ABSTRACT/SUMMARY Obesity-related hypertension (OHT), an etiologically prevalent disorder accounting for ~75% of patients with hypertension, is however hard to control, and this clinical difficulty is related to the specific yet much unclear mechanism of OHT. Having recently appreciated that the hypothalamic neuronal basis of OHT is significantly due to obesity-induced IKKβ/NF-κB-dependent hypothalamic inflammation, the long-term objective of this research is to study hypothalamic neural types and molecular cascades that mediate OHT. In preliminary studies, using mouse models with hypothalamic astrocytic IKKβ/NF-κB activation or inhibition, supportive evidence has been obtained suggesting that hypothalamic astrocytes have site-specific multiple programs in causing hypertension. Hence, the hypothesis of this proposal is, under chronic high-fat diet feeding, hypothalamic astrocytic IKKβ/NF-κB is activated to cause OHT, mechanistically mediated by (a) converging effects of adipokines and consequent hypothalamic ER stress due to blood-brain barrier (BBB) breakdown, (b) activation of POMC neurons due to astrocytic cytokine-induced dysfunction of arcuate DA neurons, and (c) excess of α-MSH and glutamate in the PVN due to impaired astrocytic clearance. Three Aims are proposed to: (1) study the neuroanatomic and BBB breakdown basis for the role of astrocytic IKKβ/NF-κB in OHT; (2) study altered MBH astrocyte-neuron relationship in obesity and the contribution to OHT; and (3) study altered PVN astrocyte-neuron relationship in obesity and the contribution to OHT. Experiments will be carried out using mouse models of site- and cell-specific IKKβ/NF-κB manipulations as well as manipulations of the downstream molecular pathways in astrocytes and relevant neurons. Blood pressure phenotypes will be examined in these models in the context of dietary obesity or genetic manipulations of proposed mechanisms. Astrocytic changes, downstream programs, and further downstream neuronal alterations will be rigorously analyzed. Overall, successful completion of this project can yield new insights into the hypothalamic mechanism of OHT and enlighten the strategy of targeting hypothalamic astrocytic programs in combating this disease.