? ? A major problem with recombinant tissue plasminogen activator (rt-PA) for ischemic stroke is the limited time window for effective therapy and the related complications of cerebral hemorrhage and edema. In response to RFA-HL-05-004, we propose a series of translational animal experiments to test the idea that simultaneously inhibiting matrix metalloproteinases (MMPs) will reduce rt-PA complications, and significantly increase the time window for reperfusion therapy. ? ? In Aim 1, we will use a well characterized rat model of embolic (clot-based) focal cerebral ischemia to test the effects of combining rt-PA with the broad spectrum MMP inhibitors BB-94 and minocycline. We will assess the effects of different times of treatment 3-12 h post-ischemia to see whether MMP inhibition can lengthen the time window for effective rt-PA reperfusion.
In Aim 2, we will assess the use of immunoliposomes to target our MMP inhibitors to areas of neurovascular damage. Because MMPs also participate in normal physiology, this form of targeting may be required to optimize clinical use. We will test anti-actin and anti-adhesion molecule (e.g. ICAM-1, E-selectin) immunoliposomes that target cells with damaged membranes and activated (""""""""inflammed"""""""") endothelium and astrocytes. In the rat model of embolic clot stroke, we will compare the effects of """"""""naked"""""""" BB-94 and minocycline versus immunoliposome-encapsulated compounds. Finally, in Aim 3, we will use in vivo 2-photon imaging to assess rt-PA, MMP inhibition, and vascular leakage within cranial windows in the rat model of embolic stroke. DQ-FITC-gelatin will be infused into the cranial windows, then in vivo 2-photon imaging will be used to map neurovascular MMP activity overtime. Blood-brain barrier integrity will be assessed using fluorescent dextrans of different sizes. We will compare MMP profiles after saline, rt-PA, or rt-PA plus MMP inhibitors. ? ? Over the past 6 years, our lab has accumulated cellular and mechanistic data implicating MMPs in rt-PA thrombolytic complications after stroke. We are now ready to perform the required translational studies derived from our basic findings. If we can obtain proof-of-concept in our animal models that rt-PA plus MMP inhibitors can significantly lengthen the time window for safe and effective reperfusion, this may be an important step forward for combination stroke therapy. (End of Abstract) ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS056458-01
Application #
7008445
Study Section
Special Emphasis Panel (ZHL1-CSR-H (O1))
Program Officer
Jacobs, Tom P
Project Start
2006-02-15
Project End
2011-01-31
Budget Start
2006-02-15
Budget End
2007-01-31
Support Year
1
Fiscal Year
2006
Total Cost
$268,430
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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