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Mechanistic bases for the exaggerated mechanoreflex in peripheral arterial disease

Award Number: F31HL154779
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2021

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Mechanistic bases for the exaggerated mechanoreflex in peripheral arterial disease - PROJECT SUMMARY Peripheral artery disease (PAD) is a common vascular disease that currently affects >10 million people in the U.S. and >200 million people worldwide. PAD prevalence and incidence are sharply age-related and with our national population ever aging, we will see a huge rise of PAD diagnoses. PAD refers to atherosclerotic occlusion of vessels supplying lower extremities creating an ischemic environment during exercise. The ischemic environment causes intermittent pain (i.e., claudication) and exercise intolerance. Along with pain, these patients experience exaggerated increases in blood pressure which increase their risk of suffering an adverse ischemic event in the form of cardiac fibrillation and/or stroke. Patients are frequently advised to avoid strenuous physical activity, however, a marked increase in blood pressure occurs during even low intensity walking exercise. The exercise pressor reflex, a feedback neural control mechanism activated by the mechanical and metabolic signals associated with skeletal muscle contraction, contributes importantly to autonomic and cardiovascular adjustments during exercise. This reflex is exaggerated in PAD and multiple lines of evidence indicate that the mechanical portion of the reflex (i.e., the mechanoreflex) specifically underlies that exaggeration. Thus, the mechanoreflex contributes to exaggerated increases in blood pressure and exercise intolerance in PAD patients. The overall goal of the experiments proposed is to uncover the mechanisms of mechanoreflex exaggeration in PAD. I plan to use the decerebrate, unanaesthetized rat model of simulated PAD in which a femoral artery is ligated for ~72 hours. To isolate the mechanical from the metabolic signals associated with skeletal muscle contraction, I use a 30 s dynamic passive hindlimb skeletal muscle stretch protocol which mimics the exaggerated mechanoreflex in PAD patients. My preliminary data indicates that the thromboxane A2 receptors (TxA2-R) located on the sensory endings of skeletal muscle afferents plays a role in the exaggerated mechanoreflex. TxA2-R are Gq-protein coupled receptors that signal the formation of inositol triphosphate 3 (IP3) which plays a major role in intracellular signaling. While this second messenger pathway is well defined in isolated neurons and in the chronic pain response seen in rodent models of pain, it has not been investigated in our field of blood pressure regulation during exercise. My aim is to target IP3 receptors within skeletal muscle sensory neurons to determine the role of second messenger signaling in the exaggerated blood pressure response during mechanoreflex activation in a rat model of PAD. The proposed experiments will enhance our understanding of second messenger signaling within sensory neurons that will provide the foundation for the future development of specific therapeutic targets to improve cardiovascular and autonomic function during physical activity and exercise in PAD patients.


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: 2023 ( Subtotal = $0 )
2023	2020	KANSAS STATE UNIVERSITY	1601 VATTIER STREET	MANHATTAN	KS	66506	RILEY	USA	Cardiovascular Diseases Research	000	1	11/23/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = -$1,549 )
2022	2020	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Cardiovascular Diseases Research	000	1	12/6/2021	NEW	-$1,549
														Subtotal = -$1,549

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2021	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Cardiovascular Diseases Research	001	2	8/31/2021	NON-COMPETING CONTINUATION	-$34,287
2021	2021	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Cardiovascular Diseases Research	000	2	8/4/2021	NON-COMPETING CONTINUATION	$34,287
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $33,771 )
2020	2020	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Cardiovascular Diseases Research	001	1	7/17/2020	NEW	$0
2020	2020	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Cardiovascular Diseases Research	000	1	7/17/2020	NEW	$33,771
														Subtotal = $33,771

Grand Total All Awards = $32,222

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Mechanistic bases for the exaggerated mechanoreflex in peripheral arterial disease

Award Number: F31HL154779

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2021

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