ROLE OF NRF2 IN NITRERGIC MEDIAITED STOMACH MOTILITY

NRF2 在氮介导的胃动力中的作用

基本信息

批准号：
10004085
负责人：
PANDU R GANGULA
金额：
$ 36.38万
依托单位：
MEHARRY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-12 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004085
关键词：
Adenoviruses Affect Age Animals Antioxidants Applications Grants Biochemical Biological Biological Assay Biological Availability CUL1 gene CUL3 gene Chronic Complications of Diabetes Mellitus Data Defect Development Diabetes Mellitus Diabetic mouse Diet Dimerization Disease Drug Metabolic Detoxication Erythroid Estradiol Estrogens Exclusion Female Functional disorder Gastric Emptying Gastrointestinal Motility Gastroparesis Gene Expression Gene Transfer Genes Glycogen Synthase Kinases Goals Gonadal Steroid Hormones Hyperglycemia Impairment In Vitro Insulin-Dependent Diabetes Mellitus Intervention Intestinal permeability Link Measures Mechanics Mediating Methods Molecular Mus NF-E2-related factor 2 Neurons Nitrergic Neurons Nitric Oxide Nitric Oxide Synthase Type I Nuclear Obesity Oxidative Stress Pathogenicity Pathway interactions Periodontal Diseases Pharmacology Phase Play Progesterone RBX1 gene Reactive Oxygen Species Regulation Relaxation Research Rodent Rodent Model Role SOD2 gene Stomach Supplementation Syndrome Systemic disease Testing Transfection Type 2 diabetic Wild Type Mouse Woman Xenobiotics antioxidant enzyme antioxidant therapy catalase cell motility cofactor copper zinc superoxide dismutase diabetic diabetic gastroparesis diabetic patient dysbiosis enzyme activity experience female sex hormone glutathione peroxidase glycogen synthase kinase 3 beta gut microbiome in vivo motility disorder mouse model novel oxidation periodontopathogen receptor restoration stomach motility tetrahydrobiopterin transcription factor type I diabetic ubiquitin-protein ligase vector

项目摘要

Gastroparesis is a common complication of diabetes and can involve pathogenic oxidative stress. In rodent models, reduced nitric oxide (NO) bioavailability as a result of neuronal nitric oxide synthase (nNOS) uncoupling and increased reactive oxygen species (ROS) has been shown to play a role in delayed gastric emptying. The transcription factor nuclear factor (erythroid-derived-2)-like 2 (NRF2) regulates the expression of Phase II antioxidant and detoxification genes. Preliminary studies in rodent model of diabetes showed that the expression of NRF2 and its target genes, Gclc and Gclm, is suppressed while oxidative stress is elevated. We have demonstrated that loss of NRF2 (Nfe2/2-/-) resulted in decreased levels of tetrahydrobiopterin (BH4, a critical cofactor for nNOS dimerization and enzyme activity) and that this led to oxidative stress, uncoupling of nNOS, reduced NO levels, gastric nitrergic neuron dysfunction, and delayed gastric emptying compared to age-matched wild-type mice. These data support the notion that loss of NRF2 expression in diabetes impairs antioxidant gene expression, which deregulates NO synthesis, thereby contributing to the development of gastroparesis. We provide evidence that sex hormone, estradiol-17β (E2) mediated NRF2/nNOS expression and function is impaired in the onset of diabetes. In addition, we have shown that glycogen synthase kinase 3beta (GSK-3β) or E2 regulate the synthesis of NO in female stomachs. This data suggest that loss of NRF2 expression during hyperglycemia is a consequence of activation of a GSK-3β/CUL1/SCF/TrCP/RBX1 axis. Our central hypothesis is that nitrergic mediated gastric motility is regulated by NRF2. Specific Aim 1: will test the hypothesis that loss of NRF2 expression during hyperglycemia is a consequence of activation of a GSK-3β/CUL1/SCF/TrCP/RBX1 axis; Specific Aim 2: will test the hypothesis that restoration of NRF2 and NRF2-regulated antioxidant enzyme expression in diabetes will result in normal gastric motility and gastric emptying; and Specific Aim 3: will test the hypothesis that NRF2 and nNOS mediated gastric motility are regulated by female sex hormones; 17-estradiol (E2), progesterone and/or their gastric receptors in diabetic animals. Specific Aim 4: Investigate whether periodontal pathogens inhibit gastrointestinal (GI) motility in obese/diabetic female mice. The data from these studies will provide important information as to the mechanisms of regulation of NRF2-mediated nNOS function and thereby enhance our understanding of the pathophysiology of gastroparesis. The research outlined in these aims has translational relevance as it has the potential to identify novel treatment options for diabetes-induced gastroparesis.

