Adipose inflammation mediates obesity-induced deficits in hippocampal plasticity

描述(由申请人提供)：拟议研究的广泛、长期目标是确定肥胖和糖尿病患者增加与年龄相关的认知能力下降和痴呆症易感性的潜在机制。这一目标将通过在两种由饮食或基因操作引起的肥胖小鼠模型上进行一系列实验来实现。中心假设是，脂肪是炎性细胞因子的来源，通过在海马体诱导局部炎症来损害认知，海马体是大脑中参与学习和记忆的区域。虽然大脑通常受到保护，不受系统性炎症的影响，但肥胖患者血液和大脑之间的保护屏障受到损害，这些研究的目标是确定肥胖和糖尿病患者的认知障碍与血液传播的信号有关。这些实验与国家糖尿病、消化和肾脏疾病研究所(NIDDK)的目标相关，因为重点是肥胖症和糖尿病的炎症，以及炎症增加对患有这些衰弱疾病的人的认知的影响。拟议的研究将在佐治亚医学院生理学系进行，该学院在糖尿病和肥胖症研究方面拥有卓越的机构记录。这种环境非常有利于当前申请中描述的研究职业发展计划，其中包括教学和实验方法，以促进候选人建立神经免疫学独立研究计划的目标。根据这一奖项进行额外培训的理由有两个：第一，候选人在神经内分泌学方面表现出卓越的表现，但对免疫学的方法和理论没有经验，因此为了继续这项申请的研究，需要额外的培训；第二，虽然候选人目前拥有助理教授职位，但候选人博士后培训的时间较短(两年)意味着将需要额外的时间和培训来建立 神经免疫学方面的富有成效的研究计划。候选人的直接职业目标是建立一个外部资助的研究项目，并在出版物上展示独立性。从长远来看，这位候选人希望进行研究，确定将新陈代谢和免疫功能与认知联系起来的分子中介。通过在糖尿病和肥胖症以及学习和记忆研究领域之间架起一座桥梁，有可能开发出个性化的干预措施，以防止具有代谢综合征特征的个人认知障碍和痴呆症发病率的增加。

DESCRIPTION (provided by applicant): 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 application, 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.