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Nuclear lipid-sensor in Type II Diabetic Neuropathy

II 型糖尿病神经病变中的核脂质传感器

基本信息

批准号：
10338086
负责人：
Virginie Mansuy Aubert
金额：
$ 37.11万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10338086
关键词：
Address Adipocytes Affect Afferent Neurons Agonist Biological Cells Cellular Neurobiology Cholesterol Chronic Clinical Complex Complication Complications of Diabetes Mellitus Cytometry Data Data Analyses Diabetic Neuralgia Diabetic Neuropathies Diet Dietary Fats Disease Dose Dyslipidemias Fatty Acids Fiber Functional disorder Future Genes Genetic Models Genetic Transcription Green Fluorescent Proteins Hepatocyte High Fat Diet Hypersensitivity In Vitro Individual Inflammation Injections LXRalpha protein Lead Ligands Lipids Liver X Receptor Luciferases Measurement Mechanics Mediating Messenger RNA Metabolic syndrome Modeling Molecular Molecular Neurobiology Morbidity - disease rate Mus Nerve Nerve Tissue Nervous System Physiology Neural Conduction Neurons Neuropathy Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Receptors Obesity Oleates Outcome Pain Palmitates Pathogenesis Pathway interactions Peripheral Peripheral Nervous System Phenotype Physiological Play Prediabetes syndrome Public Health Quality of life Receptor Activation Receptor Signaling Reporter Reporting RiboTag Ribosomes Role Sensory Signal Transduction Spinal Ganglia Testing Tissues Tomatoes Translations Type 2 diabetic allodynia diabetic patient drug development endoplasmic reticulum stress fat nutrition study feeding improved in vivo in vivo Model insight lipid metabolism long chain fatty acid macrophage mechanical allodynia mouse model neurophysiology novel obese person particle programs research and development response sensor transcription factor

项目摘要

ABSTRACT Diabetic neuropathy is the most common complication of diabetes, affecting ~ 50% of obese individuals with type II diabetes. Recent clinical and biological evidence indicate that painful type II diabetic neuropathy is highly associated with lipids, but the molecular and cellular neurophysiology underlying these observations is not known. Recent studies comparing dysregulated pathways in the peripheral nervous system (PNS) of individuals with type II diabetic neuropathy highlighted alterations in lipid-sensor nuclear receptor, suggesting a novel possible physiological basis for diabetic neuropathy. Our additional preliminary data suggest that nuclear receptor LXRs expressed in sensory neurons may be involved. This project combines in vivo and in vitro approaches to 1) study LXRs direct activation and as well as the downstream pathways regulated by lipids in sensory neurons, 2) determine whether the LXR pathway contributes to type II diabetic neuropathy in sensory neurons using a neuronal-specific deletion mouse model and high fat diet (HFD)-induced neuropathy models (cre-lox model), 3) to determine if LXR agonist protect against HFD induced neuropathy by regulating pathway(s) in the DRG small sensory neurons (RiboTag model). The central unifying hypothesis is that activation of LXRs in PNS neurons regulates downstream LXR-dependent program to maintain normal PNS function in the face of high-fat nutrition. Chronic rich lipid diets are expected to induce LXR signaling alterations that lead to PNS dysfunction. These studies will begin to decipher the cellular, molecular, and physiological role of lipid-sensor nuclear receptors in peripheral neurons in a type II diabetic mouse model. The results are expected to inform future mechanistic research and drug development aimed at addressing the unmet clinical need to treat neuropathy induced by obesity and its major complication, type II diabetes.

摘要

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

LXR agonist modifies neuronal lipid homeostasis and decreases PGD2 in the dorsal root ganglia in western diet-fed mice.

DOI：
10.1038/s41598-022-14604-0
发表时间：
2022-06-24
期刊：
SCIENTIFIC REPORTS
影响因子：
4.6
作者：
Elshareif, Nadia;Gavini, Chaitanya K.;Mansuy-Aubert, Virginie
通讯作者：
Mansuy-Aubert, Virginie

Communication between the gut microbiota and peripheral nervous system in health and chronic disease.

DOI：
10.1080/19490976.2022.2068365
发表时间：
2022-01
期刊：
GUT MICROBES
影响因子：
12.2
作者：
Cook, Tyler M.;Mansuy-Aubert, Virginie
通讯作者：
Mansuy-Aubert, Virginie

LXR agonist improves peripheral neuropathy and modifies PNS immune cells in aged mice.

DOI：
10.1186/s12974-022-02423-z
发表时间：
2022-02-26
期刊：
Journal of neuroinflammation
影响因子：
9.3
作者：
Gavini CK;Elshareif N;Aubert G;Germanwala AV;Calcutt NA;Mansuy-Aubert V
通讯作者：
Mansuy-Aubert V

Comparison of western diet-induced obesity and streptozotocin mouse models: insights into energy balance, somatosensory dysfunction, and cardiac autonomic neuropathy.

西方饮食诱导的肥胖症和链霉菌素小鼠模型的比较：对能量平衡，体感功能障碍和心脏自主神经神经病的见解。

DOI：
10.3389/fphys.2023.1238120
发表时间：
2023
期刊：
Frontiers in physiology
影响因子：
4
作者：
通讯作者：

Vagal neuron expression of the microbiota-derived metabolite receptor, free fatty acid receptor (FFAR3), is necessary for normal feeding behavior.

DOI：
10.1016/j.molmet.2021.101350
发表时间：
2021-12
期刊：
Molecular metabolism
影响因子：
8.1
作者：
Cook TM;Gavini CK;Jesse J;Aubert G;Gornick E;Bonomo R;Gautron L;Layden BT;Mansuy-Aubert V
通讯作者：
Mansuy-Aubert V