Stroke remains the second leading cause of death globally, with a total of 5.5 million deaths in ... more Stroke remains the second leading cause of death globally, with a total of 5.5 million deaths in 2016 and an estimated global lifetime risk of stroke for those aged 25 years or older at 24.9%. A key feature of stroke and poststroke injury is the inflammatory response, which is driven by a variety of pro-inflammatory cytokines to include interleukin-1 (IL-1). Evidence from pre-clinical studies have demonstrated a deleterious effect of IL-1 poststroke with a beneficial effect observed after blocking IL-1 in both pre-clinical and clinical settings. The IL-1 family has both IL-1β and IL-1α forms, and although IL-1β has been most closely studied, the distinct roles of both IL-1 isoforms during poststroke inflammation is largely unknown. In this study, we examined the contribution of IL-1α in ischemic stroke. We characterized the spatio-temporal effect of IL-1 in the brain after stroke using an in vivo model of middle cerebral artery thrombosis in an inducible IL-1α knockout mouse through...
The role of inflammation driven by the pro-inflammatory cytokine interleukin-1 (IL-1) during post... more The role of inflammation driven by the pro-inflammatory cytokine interleukin-1 (IL-1) during poststroke injury has been the focus of intense research. Indeed, pre-clinical studies have demonstrated the deleterious actions of IL-1 after stroke, whilst blocking its actions is beneficial in pre-clinical and clinical settings. Whilst most studies have focused on the role of IL-1β, the role of IL-1α during poststroke inflammation has been largely overlooked and very little has been done to examine the selective contribution of each IL-1 isoform in ischaemic stroke. In this study, we have investigated the contribution of IL-1α to ischaemic and haemorrhagic stroke. Methods : in vivo model of middle cerebral artery thrombosis through topical application of FeCl3 (40%) (n=4/group (4, 24, 72h) histology, n=6 /group (4, 24, 72 ) qPCR) in vivo model of haemorrhagic stroke induced by using the collagenase model (intra-striatal injection of collagenase VII-S, 0.045U) (n=4/group (4, 24h) histology...
Parkinson’s disease (PD) is the most common motor disease in the USA and results from loss of dop... more Parkinson’s disease (PD) is the most common motor disease in the USA and results from loss of dopaminergic (DA) neurons in the substantia nigra with autophagy dysfunction being closely linked to this disease. Recently, a PD-causing mutation in VPS35 (D620N) was reported to block autophagy. Using overexpression and shRNA-mediated gene repression, our lab has discovered evidence supporting a role for altered signlaing by the Insulin-like Growth Factor-1 Receptor (IGF-1R), a receptor known to regulate autophagy, in VPS35 D620N-expressing cells. This work may lead to the identification of new targets for PD therapy
Autophagy dysfunction is associated with a large number of human diseases that include Parkinson’... more Autophagy dysfunction is associated with a large number of human diseases that include Parkinson’s and Alzheimer’s disease. Autophagy is an essential cellular process for breaking down organelles and protein aggregates. To date, considerable efforts have been directed towards modulating autophagy for therapeutic benefit. However, these efforts have not yielded a single successful clinical treatment that harnesses autophagy. Consequently, we are focusing upon identifying lipid regulators of autophagy- a research area garnering little attention. We have discovered two novel modulators of autophagy through lipidomic analysis, 5-OXO-ETE and hydroxystearic acid. In order to better understand the molecular mechanism for their inhibition of autophagy, we are assessing mTOR signaling, a canonical autophagy-regulating pathway, following treatment with these two lipids. Our hope is that understanding how these lipids affect autophagic activity will lead to innovative treatments for human disease
The neuromuscular junction (nmj) is a commonly studied synapse, used often to investigate recipro... more The neuromuscular junction (nmj) is a commonly studied synapse, used often to investigate reciprocal signaling between a motor neuron and the appropriate target muscle. In Caenorhabditis elegans, ectopic nmjs can be created by eliminating selected embryonic muscle cells that act as guideposts for the migration of post-embryonic muscles. The ectopic muscles are required to induce sprouting from DD motor neurons, indicating the presence of a muscle derived signaling molecule that interacts with the neurons. A TGF-β homolog, unc-129, is reported to be transiently expressed in the dorsal body wall muscles. The timing of the expression of TGF-β coincides with the time that the DD motor neurons respecify their synapses. In this study, we show that TGF-β is expressed by the ectopic muscle and that in unc-129 mutant animals, the ectopic muscle is unable to induce sprouting from the DD motor neurons. Therefore, we conclude that TGF-β is necessary for ectopic nmj formation in C.elegans. INDEX...
