacodynamicsPhenotypePopulationProductionPropertyRattusRepressionRodentRodent ModelRoleSafetySaturated Fatty AcidsScienceSignal TransductionSkeletal MuscleSolubilitySphingolipidsStressStructure of beta Cell of isletTestingTherapeuticTissuesTransgenic MiceTreatment EfficacyWorkaqueousbiological adaptation to stresscell regenerationcytokinedetection of nutrientdiabeticdihydroceramidedihydroceramide desaturasedrug candidateefficacy testingimpaired glucose toleranceimprovedin vivoinhibitorinsulin secretionisletislet xenograftmetabolomicsmouse modelnovelnovel therapeuticsoverexpressionpeptide hormonepharmacologicpi bondpreservationpreventsaturated fatsingle cell sequencingsmall molecule inhibitortheoriestherapeutic evaluationtherapeutic targettooltype I and type II diabetesuptake
项目摘要
SUMMARY
This proposal explores the hypothesis that sphingolipids such as ceramides serve as common, cell-autonomous
signals that impair beta cell function and contribute to the development of type 1 and type 2 diabetes. The idea
is predicated upon data presented herein showing that the administration of a pharmacological inhibitor of
ceramide biosynthesis to rodents preserves the beta cell and prevents the development of both forms of the
disease (i.e. in Zucker Diabetic Fatty rats as well as Non-Obese Diabetic mice). The theory is further supported
by studies in human and mouse islets implicating ceramides as intermediates linking saturated fatty acids and
inflammatory cytokines to the impairment of insulin secretion, mitochondrial function, and beta cell survival. We
will evaluate this hypothesized role for ceramides and its metabolites in the pancreatic islet through the following
aims:
· First, we will study new mouse models allowing for the conditional, beta cell-specific modulation of genes
involved in ceramide synthesis or degradation, allowing us to determine whether the lipids are either (a)
necessary or (b) sufficient for beta cell failure and the onset of frank hyperglycemia.
· Second, we will test the efficacy of a new class of ceramide synthesis inhibitors targeting dihydroceramide
desaturase-1 as therapeutics that improve insulin secretion and prevent type 1 or type 2 diabetes in
rodents.
· Third, we will determine the mechanisms through which ceramides impair the function of mouse and
human islets. We will test a hypothesized role for ceramides as drivers of metabolic reprogramming using
state-of-the-art metabolic tracing, mitochondrial phenotyping, and cell function assays.
Findings obtained from these studies could uncover new nutrient-sensing and/or inflammatory mechanisms that
modulate islet function, survival and growth. Moreover, the translational component of this work could lead to
the development of new therapeutic alternatives for preventing or treating diabetes.
摘要
这一建议探索了神经酰胺等鞘磷脂作为普通的、细胞自主的
损害β细胞功能并导致1型和2型糖尿病发生的信号。这个想法
是基于这里提供的数据表明,给药一种药物抑制剂
神经酰胺对啮齿动物的生物合成保护了β细胞,并防止了这两种形式的
疾病(即Zucker糖尿病肥胖大鼠和非肥胖糖尿病小鼠)。这一理论进一步得到了支持
通过对人和小鼠的胰岛进行研究,发现神经酰胺是连接饱和脂肪酸和
炎性细胞因子对胰岛素分泌、线粒体功能和β细胞存活的损害。我们
将通过以下方式评估神经酰胺及其代谢物在胰岛中的这一假设作用
目标:
·首先,我们将研究新的小鼠模型,允许对基因进行有条件的、β细胞特异性的调制
参与神经酰胺的合成或降解,使我们能够确定脂类是否为(A)
(B)对于β细胞衰竭和出现明显的高血糖来说是必要的或足够的。
·第二,我们将测试一类针对二氢神经酰胺的新型神经酰胺合成抑制剂的疗效
去饱和酶-1用于改善胰岛素分泌和预防1型或2型糖尿病的治疗
啮齿动物。
·第三,我们将确定神经酰胺损害小鼠和
人类的小岛。我们将测试神经酰胺作为代谢重编程驱动因素的假设作用。
最先进的新陈代谢跟踪、线粒体表型和细胞功能分析。
从这些研究中获得的发现可能会揭示新的营养感知和/或炎症机制
调节胰岛功能、存活和生长。此外,这项工作的翻译部分可能会导致
开发预防或治疗糖尿病的新的治疗替代品。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Germline and conditional ghrelin knockout increases islet size.
- DOI:10.1172/jci175799
- 发表时间:2023-12-15
- 期刊:
- 影响因子:15.9
- 作者:Tatum, Sean M.;Holland, William L.
- 通讯作者:Holland, William L.
