Myeloid cells, aging and the metabolic syndrome

骨髓细胞、衰老和代谢综合征

• 批准号: 8702069
• 负责人: Xiaoxia Li
• 金额: $ 19.81万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8702069
• 关键词: Address; Affect; Age; Age-associated memory impairment; Aging; Animals; Applications Grants; Atherosclerosis; Blood Cells; Blood Circulation; Brain; CX3CL1 gene; Cell Aging; Cells; Cholesterol; Clinical; Cognition; Cognitive; Cytokine Signaling; Data; Dementia; Diet; Fatty Liver; Fatty acid glycerol esters; Genetic Recombination; Hippocampus (Brain); Human; IL1R1 gene; ITGAM gene; Immune; Immunologic Deficiency Syndromes; Individual; Inflammation; Inflammatory; Injection of therapeutic agent; Insulin Resistance; Interleukin-1 Receptors; Learning; Long-Term Potentiation; Memory; Metabolic syndrome; Microglia; Motor; Mus; Myelogenous; Myeloid Cells; Natural Immunity; Neuraxis; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pathway interactions; Peripheral; Pharmaceutical Preparations; Population; Protocols documentation; Reaction; Research; Risk Factors; Role; Signal Transduction; Specific qualifier value; Steatohepatitis; Syndrome; TLR3 gene; Tamoxifen; Testing; Time; Tissues; Toll-like receptors; age related; age related cognitive change; aged; behavior test; cell age; cognitive function; cytokine; feeding; improved; macrophage; monocyte; morris water maze; neurophysiology; novel; object recognition; public health relevance; research study

DESCRIPTION (provided by applicant): Inflammation contributes to metabolic syndrome, including insulin resistance and atherosclerosis. Further, metabolic syndrome represents a risk factor for age-related dementias. This proposal focuses on the role of MyD88, required for signaling from cytokine and Toll Like Receptors. We showed that selective deletion of MyD88 from myeloid cells virtually eliminated diet-induced metabolic syndrome in obese mice. Here we extend this research to effects of inflammatory signaling for age-related cognitive decline in aging obese mice with or without metabolic syndrome. The present proposal addresses the hypothesis that deleting MyD88 from all CD11b+ myeloid cells will ameliorate age-related cognitive impairment in mice with obesity but without metabolic syndrome. Furthermore, we propose that selective deletion of MyD88 from microglia will also reduce age-related cognitive impairment in mice with metabolic syndrome, without affecting the systemic syndrome. Importantly, MyD88 appears functionally orthologous in humans and mice, and its absence does not cause unacceptable immunodeficiency suggesting the pathway is potentially druggable. The specific aims are: 1. Establish whether ameliorating metabolic syndrome in MyD88fl/fl::CD11bCre mice on high-fat diet (HFD) is associated with improvement of age-related cognitive change. MyD88fl/fl::CD11bCre mice will be placed on HFD or chow and undergo serial behavior testing as well as hippocampal long-term potentiation (LTP). Pathological analyses of peripheral and CNS tissues will be performed. These data will address whether declining cognition is ameliorated in aging mice fed HFD by blocking innate immune reactions of myeloid cells and reducing metabolic syndrome systemically. 2. Determine if reduced microglial reaction in tamoxifen-injected MyD88fl/fl::CX3CR1(ER)-Cre mice on high-fat diet (HFD) improves age-related cognitive change. We anticipate that MyD88fl/fl::CD11bCre mice lacking myeloid-cell MyD88 will show improved age-related cognition as compared to controls. The mechanisms however could be exerted either systemically, in the CNS or both. The CX3CR1(ER)-Cre driver efficiently deletes 'floxed' targets from CX3CR1+ cells, and recombination is highly-selective for microglia by about one month after induction. MyD88fl/fl::CX3CR1(ER)- Cre mice will receive tamoxifen to induce recombination and will be placed on HFD or chow. Mice will be subjected to serial behavior testing and hippocampal LTP as in Aim 1. Focused pathological and immunohistochemical analyses of the peripheral and CNS tissues will be performed. These data will address whether declining cognition in aging mice is ameliorated by blocking innate immunity in microglia despite systemic metabolic syndrome. Data from these experiments will contribute to our knowledge of the systemic and CNS mechanisms by which metabolic syndrome-associated inflammation worsens cognitive function in aging individuals and will identify salient peripheral and CNS treatment targets.

描述(申请人提供)：炎症导致代谢综合征，包括胰岛素抵抗和动脉粥样硬化。此外，代谢综合征是与年龄相关的痴呆的危险因素。这项建议侧重于MyD88的作用，它是细胞因子和Toll样受体发出信号所必需的。我们发现，选择性地从髓系细胞中删除MyD88实际上消除了肥胖小鼠中饮食诱导的代谢综合征。在这里，我们将这项研究扩展到炎症信号对伴有或不伴有代谢综合征的老年肥胖小鼠年龄相关认知能力下降的影响。目前的建议解决了这样的假设，即从所有CD11b+髓系细胞中删除MyD88将改善肥胖但没有代谢综合征的小鼠的年龄相关认知障碍。此外，我们建议选择性地从小胶质细胞中删除MyD88也将减少代谢综合征小鼠与年龄相关的认知障碍，而不影响全身综合征。重要的是，MyD88在人类和小鼠中似乎在功能上是同源的，它的缺失并不会导致不可接受的免疫缺陷，这表明该途径可能是可药物的。具体目的是：1.建立高脂饮食(HFD)改善MyD88fl/fl：：CD11bCre小鼠代谢综合征是否与改善增龄相关的认知改变有关。MyD88fl/fl：：CD11bCre小鼠将被置于高脂饲料或饲料中，并接受一系列行为测试以及海马长时程增强(LTP)。将进行外周和中枢神经系统组织的病理分析。这些数据将解决是否通过阻断髓系细胞的先天免疫反应和系统性地减少代谢综合征来改善服用HFD的老龄小鼠认知能力下降的问题。2.确定高脂饮食(HFD)下注射他莫昔芬的MyD88fl/fl：：CX3CR1(ER)-Cre小鼠的小胶质细胞反应减少是否改善了与年龄相关的认知改变。我们预计，与对照组相比，缺乏髓系细胞MyD88的MyD88fl/fl：：CD11bCre小鼠将表现出更好的年龄相关认知能力。然而，这些机制可以在系统地、在中枢神经系统或在两者中实施。CX3CR1(ER)-Cre驱动程序有效地删除CX3CR1+细胞中的“花状”靶标，重组对小胶质细胞具有高度选择性，诱导后约一个月。MyD88fl/fl：：CX3CR1(ER)-Cre小鼠将接受他莫昔芬诱导重组，并将被放置在HFD或食物中。小鼠将接受一系列的行为学测试和海马区的LTP测试，并对周围和中枢组织进行重点病理和免疫组织化学分析。这些数据将解决是否通过阻断小胶质细胞的天然免疫来改善衰老小鼠认知能力下降的问题，尽管存在全身代谢综合征。这些实验的数据将有助于我们了解代谢综合征相关炎症导致老年人认知功能恶化的系统和中枢神经系统机制，并将确定重要的外周和中枢神经系统治疗靶点。