Background Stroke remains a leading cause of death and disability worldwide despite recent treatm... more Background Stroke remains a leading cause of death and disability worldwide despite recent treatment breakthroughs. A primary event in stroke pathogenesis is the development of a potent and deleterious local and peripheral inflammatory response regulated by the pro-inflammatory cytokine interleukin-1 (IL-1). While the role of IL-1β (main released isoform) has been well studied in stroke, the role of the IL-1α isoform remains largely unknown. With increasing utilization of intravenous tissue plasminogen activator (t-PA) or thrombectomy to pharmacologically or mechanically remove ischemic stroke causing blood clots, respectively, there is interest in pairing successful cerebrovascular recanalization with neurotherapeutic pharmacological interventions (Fraser et al., J Cereb Blood Flow Metab 37:3531–3543, 2017; Hill et al., Lancet Neurol 11:942–950, 2012; Amaro et al., Stroke 47:2874–2876, 2016). Methods Transient stroke was induced in mice via one of two methods. One group of mice wer...
Although harboring the apolipoprotein E4 (APOE4) allele is a well known risk factor in Alzheimer&... more Although harboring the apolipoprotein E4 (APOE4) allele is a well known risk factor in Alzheimer's disease (AD), the mechanism by which it contributes to disease risk remains elusive. To investigate the role of proteolysis of apoE4 as a potential mechanism, we designed and characterized a site-directed cleavage antibody directed at position D151 of the mature form of apoE4 and E3. Characterization of this antibody indicated a high specificity for detecting synthesized recombinant proteins corresponding to the amino acid sequences 1-151 of apoE3 and E4 that would generate the 17 kDa (p17) fragment. In addition, this antibody also detected a ~17 kDa amino-terminal fragment of apoE4 following incubation with collagenase and matrix metalloproteinase-9 (MMP-9), but did not react with full-length apoE4. Application of this amino-terminal apoE cleavage-fragment (nApoECFp17) antibody, revealed nuclear labeling within glial cells and labeling of a subset of neurofibrillary tangles in the...
Stroke is a major cause of death and disability worldwide. Yet therapeutic strategies available t... more Stroke is a major cause of death and disability worldwide. Yet therapeutic strategies available to treat stroke are very limited. There is an urgent need to develop novel therapeutics that can effectively facilitate functional recovery. The injury that results from stroke is known to induce neurogenesis in penumbra of the infarct region. There is considerable interest in harnessing this response for therapeutic purposes. This review summarizes what is currently known about stroke-induced neurogenesis and the factors that have been identified to regulate it. Additionally, some key studies in this field have been highlighted and their implications on future of stroke therapy have been discussed. There is a complex interplay between neuroinflammation and neurogenesis that dictates stroke outcome and possibly recovery. This highlights the need for a better understanding of the neuroinflammatory process and how it affects neurogenesis, as well as the need to identify new mechanisms and p...
The function of dopaminergic neurons in the substantia nigra is of central importance to the coor... more The function of dopaminergic neurons in the substantia nigra is of central importance to the coordination of movement by the brain's basal ganglia circuitry. This is evidenced by the loss of these neurons, resulting in the cardinal motor deficits associated with Parkinson's disease. In order to fully understand the physiology of these key neurons and develop potential therapies for their loss, it is essential to determine if and how dopaminergic neurons are replenished in the adult brain. Recent work has presented evidence for adult neurogenesis of these neurons by Nestin/Sox2neural progenitor cells. We sought to further validate this finding and explore a potential atypical origin for these progenitor cells. Since neural progenitor cells have a proximal association with the vasculature of the brain and subsets of endothelial cells are Nestin, we hypothesized that dopaminergic neural progenitors might share a common cell lineage. Therefore, we employed a VE-cadherin promoter...
International journal of physiology, pathophysiology and pharmacology, 2017
Although harboring the apolipoprotein E4 (APOE4) allele is a well known risk factor in Alzheimer&... more Although harboring the apolipoprotein E4 (APOE4) allele is a well known risk factor in Alzheimer's disease (AD), the mechanism by which it contributes to disease risk remains elusive. To investigate the role of proteolysis of apoE4 as a potential mechanism, we designed and characterized a site-directed cleavage antibody directed at position D151 of the mature form of apoE4 and E3. Characterization of this antibody indicated a high specificity for detecting synthesized recombinant proteins corresponding to the amino acid sequences 1-151 of apoE3 and E4 that would generate the 17 kDa (p17) fragment. In addition, this antibody also detected a ~17 kDa amino-terminal fragment of apoE4 following incubation with collagenase and matrix metalloproteinase-9 (MMP-9), but did not react with full-length apoE4. Application of this amino-terminal apoE cleavage-fragment (nApoECFp17) antibody, revealed nuclear labeling within glial cells and labeling of a subset of neurofibrillary tangles in the...