胃轻瘫是糖尿病的常见并发症，可能涉及致病性氧化应激，在啮齿动物模型中，神经元一氧化氮合酶 (nNOS) 解偶联和活性氧 (ROS) 增加导致一氧化氮 (NO) 生物利用度降低。转录因子核因子（红细胞衍生 2）样 2 (NRF2) 调节 II 相抗氧化剂和糖尿病啮齿动物模型的初步研究表明，NRF2 及其靶基因 Gclc 和 Gclm 的表达受到抑制，而氧化应激则升高。四氢生物蝶呤（BH4，nNOS 二聚化和酶活性的关键辅助因子）水平，这会导致氧化应激，解偶联与年龄匹配的野生型小鼠相比，nNOS、NO 水平降低、胃氮能神经元功能障碍和胃排空延迟这些数据支持这样的观点，即糖尿病中 NRF2 表达的丧失会损害抗氧化基因的表达，从而使 NO 合成失调，从而导致糖尿病。我们提供的证据表明性激素、雌二醇-17β (E2) 介导的 NRF2/nNOS 表达和功能在糖尿病发作时受到损害。我们已经证明，糖原合酶激酶 3β (GSK-3β) 或 E2 调节女性胃中 NO 的合成。该数据表明，高血糖期间 NRF2 表达的丧失是 GSK-3β/CUL1/SCF/TrCP 激活的结果。 /RBX1 轴。我们的中心假设是氮能介导的胃运动受 NRF2 调节。具体目标 1：将检验 NRF2 缺失的假设。高血糖期间的表达是 GSK-3β/CUL1/SCF/TrCP/RBX1 轴激活的结果；具体目标 2：将检验糖尿病中 NRF2 和 NRF2 调节的抗氧化酶表达的恢复将导致胃运动正常的假设和胃排空；以及具体目标 3：将检验 NRF2 和 nNOS 介导的胃运动受女性性激素调节的假设；糖尿病动物中的 17-雌二醇 (E2)、黄体酮和/或其胃受体。具体目标 4：研究牙周病原体是否抑制肥胖/糖尿病雌性小鼠的胃肠道 (GI) 运动。这些研究的数据将提供有关以下方面的重要信息。 NRF2 介导的 nNOS 功能的调节机制，从而增强我们对胃轻瘫病理生理学的理解。相关性，因为它有可能为糖尿病引起的胃轻瘫确定新的治疗方案。

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）

SARS-CoV-2 Infection and Oral Health: Therapeutic Opportunities and Challenges.

SARS-CoV-2 感染和口腔健康：治疗机遇和挑战。

DOI：
发表时间：
2021-01-05
期刊：
影响因子：
0
作者：
Coke, Christopher J;Davison, Brandon;Fields, Niariah;Fletcher, Jared;Rollings, Joseph;Roberson, Leilani;Challagundla, Kishore B;Sampath, Chethan;Cade, James;Farmer;Gangula, Pandu R
通讯作者：
Gangula, Pandu R

Impairment of Nrf2- and Nitrergic-Mediated Gastrointestinal Motility in an MPTP Mouse Model of Parkinson's Disease.

帕金森病 MPTP 小鼠模型中 Nrf2 和氮能介导的胃肠动力受损。