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Neuroinflammatory mechanisms involved in hypertension and diabetes

This project will investigate the acute and chronic effects of NF-κB and its activator IkB kinase (IKKβ) in the area postrema. This area is essential for control of the sympathetic system, blood pressure, and blood glucose.

Aims

The successful completion of the project will increase our understanding of whether NF-κB in the area postrema is a major contributor to the development of hypertension and diabetes. Additionally, it will determine if the blockade of the neuroinflamatory cascade ameliorates the symptoms of hypertension and diabetes.

Cardiovascular disease is a major cause of death in Australia, whereas diabetes is considered the fastest growing chronic condition worldwide having a devastating impact on quality of life. While current therapies target the symptoms of these diseases, the brain mechanisms that contribute to their underlying causes are unknown. A key common factor linking these diseases is diet-related brain inflammation that results in neurodegeneration. The pro-inflammatory molecule nuclear factor kB (NF-κB) seems to play an essential role in these mechanisms, by initiating the cytokine inflammatory cascade. Nevertheless, the changes in the autonomic nervous system that account for the development of hypertension and diabetes are still unknown.

We will use the following disease models: STZ-induced diabetic rats or 2 kidney 1 clip hypertensive rats. For instance, TNF-α pro-inflamatory cytokine related to NF-κB elicits increases in blood pressure (BP), and sympathetic nerve activity to the heart (CSNA) and kidney (RSNA).

The techniques to be used is this study are the following:

*small animal surgery (induction of diabetes or hypertension)

*stereotaxic microinjections

*electrophysiological preparation in anaesthetized rats

*tissue sectioning

*microscopy (light, fluorescence)

Further Reading:

Trends Endocrinol Metab. 2013 24:40-47. PMID:23265946

Curr Opin Nephrol Hypertens. 2016 25:410-416. PMID:27490783

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