The long term goal of this proposal is to develop a clinically relevant therapeutic protocol to treat patients with limb threatening acute arterial insufficiency, to enhance skeletal muscle regeneration and restore limb function. Since ischemia reperfusion injury results in metabolic, thrombotic and inflammatory consequences which contribute to muscle injury and dysfunction, our research has focused on treatments that will simultaneously address these specific components. In addition, effective treatment protocols should provide benefit in a clinically relevant scenario, i.e. after the onset of ischemia. Poly ADP-Ribose Polymerase (PARP) deserves special attention in these studies because it is a nuclear and mitochondrial protein that modulates cellular transcription and metabolism through a variety of intracellular pathways. PARP inhibitors have been shown to alter endothelial dysfunction, tissue loss, metabolism and inflammation in models acute and chronic injury in normal and diabetic mice. In our lab, we have shown that administration of a PARP inhibitor after the onset of ischemia resulted in preservation of murine skeletal muscle structure, and energy levels;in addition, markers of inflammation were decreased as compared to untreated animals. While experiments provided herein clearly show that PARP inhibition modulates the acute response to hind limb ischemia reperfusion, for any therapeutic intervention to be of clinical benefit, it is important to demonstrate that there is long term functional, and anti-inflammatory benefit during the healing phase of reperfusion injury. It is also important to determine whether PARP inhibition modulates tissue injury in murine models which reflect the phenotype of patients who are at greatest risk for limb loss following an acute arterial occlusion, i.e. diabetic patients. Finally, since PARP inhibition appears to be experimentally feasible, it is important to develop a mechanistic understanding of how tissue recovery and muscle regeneration is achieved. Thus, this proposal is designed to provide mechanistic and translationally relevant information on how PARP inhibition modulates local muscle injury, metabolism, muscular regeneration and functional recovery in a murine model of moderate and severe ischemia reperfusion. Furthermore, we assess these indices of injury/healing/function in a "normal mouse" and murine model of human type two diabetes.

Public Health Relevance

As risks factors such as diabetes mellitus continue to increase, the risk of limb loss due to vascular disease also increases. This proposal seeks novel translationally relevant approaches to decrease limb loss and encourage functional recovery following acute interruptions in extremity blood flow, which are common in patients with vascular disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR055843-05
Application #
8259388
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Nuckolls, Glen H
Project Start
2008-08-05
Project End
2013-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$363,408
Indirect Cost
$154,320
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Albadawi, Hassan; Oklu, Rahmi; Cormier, Nicholas R et al. (2014) Hind limb ischemia-reperfusion injury in diet-induced obese mice. J Surg Res 190:683-91
Albadawi, Hassan; Haurani, Mounir J; Oklu, Rahmi et al. (2013) Differential effect of zoledronic acid on human vascular smooth muscle cells. J Surg Res 182:339-46
Kuver, Rahul (2013) The expanding universe of bile acid physiology: delving into the mysteries of dark (green) matter. J Surg Res 182:207-9
Oklu, Rahmi; Albadawi, Hassan; Jones, John E et al. (2013) Reduced hind limb ischemia-reperfusion injury in Toll-like receptor-4 mutant mice is associated with decreased neutrophil extracellular traps. J Vasc Surg 58:1627-36
Long, Chandler A; Boulom, Valy; Albadawi, Hassan et al. (2013) Poly-ADP-ribose-polymerase inhibition ameliorates hind limb ischemia reperfusion injury in a murine model of type 2 diabetes. Ann Surg 258:1087-95
Crawford, Robert S; Albadawi, Hassan; Robaldo, Alessandro et al. (2013) Divergent systemic and local inflammatory response to hind limb demand ischemia in wild-type and ApoE-/- mice. J Surg Res 183:952-62
Oklu, Rahmi; Albadawi, Hassan; Watkins, Michael T et al. (2012) Detection of extracellular genomic DNA scaffold in human thrombus: implications for the use of deoxyribonuclease enzymes in thrombolysis. J Vasc Interv Radiol 23:712-8
Patel, Rajendra; Albadawi, Hassan; Steudel, Wolfgang et al. (2012) Inhalation of carbon monoxide reduces skeletal muscle injury after hind limb ischemia-reperfusion injury in mice. Am J Surg 203:488-95
Crawford, Robert S; Albadawi, Hassan; Atkins, Marvin D et al. (2011) Postischemic treatment with ethyl pyruvate prevents adenosine triphosphate depletion, ameliorates inflammation, and decreases thrombosis in a murine model of hind-limb ischemia and reperfusion. J Trauma 70:103-10; discussion 110
Crawford, Robert S; Albadawi, Hassan; Atkins, Marvin D et al. (2010) Postischemic poly (ADP-ribose) polymerase (PARP) inhibition reduces ischemia reperfusion injury in a hind-limb ischemia model. Surgery 148:110-8

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