Application objective: The proposal describes a five-year program of basic science research coupled with closely mentored laboratory guidance, coursework and seminars that will significantly broaden my scientific education and help me become an independent clinician/scientist in an academic medical center. Research: Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis affecting approximately 8.4 million people in the US, most of them elderly. The current treatment options for patients with PAD are limited to revascularization operations (100,000 per year) or amputations (50,000 per year), while effective non-operative treatment options are very few. The manifestations of PAD, including claudication and gangrene, result from decreased energy levels within the affected tissue. This reduced energy state appears to result not only from reduced blood flow through diseased arteries, but also faulty ATP production from dysfunctional mitochondria. We have earlier demonstrated the presence of mitochondrial dysfunction in both human and mouse chronically ischemic skeletal muscle. Preliminary results from our murine model of hindlimb ischemia suggest that the defects originate from decreased activity of electron transport chain complexes III and IV. Furthermore, our results point to an association between the mitochondrial defects and oxidative stress. The goal of this proposal is to utilize our murine model to further delineate the electron transport chain defects and to correlate mitochondrial defects with muscle dysfunction and oxidative damage. The identified defects may provide an important therapeutic target for treating PAD patients, especially those with unreconstructible disease. We hypothesize that chronic skeletal muscle ischemia is associated with alterations in the activity and content of the electron transport chain complexes III and IV, and that these defects correlate with muscle contractile dysfunction and evidence of oxidative stress. Four focused specific aims are proposed:
Aim 1 : Identify and quantify defects in the function of electron transport chain complexes I through IV in mitochondria from ischemic muscle.
Aim 2 : Identify the subunit defects in the dysfunctional electron transport chain complexes.
Aim 3 : Correlate mitochondrial dysfunction with muscle contractile properties.
Aim 4 : Correlate mitochondrial dysfunction with oxidative damage in the ischemic skeletal muscle.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL079967-02
Application #
7052111
Study Section
Special Emphasis Panel (ZHL1-CSR-M (F2))
Program Officer
Commarato, Michael
Project Start
2005-04-15
Project End
2010-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
2
Fiscal Year
2006
Total Cost
$130,680
Indirect Cost
Name
University of Nebraska Medical Center
Department
Surgery
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Thompson, J R; Swanson, S A; Haynatzki, G et al. (2015) Protein concentration and mitochondrial content in the gastrocnemius predicts mortality rates in patients with peripheral arterial disease. Ann Surg 261:605-10
Kamenskiy, Alexey V; Mactaggart, Jason N; Pipinos, Iraklis I et al. (2013) Hemodynamically motivated choice of patch angioplasty for the performance of carotid endarterectomy. Ann Biomed Eng 41:263-78
Weiss, Dustin J; Casale, George P; Koutakis, Panagiotis et al. (2013) Oxidative damage and myofiber degeneration in the gastrocnemius of patients with peripheral arterial disease. J Transl Med 11:230
Thompson, Jonathan R; Swanson, Stanley A; Casale, George P et al. (2013) Gastrocnemius mitochondrial respiration: are there any differences between men and women? J Surg Res 185:206-11
Kamenskiy, Alexey V; Dzenis, Yuris A; MacTaggart, Jason N et al. (2012) Nonlinear mechanical behavior of the human common, external, and internal carotid arteries in vivo. J Surg Res 176:329-36
Kamenskiy, Alexey V; MacTaggart, Jason N; Pipinos, Iraklis I et al. (2012) Three-dimensional geometry of the human carotid artery. J Biomech Eng 134:064502
Kamenskiy, Alexey V; Pipinos, Iraklis I; MacTaggart, Jason N et al. (2011) Comparative analysis of the biaxial mechanical behavior of carotid wall tissue and biological and synthetic materials used for carotid patch angioplasty. J Biomech Eng 133:111008
Kamenskiy, Alexey V; Dzenis, Yuris A; Mactaggart, Jason N et al. (2011) In vivo three-dimensional blood velocity profile shapes in the human common, internal, and external carotid arteries. J Vasc Surg 54:1011-20
Koutakis, Panagiotis; Pipinos, Iraklis I; Myers, Sara A et al. (2010) Joint torques and powers are reduced during ambulation for both limbs in patients with unilateral claudication. J Vasc Surg 51:80-8
Pisimisis, George T; Kantor, Birgit; Kalra, Manju et al. (2010) Thrombus of the internal carotid artery: the contribution of computed tomographic angiography to clinical management. Vasc Endovascular Surg 44:302-4

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