Stroke remains the second leading cause of death globally, with a total of 5.5 million deaths in ... more Stroke remains the second leading cause of death globally, with a total of 5.5 million deaths in 2016 and an estimated global lifetime risk of stroke for those aged 25 years or older at 24.9%. A key feature of stroke and poststroke injury is the inflammatory response, which is driven by a variety of pro-inflammatory cytokines to include interleukin-1 (IL-1). Evidence from pre-clinical studies have demonstrated a deleterious effect of IL-1 poststroke with a beneficial effect observed after blocking IL-1 in both pre-clinical and clinical settings. The IL-1 family has both IL-1β and IL-1α forms, and although IL-1β has been most closely studied, the distinct roles of both IL-1 isoforms during poststroke inflammation is largely unknown. In this study, we examined the contribution of IL-1α in ischemic stroke. We characterized the spatio-temporal effect of IL-1 in the brain after stroke using an in vivo model of middle cerebral artery thrombosis in an inducible IL-1α knockout mouse through...
The role of inflammation driven by the pro-inflammatory cytokine interleukin-1 (IL-1) during post... more The role of inflammation driven by the pro-inflammatory cytokine interleukin-1 (IL-1) during poststroke injury has been the focus of intense research. Indeed, pre-clinical studies have demonstrated the deleterious actions of IL-1 after stroke, whilst blocking its actions is beneficial in pre-clinical and clinical settings. Whilst most studies have focused on the role of IL-1β, the role of IL-1α during poststroke inflammation has been largely overlooked and very little has been done to examine the selective contribution of each IL-1 isoform in ischaemic stroke. In this study, we have investigated the contribution of IL-1α to ischaemic and haemorrhagic stroke. Methods : in vivo model of middle cerebral artery thrombosis through topical application of FeCl3 (40%) (n=4/group (4, 24, 72h) histology, n=6 /group (4, 24, 72 ) qPCR) in vivo model of haemorrhagic stroke induced by using the collagenase model (intra-striatal injection of collagenase VII-S, 0.045U) (n=4/group (4, 24h) histology...
Parkinson’s disease (PD) is the most common motor disease in the USA and results from loss of dop... more Parkinson’s disease (PD) is the most common motor disease in the USA and results from loss of dopaminergic (DA) neurons in the substantia nigra with autophagy dysfunction being closely linked to this disease. Recently, a PD-causing mutation in VPS35 (D620N) was reported to block autophagy. Using overexpression and shRNA-mediated gene repression, our lab has discovered evidence supporting a role for altered signlaing by the Insulin-like Growth Factor-1 Receptor (IGF-1R), a receptor known to regulate autophagy, in VPS35 D620N-expressing cells. This work may lead to the identification of new targets for PD therapy
Autophagy dysfunction is associated with a large number of human diseases that include Parkinson’... more Autophagy dysfunction is associated with a large number of human diseases that include Parkinson’s and Alzheimer’s disease. Autophagy is an essential cellular process for breaking down organelles and protein aggregates. To date, considerable efforts have been directed towards modulating autophagy for therapeutic benefit. However, these efforts have not yielded a single successful clinical treatment that harnesses autophagy. Consequently, we are focusing upon identifying lipid regulators of autophagy- a research area garnering little attention. We have discovered two novel modulators of autophagy through lipidomic analysis, 5-OXO-ETE and hydroxystearic acid. In order to better understand the molecular mechanism for their inhibition of autophagy, we are assessing mTOR signaling, a canonical autophagy-regulating pathway, following treatment with these two lipids. Our hope is that understanding how these lipids affect autophagic activity will lead to innovative treatments for human disease
The neuromuscular junction (nmj) is a commonly studied synapse, used often to investigate recipro... more The neuromuscular junction (nmj) is a commonly studied synapse, used often to investigate reciprocal signaling between a motor neuron and the appropriate target muscle. In Caenorhabditis elegans, ectopic nmjs can be created by eliminating selected embryonic muscle cells that act as guideposts for the migration of post-embryonic muscles. The ectopic muscles are required to induce sprouting from DD motor neurons, indicating the presence of a muscle derived signaling molecule that interacts with the neurons. A TGF-β homolog, unc-129, is reported to be transiently expressed in the dorsal body wall muscles. The timing of the expression of TGF-β coincides with the time that the DD motor neurons respecify their synapses. In this study, we show that TGF-β is expressed by the ectopic muscle and that in unc-129 mutant animals, the ectopic muscle is unable to induce sprouting from the DD motor neurons. Therefore, we conclude that TGF-β is necessary for ectopic nmj formation in C.elegans. INDEX...
