Sphingolipid and Fatty Acid Biology in Prediabetes and Neuropathy
糖尿病前期和神经病变中的鞘脂和脂肪酸生物学
基本信息
- 批准号:10612104
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-15 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAmericanApoptosisBiologyCeramidesComplicationComplications of Diabetes MellitusDevelopmentDiabetes MellitusDiabetic NeuropathiesDiabetic mouseDietary InterventionDiseaseDyslipidemiasEconomic BurdenFatty AcidsFoundationsFutureGoalsHigh Fat DietIn VitroIndividualKnockout MiceLimb structureLipidsMediatingMentorsMetabolic dysfunctionMitochondriaMonounsaturated Fatty AcidsMorphologyMotorMusNerveNervous System controlNeuronsNeuropathyNon-Insulin-Dependent Diabetes MellitusNumbnessObese MiceObesityPathway interactionsPeripheral NervesPeripheral Nervous SystemPeripheral Nervous System DiseasesPhasePlasmaPlayPrediabetes syndromePrevalenceProductivityResearchRoleSaturated Fatty AcidsSensorySeveritiesSpectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationSphingolipidsSpinal GangliaStructureSupplementationSymptomsTestingToxic effectTrainingTranscriptType 2 diabeticUnited StatesUnsaturated Fatty Acidsafferent nervecareerdiabetic patientdiet-induced obesitydihydroceramide desaturaseefficacy evaluationfatty acid supplementationimprovedin vivolipidomicsmass spectrometric imagingmitochondrial dysfunctionmouse modelneurotoxicneurotoxicitynew therapeutic targetperipheral nerve damagepreventsciatic nervesuralsural nervetargeted treatmenttherapeutic targettranscriptomics
项目摘要
ABSTRACT
Prediabetes – a condition that precedes type 2 diabetes – affects more than 80 million Americans. Peripheral
neuropathy is a diabetic complication that results in a loss of sensation in the limbs due to peripheral nerve
damage, and it can develop in both type 2 diabetic as well as prediabetic patients. Despite the prevalence and
severity of peripheral neuropathy, there are currently no disease-modifying options. Novel therapeutic targets
are therefore of critical importance for future treatments. Dyslipidemia is characterized by increased levels of
saturated fatty acids in the plasma, resulting in altered levels of sphingolipids. Ceramides are one type of
sphingolipid that are lipotoxic to neurons. Accumulation of saturated fatty acids leads to mitochondrial
dysfunction, and cellular apoptosis and may play a central role in the development of peripheral neuropathy.
However, monounsaturated fatty acids protect neurons from ceramide-mediated toxicity in vitro, likely via the
formation of intracellular lipid droplets. Reversal of ceramide accumulation using monounsaturated fatty acid
supplementation may therefore be an effective strategy for normalizing ceramide profiles and preventing
peripheral neuropathy. We hypothesize that peripheral neuropathy in prediabetes is the result of toxic
ceramide accumulation in neurons in vivo. We further hypothesize that supplementing prediabetic mice with
monounsaturated fatty acids will enhance lipid droplet synthesis in neurons to prevent ceramide accumulation
and subsequent neurotoxicity. We will test these hypotheses by: 1) determining the ceramide profile of
prediabetic mice with neuropathy in both plasma and peripheral nerves, 2) evaluating the efficacy of
monounsaturated fatty acid supplementation on ceramide accumulation in prediabetic mice during neuropathy,
and 3) determining the mechanisms by which ceramides damage the peripheral nervous system as well as
determining the mechanisms by which monounsaturated fatty acid ameliorate this damage. Together, these
studies will demonstrate that dyslipidemia plays a central role in the development of peripheral neuropathy and
provide an immediate therapeutic target for future treatments.
抽象的
糖尿病前期——一种先于 2 型糖尿病的疾病——影响着超过 8000 万美国人。
神经病变是一种糖尿病并发症,由于周围神经的影响导致四肢感觉丧失
尽管其患病率很高,但 2 型糖尿病和糖尿病前期患者都可能出现这种损害。
由于周围神经病变的严重程度,目前没有新的治疗靶点。
因此,对于未来的治疗至关重要。血脂异常的特点是血脂水平升高。
血浆中的饱和脂肪酸会导致鞘脂水平发生变化,神经酰胺就是其中一种。
对神经元具有脂毒性的鞘脂会导致线粒体的饱和脂肪酸积累。
功能障碍和细胞凋亡,可能在周围神经病的发展中发挥核心作用。
然而,单不饱和脂肪酸在体外保护神经元免受神经酰胺介导的毒性,可能是通过
使用单不饱和脂肪酸逆转细胞内脂滴的形成。
因此,补充可能是使神经酰胺谱正常化和预防的有效策略。
我们认为糖尿病前期的周围神经病变是中毒的结果。
我们进一步发现补充糖尿病前期小鼠体内神经酰胺的积累。
单不饱和脂肪酸将增强神经元中的脂滴合成,防止神经酰胺积累
以及随后的神经毒性。我们将通过以下方式测试这些假设:1)确定神经酰胺的特征。
血浆和周围神经均患有神经病变的糖尿病前期小鼠,2)评估
补充单不饱和脂肪酸对糖尿病前期小鼠神经病变期间神经酰胺积累的影响,
3)确定神经酰胺损害周围神经系统的机制以及
确定单不饱和脂肪酸改善这种损害的机制。
研究将证明血脂异常在周围神经病的发展中起着核心作用
为未来的治疗提供直接的治疗目标。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A High-Fat Diet Disrupts Nerve Lipids and Mitochondrial Function in Murine Models of Neuropathy.
- DOI:10.3389/fphys.2022.921942
- 发表时间:2022
- 期刊:
- 影响因子:4
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Amy E. Rumora其他文献
Amy E. Rumora的其他文献
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{{ truncateString('Amy E. Rumora', 18)}}的其他基金
Sphingolipid and Fatty Acid Biology in Prediabetes and Neuropathy
糖尿病前期和神经病变中的鞘脂和脂肪酸生物学
- 批准号:
10476670 - 财政年份:2021
- 资助金额:
$ 24.9万 - 项目类别:
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