Role of Hypothalamic IKK-beta/NF-kappaB in Nutritional Control of Aging

说明(申请人提供)：衰老不仅是一种重要的生物现象，而且是许多有害的衰老相关疾病的核心基础。由于认识到IKKB/NF-kB依赖的炎症介导了下丘脑衰老的机制，本研究的长期目标是研究涉及的神经类型和分子级联，以开发治疗衰老相关疾病的策略。在初步研究中，利用星形胶质细胞特异性IKKB/NF-kB激活或抑制的小鼠模型，以下丘脑星形胶质细胞为靶点。初步数据表明，下丘脑星形胶质细胞中IKKB/NF-kB的激活或抑制分别足以导致衰老加速或延缓。因此，在这些数据的支持下，本项目的假设是星形胶质细胞IKKB/NF-kB在衰老的早期被激活，从而诱导神经元炎症，从而介导了下丘脑的衰老机制。这一假说预测，抑制星形胶质细胞IKKB/NF-kB可以减少与衰老相关的下丘脑神经元炎症，从而提供延缓衰老的作用。这一假说将在三个方面得到验证：(1)研究星形胶质细胞IKKB/NF-kB在衰老相关下丘脑炎症中的作用；(2)研究脑或下丘脑星形胶质细胞IKKB/NF-kB在衰老生理和寿命中的作用；(3)研究星形胶质细胞IKKB/NF-kB介导的衰老发育的神经元机制。这些目标的实验将通过使用特定部位和特定细胞类型的IKKB/NF-kB激活或抑制的小鼠模型来进行。一系列分子方法将用于分析星形胶质细胞和神经元炎性变化，以及对SIRT和FOXO等抗衰老分子标志物的抑制影响。此外，还将使用一系列生理学和组织学方法来分析小鼠模型的衰老。总体而言，该项目的成功完成可以对下丘脑的衰老机制产生新的见解，并为以下丘脑为靶点管理健康衰老和对抗致命的衰老相关疾病提供潜在的启示。

DESCRIPTION (provided by applicant): Aging is not only an important biological phenomenon but a core basis in many deleterious aging-related diseases. Having appreciated that IKKb/NF-kB-dependent inflammation mediates hypothalamic mechanism of aging, the long-term objective of this research is to study the involved neural types and molecular cascades, in order to develop strategies for treating aging-related diseases. In preliminary studies, hypothalamic astroglia have been targeted, using mouse models of astroglia-specific IKKb/NF-kB activation or inhibition. Preliminary data have demonstrated IKKb/NF-kB activation or inhibition in hypothalamic astroglia was sufficient to lead to aging acceleration or retardation, respectively. Hence, supported by these data, the hypothesis of this project is that astroglial IKKb/NF-kB is activated during early aging to induce neuronal inflammation and thus mediates the hypothalamic mechanism of aging. This hypothesis predicts that astroglial IKKb/NF-kB inhibition can reduce aging-related hypothalamic neuronal inflammation and therefore provide anti-aging effects. This hypothesis will be examined in 3 Aims: (1) Study the role of astroglial IKKb/NF-kB in aging-related hypothalamic inflammation; (2) Study the role of brain or hypothalamic astroglial IKKb/NF-kB in aging physiology and lifespan; (3) Study the neuronal mechanism in astroglial IKKb/NF-kB -mediated aging development. Experiments in these Aims will be carried out by using mouse models of site- and cell type-specific IKKb/NF-kB activation or inhibition. A list of molecular methods will be used to analyze astroglial and neuronal inflammatory changes as well as the inhibitory impacts on anti-aging molecular markers such as SIRTs and FOXOs. Also, a battery of physiological and histological approaches will be used to analyze aging of mouse models. Overall, successful completion of this project can yield new insights into the hypothalamic mechanism of aging, and enlighten a potential of targeting the hypothalamus for managing healthy aging and counteracting deadly aging-related diseases.