The contribution of JNK signaling to development of EPR dysfunction in primary hypertension

The National Heart, Lung, and Blood Institute awarded Cincinnati Children's Hospital Medical Center $128,589 on September 27, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate the contribution of JNK signaling to exercise pressor reflex dysfunction in primary hypertension.

The research tests the hypothesis that enhanced JNK signaling in dorsal root ganglia of hypertensive mice occurs through increased peripheral tumor necrosis factor-alpha, resulting in dysfunctional exercise pressor reflex. The work uses a spontaneously hypertensive mouse model (BPH/2J) with neuronal knockdown and overexpression utilizing adenovirus-associated viral vectors to determine the effects of JNK signaling on cardiovascular reflexes through specific neuronal subpopulations following the onset of hypertension. The research addresses acid-sensing ion channel 3 expression alterations in primary hypertension and how ASIC3 modulates exercise pressor reflex function by altering the way sensory neurons respond to metabolites produced within contracting muscles, including lactate, ATP, and protons.

Performance occurs in Cincinnati, Ohio, with a period of performance ending April 30, 2028. This is a project grant, an assistance type supporting discrete research projects.

Abstract

Primary hypertension (PH) is the most common form of hypertension. PH patients often suffer from exercise intolerance, regardless of their medication status. Exercise pressor reflex (EPR) dysfunction can cause exercise intolerance. Group III/IV primary muscle afferent neurons comprise the sensory arm of the EPR. PH-related abnormalities have been identified within the sensory arm of the EPR but need further investigation. Acid-sensing ION channel 3 (ASIC3) expression is known to be altered in PH. This channel regulates group III/IV muscle afferent responsiveness. ASIC3 is known to modulate EPR function by altering the way sensory neurons respond to changes in metabolites produced within contracting muscles, such as lactate, ATP, and protons. Pilot data demonstrated an increase in ASIC3+ and phospho-JUN n-terminal kinase positive (pjnk+) cells within the dorsal root ganglion (DRG) of a hypertensive mouse model and increased levels of tumor necrosis factor-alpha (tnfα) within the skeletal muscle of these mice. After systemic and neuronal JNK inhibition, ASIC3 expression within hypertensive drgs was reduced and blood pressure is restored. Since TNF is known to modulate JNK activation, this may implicate a novel pathway driving EPR dysfunction in where skeletal muscle tnfα activates neuronal JNK signaling leading to upregulation of ASIC3 within drgs. Therefore, we will test the central hypothesis that enhanced JNK signaling in the drgs of hypertensive mice occurs through increased peripheral tnfα, resulting in a dysfunctional EPR. A spontaneously hypertensive mouse model (BPH/2J) along with neuronal knockdown and overexpression utilizing adenovirus- associated viral (AAV) vectors will be used to determine the effects of JNK signaling on cardiovascular reflexes through specific neuronal subpopulations following the onset of hypertension. EPR tests (blood pressure/ heart rate post exercise), plethysmography, EX vivo forepaw muscle/tibial/DRG/spinal cord electrophysiological recording preparations, and molecular analyses (real-time PCR/RNA-SEQ and immunofluorescence) of drgs will be conducted. Aim 1 will determine whether neuronal JNK signaling is necessary and sufficient to develop a dysfunctional EPR. Through AAV knockdown and overexpression of sensory neuron JNK in BPH2J mice and their normotensive counterparts, we will test the working hypothesis that reduction of neuronal JNK signaling regulates group III/IV muscle afferent responsiveness and EPR function. Aim 2 will elucidate if the pro-inflammatory cytokine, tnfα, drives EPR dysfunction in primary hypertension. Through knockout of tnfα receptors on group III/IV muscle afferents and inhibition of peripheral tnfα via an antibody strategy, we will test the working hypothesis that enhanced tnfα within the muscles of BPH2J mice regulates neuronal JNK signaling resulting in EPR dysfunction. This research will be the first to assess the tnfα-JNK pathway in EPR dysfunction. IT will provide some of the first evidence to support the concept that sensory neurons drive the progression of primary hypertension which will provide excellent training for me as a future investigator.