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
WILLIAM L HOLLAND其他文献
WILLIAM L HOLLAND的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('WILLIAM L HOLLAND', 18)}}的其他基金
The Role of Ceramides in the Pancreatic Beta Cell
神经酰胺在胰腺β细胞中的作用
- 批准号:
10467400 - 财政年份:2022
- 资助金额:
$ 55万 - 项目类别:
Liver-islet and intra-islet cross talk in alpha cell hyperplasia and beta cell regeneration
α细胞增生和β细胞再生中的肝胰岛和胰岛内串扰
- 批准号:
10540191 - 财政年份:2017
- 资助金额:
$ 55万 - 项目类别:
Liver-islet and intra-islet cross talk in alpha cell hyperplasia and beta cell regeneration
α细胞增生和β细胞再生中的肝胰岛和胰岛内串扰
- 批准号:
10654025 - 财政年份:2017
- 资助金额:
$ 55万 - 项目类别:
Sphingolipid-Mediated Dysregulation of Glucose and Energy Homeostasis in the CNS
鞘脂介导的中枢神经系统葡萄糖和能量稳态失调
- 批准号:
9077406 - 财政年份:2016
- 资助金额:
$ 55万 - 项目类别:
Sphingolipid-Mediated Dysregulation of Glucose and Energy Homeostasis in the CNS
鞘脂介导的中枢神经系统葡萄糖和能量稳态失调
- 批准号:
9893862 - 财政年份:2016
- 资助金额:
$ 55万 - 项目类别:
Sphingolipid-Mediated Dysregulation of Glucose and Energy Homeostasis in the CNS
鞘脂介导的中枢神经系统葡萄糖和能量稳态失调
- 批准号:
9220827 - 财政年份:2016
- 资助金额:
$ 55万 - 项目类别:
Adiponectin Receptors and S1P Signaling in Beta Cell Survival and Proliferation
脂联素受体和 S1P 信号在 Beta 细胞存活和增殖中的作用
- 批准号:
8914600 - 财政年份:2014
- 资助金额:
$ 55万 - 项目类别:
Adiponectin Receptors and S1P Signaling in Beta Cell Survival and Proliferation
脂联素受体和 S1P 信号在 Beta 细胞存活和增殖中的作用
- 批准号:
8889773 - 财政年份:2014
- 资助金额:
$ 55万 - 项目类别:
Adiponectin Receptors and S1P Signaling in Beta Cell Survival and Proliferation
脂联素受体和 S1P 信号在 Beta 细胞存活和增殖中的作用
- 批准号:
8280387 - 财政年份:2012
- 资助金额:
$ 55万 - 项目类别:
相似海外基金
Bone-Adipose Interactions During Skeletal Anabolism
骨骼合成代谢过程中骨-脂肪相互作用
- 批准号:
10590611 - 财政年份:2022
- 资助金额:
$ 55万 - 项目类别:
Bone-Adipose Interactions During Skeletal Anabolism
骨骼合成代谢过程中的骨-脂肪相互作用
- 批准号:
10706006 - 财政年份:2022
- 资助金额:
$ 55万 - 项目类别:
Bone-Adipose Interactions During Skeletal Anabolism
骨骼合成代谢过程中骨-脂肪相互作用
- 批准号:
10368975 - 财政年份:2021
- 资助金额:
$ 55万 - 项目类别:
BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): Combined long-acting PTH and calcimimetics actions on skeletal anabolism
BCCMA:针对和抵抗不利于骨骼的条件的基础研究(遏制骨折):长效 PTH 和拟钙剂联合作用对骨骼合成代谢的作用
- 批准号:
10365254 - 财政年份:2021
- 资助金额:
$ 55万 - 项目类别:
Bone-Adipose Interactions During Skeletal Anabolism
骨骼合成代谢过程中骨-脂肪相互作用
- 批准号:
10202896 - 财政年份:2021
- 资助金额:
$ 55万 - 项目类别:
BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): Combined long-acting PTH and calcimimetics actions on skeletal anabolism
BCCMA:针对和抵抗不利于骨骼的条件的基础研究(遏制骨折):长效 PTH 和拟钙剂联合作用对骨骼合成代谢的作用
- 批准号:
10531570 - 财政年份:2021
- 资助金额:
$ 55万 - 项目类别:
Dissecting molecular mechanisms implicated in age- and osteoarthritis-related decline in anabolism in articular cartilage
剖析与年龄和骨关节炎相关的关节软骨合成代谢下降有关的分子机制
- 批准号:
10541847 - 财政年份:2019
- 资助金额:
$ 55万 - 项目类别:
Dissecting molecular mechanisms implicated in age- and osteoarthritis-related decline in anabolism in articular cartilage
剖析与年龄和骨关节炎相关的关节软骨合成代谢下降有关的分子机制
- 批准号:
10319573 - 财政年份:2019
- 资助金额:
$ 55万 - 项目类别:
Dissecting molecular mechanisms implicated in age- and osteoarthritis-related decline in anabolism in articular cartilage
剖析与年龄和骨关节炎相关的关节软骨合成代谢下降有关的分子机制
- 批准号:
10062790 - 财政年份:2019
- 资助金额:
$ 55万 - 项目类别:
Promotion of NAD+ anabolism to promote lifespan
促进NAD合成代谢以延长寿命
- 批准号:
DE170100628 - 财政年份:2017
- 资助金额:
$ 55万 - 项目类别:
Discovery Early Career Researcher Award