Myeloid cells, aging and the metabolic syndrome

描述（由申请人提供）：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，代谢综合征是年龄相关性痴呆的一个危险因素。该提案侧重于MyD 88的作用，其为来自细胞因子和Toll样受体的信号传导所需。我们发现，从骨髓细胞中选择性删除MyD 88几乎消除了肥胖小鼠的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衰老肥胖小鼠中与年龄相关的认知能力下降的影响。目前的提议解决了这样一个假设，即从所有CD 11b+骨髓细胞中删除MyD 88将改善肥胖但没有代谢综合征的小鼠中与年龄相关的认知障碍。此外，我们提出，从小胶质细胞中选择性删除MyD 88也将减少代谢综合征小鼠中与年龄相关的认知障碍，而不影响全身综合征。重要的是，MyD 88在人类和小鼠中表现出功能上的正相关性，并且它的缺失不会引起不可接受的免疫缺陷，这表明该途径可能是可药物化的。具体目标是：1.确定改善高脂饮食（HFD）MyD 88 fl/fl：：CD 11bCre小鼠的代谢综合征是否与年龄相关认知变化的改善相关。将MyD 88 fl/fl：：CD 11bCre小鼠置于HFD或食物上，并进行系列行为测试以及海马长时程增强（LTP）。将对外周和CNS组织进行病理学分析。这些数据将解决是否通过阻断骨髓细胞的先天免疫反应和全身减少代谢综合征来改善喂食HFD的衰老小鼠的认知能力下降。2.确定注射他莫昔芬的MyD 88 fl/fl：：CX 3CR 1（ER）-Cre高脂饮食（HFD）小鼠中小胶质细胞反应的减少是否改善了与年龄相关的认知变化。我们预计，与对照组相比，缺乏骨髓细胞MyD 88的MyD 88 fl/fl：：CD 11bCre小鼠将显示出改善的年龄相关认知。然而，这些机制可以在全身、CNS或两者中发挥作用。CX 3CR 1（ER）-Cre驱动器有效地从CX 3CR 1+细胞中删除“floxed”靶标，并且重组在诱导后约一个月对小胶质细胞具有高度选择性。MyD 88 fl/fl：：CX 3CR 1（ER）- Cre小鼠将接受他莫昔芬以诱导重组，并将被置于HFD或食物上。如目的1所述，对小鼠进行系列行为测试和海马LTP。将对外周和CNS组织进行重点病理学和免疫组织化学分析。这些数据将解决衰老小鼠的认知能力下降是否可以通过阻断小胶质细胞的先天免疫来改善，尽管有全身性代谢综合征。这些实验的数据将有助于我们了解代谢综合征相关炎症损害老年人认知功能的全身和中枢神经系统机制，并将确定突出的外周和中枢神经系统治疗靶点。

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.