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

Award Number: F31HL179869
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/27/2026
PERIOD OF PERFORMANCE END DATE: 09/26/2027

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The contribution of JNK signaling to development of EPR dysfunction in primary hypertension - PROJECT SUMMARY: 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $42,479 )
2026	2026	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	1	3/27/2026	NEW	$42,479
														Subtotal = $42,479

Grand Total All Awards = $42,479

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

Award Number: F31HL179869

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/27/2026

PERIOD OF PERFORMANCE END DATE: 09/26/2027

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