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对年龄相关认知下降和痴呆易感性增加的潜在机制。这一目标将通过一系列实验在两个小鼠模型的肥胖所产生的饮食或遗传操作。核心假设是脂肪是炎症细胞因子的来源，通过诱导海马体（一个与学习和记忆有关的大脑区域）的局部炎症来损害认知。虽然大脑通常受到全身性炎症的保护，但血液和大脑之间的保护屏障在肥胖症中受到损害，这些研究的目标是确定哪些血液传播信号导致肥胖和糖尿病的认知障碍。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，因为重点是肥胖和糖尿病中的炎症，以及炎症增加对患有这些衰弱疾病的个体认知的影响。拟议的研究将在格鲁吉亚医学院的生理学系进行，该学院在糖尿病和肥胖研究方面有着卓越的机构记录。环境是非常支持和有利于研究职业发展计划中描述的当前应用程序，其中包括教学和实验方法，以进一步候选人的目标，建立一个独立的研究计划在神经免疫学。根据该奖项进行额外培训的理由有两个方面：首先，候选人在神经内分泌学方面表现出色，但没有免疫学方法和理论的经验，因此为了继续这项应用的研究，需要额外的培训;第二，虽然候选人目前拥有助理教授职位，候选人的博士后培训时间短（2年）意味着需要额外的时间和培训，以建立一个 神经免疫学的研究项目候选人的直接职业目标是建立一个外部资助的研究项目，并在出版物中表现出独立性。从长远来看，候选人希望进行研究，确定分子介质连接代谢和免疫功能与认知。通过在糖尿病和肥胖症与学习和记忆研究领域之间建立桥梁，有可能开发个性化干预措施，以防止具有代谢综合征特征的个体的认知障碍和痴呆率增加。

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.