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.

Public Health Relevance

Obesity-related hypertension; a serious and frequent cardiovascular complication of obesity; can arise from obesity-related inflammation mediated by IKK ? in the hypothalamus. This project will use mouse models to investigate how IKK ? induces sympathetic activation to cause obesity-related hypertension; and if inhibiting this pathway can treat and prevent obesity-related hypertension without requiring obesity control. Successful completion of this study will help to understand the brain mechanism of obesity-related hypertension; and develop novel interventional strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL113180-02
Application #
8666035
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Maric-Bilkan, Christine
Project Start
2013-06-01
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$486,395
Indirect Cost
$164,150
Name
Albert Einstein College of Medicine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Yan, Jingqi; Zhang, Hai; Yin, Ye et al. (2014) Obesity- and aging-induced excess of central transforming growth factor-? potentiates diabetic development via an RNA stress response. Nat Med 20:1001-8
Cai, Dongsheng (2013) Central mechanisms of obesity and related metabolic diseases. Rev Endocr Metab Disord 14:309-10
Purkayastha, Sudarshana; Cai, Dongsheng (2013) Disruption of neurogenesis by hypothalamic inflammation in obesity or aging. Rev Endocr Metab Disord 14:351-6