1999 — 2000 |
Pennypacker, Keith |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
U.S.-Poland Workshop On Inducible Transcription Factors in the Brain @ University of South Florida
INT 9907032 Pennypacker
This is a U.S.-Polish workshop on inducible transcription factors in the brain. The US co-organizer is Dr. Keith Pennypacker of the University of South Florida and the Polish co-organizer is Dr. Leszek Kaczmarek of the Nencki Institute of Experimental Biology of the Polish Academy of Sciences. Recent research has indicated that a handful of transcription factors may exert dramatic influence on brain physiology and pathology. An understanding of this influence and dissecting it into specific components is the major challenge at present as it should lead to advancing our knowledge of signal transduction in the brain. This workshop will bring together a group of specialists from various countries to present their recent results and to discuss their implication for approaching this challenging scientific question.
This neuroscience workshop fulfills the program objectives of bringing together leading experts in the U.S. and Poland to combine complementary efforts and capabilities in areas of strong mutual interest and competence on the basis of equality, reciprocity, and mutuality of benefit.
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0.915 |
2000 — 2003 |
Pennypacker, Keith R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Nf-Kb Signal Transduction in Brain Injury @ University of South Florida
DESCRIPTION (adapted from applicant's abstract): Nuclear factor-kB (NF-kB), a transcription factor, is a component of anti-apoptotic signal transduction in immune-derived cells initiated by tumor necrosis factor receptor-1 stimulation. NF-kB is activated in the brain after injury and many genes, such as growth factors and cytokines, associated with regeneration and repair are target genes for this transcription factor. While the function of NF-kB in brain injury has been controversial, the investigator's laboratory has discovered increased expression NF-kB p50 in neurons surviving brain injury. They have observed an extended time-course (one to two weeks after injury) of p50 and p65 expression and elevated NFkB DNA binding activity suggesting that NF-kB signal transduction is involved in regulating genes related to regeneration and repair. They propose that brain injury leads to activation of NF-kB in neurons surviving injury and that this activation induces the transcription of growth factors that play a decisive role in promoting cell survival. They plan to examine NF-kB expression and activity in the rat hippocampus in response to injury caused by excitotoxicity (kainite), ischemia (middle cerebral arterial occlusion) and neurotoxicity (trimethyltin) to observe whether activation of NF-kB is a common event in injury to the brain. Transgenic mice containing a kB responsive promoter will be used to determine kB activation in the in vivo brain. The role of NF-kB in neuronal survival in hippocampus after injury will be discerned by blocking NF-kB transcription using p50 (p105) gene knockout mice and aspirin treatment. Hippocampal neuronal counts will be determined by unbiased cell counting to determine if inhibition of NF-kB activation increases neuronal death. Nerve growth factor, an important gene in the brain's repair and recovery, has been shown to be a target gene of NF-kB-driven transcription in brain cell cultures but this has not been demonstrated in in vivo brain injury models. They will determine whether nerve growth factor is a target for NF-kB-driven transcription in brain injury using co-localization studies in these brain injury models and inhibiting NF-kB activation using p50 (p105) gene knockout mice and aspirin treatment. These studies will define the role of NF-kB in the process of brain injury and subsequent repair and regeneration processes.
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1 |
2008 — 2009 |
Pennypacker, Keith R |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Expanding the Therapeutic Window For Stroke Treatment. @ University of South Florida
DESCRIPTION (provided by applicant): Stroke is a major health problem in the US with 800,000 people killed or debilitated each year. Currently, there is only one treatment, which needs to be administered within the first three hours of stroke onset. Our laboratory is examining treatments that would extend this therapeutic window. Our studies have shown that effective post-stroke treatment must possess both neuroprotective and anti-inflammatory properties. We have found that activation of sigma receptors decrease infarct area by over 80% when delivered 24 hours post- stroke in the rat. These receptors decrease neuronal death by depressing ischemia-induced intracellular calcium elevations, increased neuroexcitability and acid-sensing ion channel activation. Sigma receptors activation is also anti-inflammatory by blocking activation, migration and release of inflammatory cytotoxins from microglia. The goal of this proposal is to extend our initial findings that sigma receptor activation is a useful stroke treatment at timepoints beyond the current three hour window. The initial studies will determine the proper dose and therapeutic window for these compounds following an ischemic insult. The proposed study examines behavioral recovery promoted by sigma receptor activation at delayed time points following an ischemic insult. Moreover, we will test the sigma receptor ligand opipramol in our stroke model. Opipramol has been used clinically for over 40 years in Europe, which would accelerate its progression to clinical trials. Sigma receptor agonists are potential compounds to treat stroke many hours to days after onset to arrest the expansion of ischemic area through increasing neurosurvival and blocking the inflammatory response. Stroke is a major health problem in the USA with only one FDA-approved treatment, which has a limited therapeutic window. Since there have been no advances in stroke therapies, innovative approaches are needed to discover new agents to combat this pathologic condition. We have found that systemic administration of DTG, a sigma receptor agonist, has neuroprotective and anti-inflammatory properties that protects against stroke-induced brain injury at 24 hours post-stroke in rats. This proposal will further examine the therapeutic capability of DTG in stroked rats. Another sigma receptor agonist, opipramol, will also be examined for its therapeutic effectiveness in stroke. Opipramol has been used in humans for over 40 years as an anxiolytic agent.
