Kamal Rahmouni, PhD, Professor of Neuroscience and Pharmacology has recently received a new R01 grant funded by the National Heart, Lung and Blood Institute. His project title Role of FGF21 Action in Hypothalamic Neurons in Obesity-Associated Hypertension will be funded through November of 2026.
Project summary: Obesity which has become common in the US and throughout the world is a major cause of hypertension, a condition that affects one billion people and a principal reversible risk factor for cardiovascular disease. However, the mechanisms underlying the relationship between obesity and hypertension remain largely unknown. The goal of this project is to identify the neuronal and molecular processes that control blood pressure and how dysregulation in these processes contribute to obesity-associated hypertension and other cardiovascular risks. We have identified the action of the hormone fibroblast growth factor 21 (FGF21) in a subset of neurons of the hypothalamus as novel mechanism that regulate blood pressure through the autonomic nervous system. We will use a multidisciplinary strategy combining cutting edge neuro-technologies to precisely and remotely modulate or monitor the activity of hypothalamic neurons in freely moving animals with unique genetically engineered mouse models that permit selective modulation of FGF21 signaling in these neurons and sophisticated integrative physiology for autonomic and cardiovascular phenotyping. This work should unravel novel mechanisms that underlie obesity-associated autonomic dysregulation and hypertension, making our work of high clinical relevance. Insights into the cellular and molecular processes that control the autonomic nervous system that regulates cardiovascular function may make it possible to selectively interfere with the damage obesity inflicts on cardiovascular autonomic functions.
Along with his new R01 grant, Dr. Rahmouni’s VA grant was also renewed. His project proposal titled Neuronal Mechanisms of Obesity-Induced Hypertension was originally awarded funding in 2019 and was recently renewed early this year.
Project summary: The high prevalence of obesity among the veterans is a major challenge for the VA healthcare system. This is because obesity is associated with increased sympathetic nerve traffic leading to hypertension, a major risk factor for end-organ damage, stroke, myocardial infarction and congestive heart failure. However, the cellular and molecular etiology of obesity-associated cardiovascular risks remain poorly understood. We and others have previously demonstrated the importance of the brain mechanisms in the pathophysiology of obesity-induced hypertension. Studies from our lab revealed the importance of a protein signaling complex called mechanistic target of rapamycin complex 1 (mTORC1) in the control of blood pressure. The goal of the current project is to understand the downstream signaling pathways underlying the control of blood pressure by mTORC1 signaling in specific neuronal populations. The neural circuitry influenced by mTORC1 signaling will also be dissected. Finally, the pathophysiological significance of mTORC1 signaling in defined neurons for obesity-related hypertension and autonomic dysfunction will be analyzed. This research will advance understanding of the mechanisms underlying the hypertension and other cardiovascular risks associated with obesity, which could improve the standard of care to prevent or manage cardiovascular risks.
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