Adipose inflammation mediates obesity-induced deficits in hippocampal plasticity

脂肪炎症介导肥胖引起的海马可塑性缺陷

• 批准号: 8618375
• 负责人: Alexis M. Stranahan
• 金额: $ 12.25万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-06 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8618375
• 关键词: Address; Adipose tissue; Adult; Age-associated memory impairment; Aging; Award; Blood; Brain; Brain region; Cell Culture Techniques; Chronic; Clinical; Cognition; Data; Dementia; Dendritic Spines; Development Plans; Diabetes Mellitus; Diet; Disease; Endocrine; Environment; Exhibits; Familiarity; Fatty acid glycerol esters; Functional disorder; Funding; Genetic; Goals; Hippocampus (Brain); Immune; Immunology; Impaired cognition; Impairment; Individual; Inflammation; Inflammatory; Interleukins; Intervention; Lead; Learning; Link; Lipectomy; Lipopolysaccharides; Long-Term Potentiation; Measures; Mediating; Mediator of activation protein; Memory; Memory impairment; Metabolic; Metabolic syndrome; Metabolism; Methods; Microglia; Modeling; Molecular; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Neuroendocrinology; Neuronal Plasticity; Neurons; Obese Mice; Obesity; Operative Surgical Procedures; Outcome; Overweight; Patients; Physiology; Population; Predisposition; Prevalence; Prevention; Public Health; Publications; Research; Risk Factors; Series; Signal Transduction; Source; Synapses; Synaptic plasticity; Testing; Time; Tissues; Training; Transplantation; United States; Vertebral column; Vulnerable Populations; Work; anakinra; base; career; career development; cell type; cytokine; db/db mouse; density; experience; genetic manipulation; high risk; immune function; improved; insight; leptin receptor; medical schools; meetings; mild cognitive impairment; mouse model; neuroimmunology; neuroinflammation; neuropathology; novel; operation; post-doctoral training; prevent; programs; public health relevance; research study; response; skills; theories

The broad, long-term objective of the proposed research is to identify the underlying mechanisms for the increased susceptibility to age-related cognitive decline and dementia in obesity and diabetes. This objective will be addressed through a series of experiments in two mouse models of obesity arising from diet or genetic manipulation. The central hypothesis is that fat is a source of inflammatory cytokines that impair cognition by inducing local inflammation in the hippocampus, a brain region involved in learning and memory. While the brain is normally protected from systemic inflammation, the protective barrier between blood and brain is compromised in obesity, and the goal of these studies is to determine what blood-borne signal contributes to cognitive impairment in obesity and diabetes. These experiments are relevant to the goals of the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) because of the focus on inflammation in obesity and diabetes, and the implications of increased inflammation for cognition in individuals suffering from these debilitating conditions. The proposed studies will take place in the Physiology Department at the Medical College of Georgia, which has an institutional track record of excellence in diabetes and obesity research. The environment is extraordinarily supportive and conducive to the research career development plan described in the current application, which includes didactic and experimental approaches to further the candidate's goal of establishing an independent research program in neuroimmunology. The rationale for additional training under this award is twofold: first, the candidate has demonstrated excellence in neuroendocrinology, but has no experience with the methods and theories of immunology, therefore in order to pursue the studies in this proposal, additional training is required; and second, although the candidate currently holds an Assistant Professorship, the short duration of the candidate's postdoctoral training (2 years) means that additional time and training will be required in order to establish a productive research program in neuroimmunology. The candidate's immediate career goal is to establish an externally funded research program and demonstrate independence in publications. Over the long term, the candidate hopes to conduct research that identifies molecular mediators linking metabolism and immune function with cognition. By building a bridge between diabetes and obesity and the field of learning and memory research, it may be possible to develop personalized interventions to prevent increased rates of cognitive impairment and dementia in individuals with metabolic syndrome features.

拟议研究的广泛、长期目标是确定潜在机制 肥胖和糖尿病患者对与年龄相关的认知能力下降和痴呆症的易感性增加。这个目标 将通过在两种由饮食或遗传引起的肥胖小鼠模型中进行一系列实验来解决 操纵。核心假设是，脂肪是炎症细胞因子的来源，炎症细胞因子会通过以下方式损害认知： 诱发海马体（参与学习和记忆的大脑区域）的局部炎症。虽然 大脑通常免受全身炎症的影响，血液和大脑之间的保护屏障是 这些研究的目的是确定血液信号对肥胖有何影响 肥胖和糖尿病导致的认知障碍。这些实验与国家的目标相关 糖尿病、消化和肾脏疾病研究所 (NIDDK)，因为重点关注肥胖引起的炎症 和糖尿病，以及炎症增加对患有这些疾病的个体认知的影响 使人衰弱的情况。拟议的研究将在医学部的生理学系进行 乔治亚学院在糖尿病和肥胖研究方面拥有卓越的机构记录。这 环境非常支持和有利于中描述的研究职业发展计划 当前的应用程序，其中包括教学和实验方法，以促进候选人的目标 建立神经免疫学的独立研究计划。额外培训的理由 该奖项具有双重意义：首先，候选人在神经内分泌学方面表现出了卓越的表现，但没有 具有免疫学方法和理论的经验，因此为了进行这方面的研究 建议，需要额外培训；其次，尽管该候选人目前拥有一名助理 教授职位，候选人的博士后培训时间较短（2年）意味着额外的时间 为了建立富有成效的神经免疫学研究计划，需要进行培训。这 候选人的近期职业目标是建立外部资助的研究计划并证明 出版物的独立性。从长远来看，候选人希望进行研究以确定 将新陈代谢和免疫功能与认知联系起来的分子介质。通过在两者之间架起一座桥梁 糖尿病和肥胖以及学习和记忆研究领域，也许有可能开发 个性化干预措施，以防止患有认知障碍和痴呆症的人的认知障碍和痴呆症发生率增加 代谢综合征的特点。