Background Stroke remains a leading cause of death and disability worldwide despite recent treatm... more Background Stroke remains a leading cause of death and disability worldwide despite recent treatment breakthroughs. A primary event in stroke pathogenesis is the development of a potent and deleterious local and peripheral inflammatory response regulated by the pro-inflammatory cytokine interleukin-1 (IL-1). While the role of IL-1β (main released isoform) has been well studied in stroke, the role of the IL-1α isoform remains largely unknown. With increasing utilization of intravenous tissue plasminogen activator (t-PA) or thrombectomy to pharmacologically or mechanically remove ischemic stroke causing blood clots, respectively, there is interest in pairing successful cerebrovascular recanalization with neurotherapeutic pharmacological interventions (Fraser et al., J Cereb Blood Flow Metab 37:3531–3543, 2017; Hill et al., Lancet Neurol 11:942–950, 2012; Amaro et al., Stroke 47:2874–2876, 2016). Methods Transient stroke was induced in mice via one of two methods. One group of mice wer...
Although harboring the apolipoprotein E4 (APOE4) allele is a well known risk factor in Alzheimer&... more Although harboring the apolipoprotein E4 (APOE4) allele is a well known risk factor in Alzheimer's disease (AD), the mechanism by which it contributes to disease risk remains elusive. To investigate the role of proteolysis of apoE4 as a potential mechanism, we designed and characterized a site-directed cleavage antibody directed at position D151 of the mature form of apoE4 and E3. Characterization of this antibody indicated a high specificity for detecting synthesized recombinant proteins corresponding to the amino acid sequences 1-151 of apoE3 and E4 that would generate the 17 kDa (p17) fragment. In addition, this antibody also detected a ~17 kDa amino-terminal fragment of apoE4 following incubation with collagenase and matrix metalloproteinase-9 (MMP-9), but did not react with full-length apoE4. Application of this amino-terminal apoE cleavage-fragment (nApoECFp17) antibody, revealed nuclear labeling within glial cells and labeling of a subset of neurofibrillary tangles in the...
Stroke is a major cause of death and disability worldwide. Yet therapeutic strategies available t... more Stroke is a major cause of death and disability worldwide. Yet therapeutic strategies available to treat stroke are very limited. There is an urgent need to develop novel therapeutics that can effectively facilitate functional recovery. The injury that results from stroke is known to induce neurogenesis in penumbra of the infarct region. There is considerable interest in harnessing this response for therapeutic purposes. This review summarizes what is currently known about stroke-induced neurogenesis and the factors that have been identified to regulate it. Additionally, some key studies in this field have been highlighted and their implications on future of stroke therapy have been discussed. There is a complex interplay between neuroinflammation and neurogenesis that dictates stroke outcome and possibly recovery. This highlights the need for a better understanding of the neuroinflammatory process and how it affects neurogenesis, as well as the need to identify new mechanisms and p...
The function of dopaminergic neurons in the substantia nigra is of central importance to the coor... more The function of dopaminergic neurons in the substantia nigra is of central importance to the coordination of movement by the brain's basal ganglia circuitry. This is evidenced by the loss of these neurons, resulting in the cardinal motor deficits associated with Parkinson's disease. In order to fully understand the physiology of these key neurons and develop potential therapies for their loss, it is essential to determine if and how dopaminergic neurons are replenished in the adult brain. Recent work has presented evidence for adult neurogenesis of these neurons by Nestin/Sox2neural progenitor cells. We sought to further validate this finding and explore a potential atypical origin for these progenitor cells. Since neural progenitor cells have a proximal association with the vasculature of the brain and subsets of endothelial cells are Nestin, we hypothesized that dopaminergic neural progenitors might share a common cell lineage. Therefore, we employed a VE-cadherin promoter...
International journal of physiology, pathophysiology and pharmacology, 2017
Although harboring the apolipoprotein E4 (APOE4) allele is a well known risk factor in Alzheimer&... more Although harboring the apolipoprotein E4 (APOE4) allele is a well known risk factor in Alzheimer's disease (AD), the mechanism by which it contributes to disease risk remains elusive. To investigate the role of proteolysis of apoE4 as a potential mechanism, we designed and characterized a site-directed cleavage antibody directed at position D151 of the mature form of apoE4 and E3. Characterization of this antibody indicated a high specificity for detecting synthesized recombinant proteins corresponding to the amino acid sequences 1-151 of apoE3 and E4 that would generate the 17 kDa (p17) fragment. In addition, this antibody also detected a ~17 kDa amino-terminal fragment of apoE4 following incubation with collagenase and matrix metalloproteinase-9 (MMP-9), but did not react with full-length apoE4. Application of this amino-terminal apoE cleavage-fragment (nApoECFp17) antibody, revealed nuclear labeling within glial cells and labeling of a subset of neurofibrillary tangles in the...
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Papers by Abir Rahman