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（由申请人提供）：炎症有助于代谢综合征，包括胰岛素抵抗和动脉粥样硬化。此外，代谢综合征代表了与年龄相关的痴呆症的危险因素。该提案的重点是MyD88的作用，MyD88是从细胞因子和像受体TOLL TOLL TOLL的信号所必需的。我们表明，从髓样细胞中选择性删除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传导对患有或没有代谢综合征的衰老肥胖小鼠与年龄相关的认知下降的影响。目前的提议解决了以下假设：从所有CD11b+髓样细胞中删除MYD88将改善与肥胖症但没有代谢综合征的小鼠相关的认知障碍。此外，我们建议从小胶质细胞中选择性删除MyD88还将减少代谢综合征小鼠与年龄相关的认知障碍，而不会影响系统性综合征。重要的是，MYD88在人类和小鼠中在功能上似乎是直系同源的，并且它的缺失并没有引起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。确定在MyD88FL/FL :: CD11BCRE小鼠高脂饮食（HFD）中的改善代谢综合征（HFD）是否与与年龄相关的认知变化的改善有关。 MYD88FL/FL :: CD11BCRE小鼠将放置在HFD或CHOW上，并进行串行行为测试以及海马长期增强（LTP）。将对周围和中枢神经系统组织进行病理分析。这些数据将通过阻止髓样细胞的先天免疫反应并系统地减少代谢综合征的先天免疫反应来解决喂养HFD的老化小鼠的认知下降。 2。确定在他莫昔芬注射MyD88FL/FL :: CX3CR1（ER）-CRE小鼠高脂饮食（HFD）中的小胶质细胞反应是否会改善与年龄相关的认知变化。我们预计与对照组相比，缺乏髓样细胞MyD88的MyD88FL :: CD11BCRE小鼠将显示出改善与年龄相关的认知。然而，该机制可以系统地在中枢神经系统或两者兼而有之。 CX3CR1（ER）-CRE驱动器有效地从CX3CR1+细胞中删除了“ Floxed”靶标，并且重组对小胶质细胞高度选择性，在诱导后大约一个月。 MYD88FL/FL :: CX3CR1（ER） - CRE小鼠将接受他莫昔芬诱导重组，并将其放置在HFD或Chow上。如AIM 1所示，小鼠将进行串行行为测试和海马LTP。将进行外围和中枢神经系统组织的聚焦病理和免疫组织化学分析。这些数据将解决尽管全身代谢综合征阻止了小胶质细胞的先天免疫力，是否会通过阻止衰老小鼠的认知下降。来自这些实验的数据将有助于我们了解代谢综合征相关炎症的系统性和中枢神经系统机制，使衰老个体的认知功能恶化，并将确定显着的外围和中枢神经系统治疗靶标。