Hypothalamic IKK-beta in obesity-related hypertension

描述（由申请人提供）：肥胖和高血压（HT）是全球两大流行性健康问题。不幸的是，这两个问题往往耦合形成肥胖相关HT（OHT），但由于对潜在机制的认识不足，目前几乎完全缺乏有效的干预措施。有趣的是，该项目的最新研究发现，OHT的机制涉及由肥胖诱导的下丘脑POMC神经元中促炎性IKK？激活引起的交感神经上调。感谢IKK POMC神经元中的OHT是肥胖和HT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 <$激活可以促进谷氨酸释放，重要的是，POMC神经元中的IKK <$和谷氨酸信号传导可以类似地介导下游前交感回路的激活以诱导HT。相反，抑制POMC神经元中的IKK或谷氨酸信号可以类似地抵消OHT。因此，该项目假设POMC神经元中的IKK？利用来自这些神经元的谷氨酸信号来激活下游前交感神经元并驱动OHT的交感诱导。本研究拟从以下三个方面来验证这一假说：（1）研究IKK和谷氨酸在POMC神经元中的降压作用;（2）研究OHT涉及IKK和谷氨酸在POMC神经元中的交感基础;（3）研究与OHT相关的POMC神经元相关的神经回路。将使用遗传和基因递送方法以及相关的心血管和神经分析来实现这些目标。所有关键的动物模型、试剂和技术都已在研究中建立，并产生了初步结果，使该建议切实可行。本课题的成功完成将有助于阐明OHT的脑机制，并对OHT的干预策略的发展有一定的启发意义。

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.