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1 |
2012 — 2019 |
Pennypacker, Keith R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Anti-Oxidant Promoting Cytokine Lif Enhances Neural Cell Survival During Ischemia
? DESCRIPTION (provided by applicant): Leukemia inhibitory factor (LIF) is an anti-inflammatory cytokine that activates the expression of endogenous antioxidants in neural cells. Our laboratory has been examining the efficacy of LIF in the rodent stroke model of middle cerebral artery occlusion (MCAO), which reflects the most commonly occluded vessel in humans. We have found that LIF administered at 6 h after MCAO improves anatomical and functional outcomes in rats. Of interest, this treatment reflects a 33% extension of the therapeutic window when extrapolated to the current clinical stroke window for therapy. LIF increased the expression of antioxidant proteins via Akt in cultured neurons and oligodendrocytes. Aim 1: Is the efficacy of LIF dependent on SOD? We have found total superoxide dismutase (SOD) levels are significantly elevated and protein levels of one isoform, SOD3, are increased several-fold at 3 days following MCAO. In this Aim, we will determine if specific SOD subtype(s) are responsible for the LIF-induced effects and determine cell-specific expression of these SOD isoforms. MCAO studies will first use knockout mice to examine the SOD subtypes and these results will then be confirmed in rats. Aim 2: Does this LIF dosing regimen translate into long-term behavioral recovery? This Aim will determine whether this treatment regimen has lasting effects. These data will be used to devise a treatment regimen to extend the short-term efficacy to long-term histological and functional recovery at 90 days post-MCAO in rats. Aim 3: Which signals are transduced following LIF activation? The efficacy of LIF is dependent on the protein kinase Akt. From analysis of antioxidant promoters, the transcription factor MZF-1 is the putative transcription factor that activates their gene expression via Akt. We will use immunohistochemistry and gel shift assays to quantify their expression and promoter binding, respectively, in the infarct regions of rats treated with LIF after MCAO. siRNA techniques with neuronal cultures will be employed to knock down expression of this factor to validate previous findings. Aim 4: Will LIF administration be effective in elderly rats after MCAO? In this Aim, we will treat elderly male and female rats in short-term studies. These studies will b used to determine if there are any age- or sex- dependent differences in LIF efficacy after MCAO. Both histological and functional recovery will be examined. This proposal is aimed to further elucidate the mechanism(s) of LIF treatment and optimize the treatment regimen for long-term efficacy. While treatment with exogenous antioxidants has failed, we believe that the systemic activation of endogenous antioxidants is a better approach and could have substantial implications for treating clinical stroke.
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1 |
2019 |
Pennypacker, Keith R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Anti-Oxidant Promoting Cytokine Lif Ebhances Neural Cell Survival During Ischemia
Summary Leukemia inhibitory factor (LIF) is an anti-inflammatory cytokine that activates the expression of endogenous antioxidants in neural cells. Our laboratory has been examining the efficacy of LIF in the rodent stroke model of middle cerebral artery occlusion (MCAO), which reflects the most commonly occluded vessel in humans. We have found that LIF administered at 6 h after MCAO improves anatomical and functional outcomes in rats. Of interest, this treatment reflects a 33% extension of the therapeutic window when extrapolated to the current clinical stroke window for therapy. LIF increased the expression of antioxidant proteins via Akt in cultured neurons and oligodendrocytes. Aim 1: Is the efficacy of LIF dependent on SOD? We have found total superoxide dismutase (SOD) levels are significantly elevated and protein levels of one isoform, SOD3, are increased several-fold at 3 days following MCAO. In this Aim, we will determine if specific SOD subtype(s) are responsible for the LIF-induced effects and determine cell-specific expression of these SOD isoforms. MCAO studies will first use knockout mice to examine the SOD subtypes and these results will then be confirmed in rats. Aim 2: Does this LIF dosing regimen translate into long-term behavioral recovery? This Aim will determine whether this treatment regimen has lasting effects. These data will be used to devise a treatment regimen to extend the short-term efficacy to long-term histological and functional recovery at 90 days post-MCAO in rats. Aim 3: Which signals are transduced following LIF activation? The efficacy of LIF is dependent on the protein kinase Akt. From analysis of antioxidant promoters, the transcription factor MZF-1 is the putative transcription factor that activates their gene expression via Akt. We will use immunohistochemistry and gel shift assays to quantify their expression and promoter binding, respectively, in the infarct regions of rats treated with LIF after MCAO. siRNA techniques with neuronal cultures will be employed to knock down expression of this factor to validate previous findings. Aim 4: Will LIF administration be effective in elderly rats after MCAO? In this Aim, we will treat elderly male and female rats in short-term studies. These studies will be used to determine if there are any age- or sex- dependent differences in LIF efficacy after MCAO. Both histological and functional recovery will be examined. This proposal is aimed to further elucidate the mechanism(s) of LIF treatment and optimize the treatment regimen for long-term efficacy. While treatment with exogenous antioxidants has failed, we believe that the systemic activation of endogenous antioxidants is a better approach and could have substantial implications for treating clinical stroke.
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0.961 |