This is a resubmission of a program project grant to the NHLBI by {four} investigators located within the College of Medicine of the Pennsylvania State University in Hershey, Pennsylvania. All investigators are highly productive scientists. All project leaders are collaborative and all will greatly benefit from this program. We believe this application fulfills the criteria for a PPG because: 1) there is a unifying theme namely that {peripheral arterial disease (PAD) accentuates autonomic reflex responses. Two models of limb ischemia will be employed: a) PAD in human subjects (Projects 1 and 4);and b) hindlimb arterial occlusion in rats (Projects 2 and 3)};2) conceptual synergy exists between the projects that will lead to important advances in cardiovascular physiology and pathophysiology;3) this PPG has broadly defined goals that can be accomplished within the first 5 year funding period;and 4) many of the ideas and concepts proposed are a direct result of previous collaborations between the project leaders. Dr. Sinoway will be the PPG Program Director (PD). He has substantial scientific and administrative experience, serving as the PD of the Penn State General Clinical Research Center (GCRC) since 1996, and PD of a PPG since 2004. In Project 1, Dr. Sinoway will examine the role the exercise pressor reflex (EPR) {plays in regulating blood pressure during muscular activity in patients with PAD.} He will examine the role oxidative stress plays in altering reflex effects in PAD patients. In Project 2, Dr. Li will determine if hindlimb arterial occlusion (rat model) leads to upregulation of P2X, TRPV1 and ASIC channels in dorsal root ganglion (DRG) neurons. Dr. Li will also examine the role nerve growth factor (NGF) plays in this response. In Project 3, Dr. Kaufman will examine group III and IV muscle afferent discharge {during contraction in rats with the hindlimb arterial occlusion model.} In Project 4, Dr. Leuenberger will examine the role intermittent hypoxia, a potent oxidative stress, plays in altering sympathetic reflexes and vasodilator responsiveness in {normal humans and those with diseases characterized by oxidative stress including PAD. Two cores are proposed: 1) Core A will be administrative;and 2) Core B will be a human physiology core.

Public Health Relevance

In PAD, autonomic reflex and vascular adjustments are understudied and of major clinical significance. PAD is common and lethal. Moreover, it is often a harbinger of other life threatening diseases (coronary and cerebral atherosclerosis). In severe PAD, blood pressure rises dramatically with wall

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL096570-03
Application #
8299963
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Maric-Bilkan, Christine
Project Start
2010-08-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$2,007,272
Indirect Cost
$708,067
Name
Pennsylvania State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Muller, Matthew D; Li, Zhijun; Sica, Christopher T et al. (2016) Muscle oxygenation during dynamic plantar flexion exercise: combining BOLD MRI with traditional physiological measurements. Physiol Rep 4:
Cui, Jian; Blaha, Cheryl; Sinoway, Lawrence I (2016) Whole body heat stress attenuates the pressure response to muscle metaboreceptor stimulation in humans. J Appl Physiol (1985) 121:1178-1186
Li, Zhijun; Muller, Matthew D; Wang, Jianli et al. (2016) Dynamic characteristics of T2*-weighted signal in calf muscles of peripheral artery disease during low-intensity exercise. J Magn Reson Imaging :
Ross, Amanda J; Gao, Zhaohui; Luck, Jonathan Carter et al. (2016) Coronary Exercise Hyperemia Is Impaired in Patients with Peripheral Arterial Disease. Ann Vasc Surg :
Copp, Steven W; Kim, Joyce S; Ruiz-Velasco, Victor et al. (2016) The mechano-gated channel inhibitor GsMTx4 reduces the exercise pressor reflex in decerebrate rats. J Physiol 594:641-55
Clark, Christine M; Monahan, Kevin D; Drew, Rachel C (2016) Omega-3 polyunsaturated fatty acid supplementation attenuates blood pressure increase at onset of isometric handgrip exercise in healthy young and older humans. Physiol Rep 4:
Stone, Audrey J; Kaufman, Marc P (2015) The exercise pressor reflex and peripheral artery disease. Auton Neurosci 188:69-73
Clark, Christine M; Monahan, Kevin D; Drew, Rachel C (2015) Aging augments renal vasoconstrictor response to orthostatic stress in humans. Am J Physiol Regul Integr Comp Physiol 309:R1474-8
Copp, Steven W; Stone, Audrey J; Li, Jianhua et al. (2015) Role played by interleukin-6 in evoking the exercise pressor reflex in decerebrate rats: effect of femoral artery ligation. Am J Physiol Heart Circ Physiol 309:H166-73
Muller, Matthew D; Drew, Rachel C; Ross, Amanda J et al. (2015) Inhibition of cyclooxygenase attenuates the blood pressure response to plantar flexion exercise in peripheral arterial disease. Am J Physiol Heart Circ Physiol 309:H523-8

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