Hypothalamic IKK-beta in obesity-related hypertension

描述（申请人提供）：肥胖和高血压（HT）是全球两大流行的健康问题。不幸的是，这两个问题经常耦合形成肥胖相关的HT (obesity-related HT， OHT)，但由于对其潜在机制的了解不够，目前几乎完全缺乏针对OHT的有效干预措施。有趣的是，该项目最近的研究发现，OHT的机制涉及由肥胖诱导的下丘脑POMC神经元中促炎IKK¿的激活引起的交感神经上调。认识到POMC神经元中的IKK¿代表肥胖和HT之间的交汇点，本研究的长期目标是研究所涉及的生理，分子和神经回路基础，最终导致治疗和预防OHT的干预策略。初步研究表明，POMC神经元中的IKK¿激活可以促进谷氨酸的释放，重要的是，POMC神经元中的IKK¿和谷氨酸信号传导同样可以介导下游前交感神经回路的激活，从而诱导HT。相反，POMC神经元中IKK¿或谷氨酸信号的抑制同样可以抵消OHT。因此，本项目假设POMC神经元中的IKK¿利用这些神经元的谷氨酸信号激活下游的前交感神经元并驱动OHT的交感诱导。为了验证这一假设，我们提出了三个具体目标：(1)研究IKK¿和谷氨酸在POMC神经元中的降压作用；(2)研究POMC神经元中IKK¿和谷氨酸参与OHT的交感基础；(3)研究与OHT相关的POMC神经元相关的神经回路。结合遗传和基因传递方法以及相关的心血管和神经分析将用于实现这些目标。所有关键的动物模型、试剂和技术已经在研究中建立，并产生了初步的结果，使该建议是可行的。综上所述，本课题的成功完成将显著阐明OHT的脑机制，并对OHT干预策略的制定具有启示意义。

DESCRIPTION (provided by applicant): Obesity and hypertension (HT) are two epidemic health problems globally. Unfortunately, these two problems are often coupled to form obesity-related HT (OHT), but due to the poor understanding about the underlying mechanism, currently there is an almost complete lack of effective interventions against OHT. Interestingly, recent research from this project has led to the discovery that the mechanism of OHT involves sympathetic upregulation arising from obesity-induced activation of proinflammatory IKK¿ in POMC neurons localized in the hypothalamus. Having appreciated that IKK¿ in POMC neurons represents a converging point between obesity and HT, the long-term objective of this research is to study the involved physiological, molecular and neural circuitry basis which can eventually lead to interventional strategies in treating and preventing OHT. Preliminary studies have revealed that IKK¿ activation in POMC neurons can promote glutamate release, and importantly, IKK¿ and glutamate signaling in POMC neurons can similarly mediate the activation of downstream presympathetic circuitry to induce HT. Conversely, inhibition of IKK¿ or glutamate signaling in POMC neurons can similarly counteract against OHT. Hence, this project hypothesizes that IKK¿ in POMC neurons employs glutamate signaling from these neurons to activate downstream presympathetic neurons and drive the sympathetic induction of OHT. Three Specific Aims are proposed to test this hypothesis: (1) Study the hypertensive role of IKK¿ and glutamate in POMC neurons; (2) Study the sympathetic basis of OHT involving IKK¿ and glutamate in POMC neurons; (3) Study the POMC neuron-related neural circuitry in relation to OHT. A combined genetic and gene delivery approaches together with relevant cardiovascular and neural analyses will be used to carry out these Aims. All key animal models, reagents and techniques have been established in the studies which generated preliminary results, making the proposal feasible. Overall, successful completion of this project will significantly clarify the brain mechanism of OHT, and enlighten the development of interventional strategies against OHT.