1986 — 1988 |
Chopp, Michael |
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. |
Prediction of Radiation/Phototherapy Response With Nmr
Presently, there is no early marker for the effectiveness of radiation therapy and phototherapy in the treatment of cancer. The goal of the present proposal is to document cellular and metabolic changes that occur in tumors in response to two therapeutic modalities, radiation therapy and phototherapy, administered at subcurative and curative treatment levels. In vivo 31P Nuclear Magnetic Resonance (NMR) will be employed to monitor intracellular pH and relative concentrations of high energy phosphate metabolites in conjunction with PO2 and pH microelectrode measurements. All measurements will be correlated with biological endpoints. Studies will be performed on C3H mouse mammary carcinoma. Experimental determinations made both during and following therapy will define both acute and long term response to the treatment. Our long term objective is to establish in vivo 31P NMR spectroscopy as a method for non-invasively assessing tumor response to radiation therapy and phototherapy.
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0.915 |
1991 — 1993 |
Chopp, Michael |
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. |
Investigation of Chronic Post Ischemic Brain Alkalosis @ Henry Ford Health System
DESCRIPTION (Adapted from the applicant's abstract): The specific aim of this study is to clarify the relationship between post ischemic brain tissue alkalosis and ischemic neuronal damage, and ultimately to demonstrate that brain alkalosis, as measured by NMR, is a useful marker of neuronal injury. The following Specific Aims are in accord with this goal: 1) To measure brain pH, using in vivo 31P phosphorous NMR spectroscopy serially for one week following the induction of ischemia, and to also measure neuronal damage in the same tissue. These measurements will be performed as a function of the duration of transient forebrain ischemia, as well as for a "protective" hypothermic intervention in the rat. The hypothesis being tested is that the extent of neuronal cell damage is directly correlated with the magnitude, onset time and duration of alkalosis detected from the same tissue. The basis for this correlation is that the temporal profile of alkalosis reflects cellular inflammatory processes, associated with neuronal damage. 2) To measure, at particular time points after ischemia, inflammatory cellular response and glial proliferation, neuronal damage and brain tissue pH, as a function of the duration of transient forebrain ischemia and for a hypothermic intervention. The hypothesis being tested is that inflammatory cellular response and glial proliferation is directly correlated to neuronal damage; hence brain tissue alkalosis is directly correlated to neuronal damage. 3) To measure, in conjunction with the above studies, cerebral blood flow and relative concentrations of brain high energy phosphates and lactates. These measurements will address the relationship between brain tissue alkalosis, and CBF and metabolic changes in the tissue. It is proposed that post ischemic brain pH changes will be closely coupled to ultimate tissue viability, and that the studies will therefore highlight the potential diagnostic significance of chronic pH measurements in stroke patients.
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0.907 |
1992 — 1994 |
Chopp, Michael |
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. |
Pdt Threshold Dose in Brain @ Henry Ford Health System
Successful Photodynamic Therapy (PDT) treatment results in necrosis of target tissue. The tissue response clearly depends on the interplay between the treatment-dependent parameters of, light irradiation technique, light "dose" to the tissue and administered dose of photosensitizer (PS), with the subject-dependent parameters of, photosensitizer uptake in the target tissue, tissue oxygenation and inherent tissue photosensitivity to the particular photosensitizer. For the purposes of understanding mechanisms of action of photosensitizers, and comparing the true photoeffectiveness of different photosensitizers in tumor and normal tissues, and thus the efficacy of PDT treatment, it is highly desirable to have a quantifiable measure of the true tissue photosensitivity, with the complexities of the particular treatment conditions factored out. The objectives of this study are therefore, to measure and modify the response of brain tumor and normal brain tissue to PDT, with the ultimate goal of improving the therapeutic efficacy for treatment of brain tumor. The Specific Aims of this project to achieve these objectives are: 1.(a,b) To test the validity of a PDT threshold model for tumor and brain tissue necrosis, and to determine the threshold dose for PDT treatment in tumor and normal rat brain. The hypothesis to be tested is; if the number of photons absorbed by the photosensitizer per unit volume of tissue exceeds a critical (threshold) value, then necrosis will occur. This number may be different for normal and tumored brain. 2. To modify the PDT threshold values in brain by varying treatment parameters including: (a) photosensitizer (b) photoactivating light intensity (c) time interval between photosensitizer administration and photoactivation (di) site of treatment in brain. (dii) Time interval between photosensitizer administration and photoactivation for gray vs. white matter. Measurements of tissue concentration of photosensitizer, optical dose and tissue P02, and radius of tissue necrosis will be used to quantify both tumored and normal brain tissue photosensitivity to PDT.
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0.907 |
1994 |
Chopp, Michael |
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. |
Chronic Post Ischemic Brain Alkalosis @ Henry Ford Health System
DESCRIPTION (Adapted from the applicant's abstract): The specific aim of this study is to clarify the relationship between post ischemic brain tissue alkalosis and ischemic neuronal damage, and ultimately to demonstrate that brain alkalosis, as measured by NMR, is a useful marker of neuronal injury. The following Specific Aims are in accord with this goal: 1) To measure brain pH, using in vivo 31P phosphorous NMR spectroscopy serially for one week following the induction of ischemia, and to also measure neuronal damage in the same tissue. These measurements will be performed as a function of the duration of transient forebrain ischemia, as well as for a "protective" hypothermic intervention in the rat. The hypothesis being tested is that the extent of neuronal cell damage is directly correlated with the magnitude, onset time and duration of alkalosis detected from the same tissue. The basis for this correlation is that the temporal profile of alkalosis reflects cellular inflammatory processes, associated with neuronal damage. 2) To measure, at particular time points after ischemia, inflammatory cellular response and glial proliferation, neuronal damage and brain tissue pH, as a function of the duration of transient forebrain ischemia and for a hypothermic intervention. The hypothesis being tested is that inflammatory cellular response and glial proliferation is directly correlated to neuronal damage; hence brain tissue alkalosis is directly correlated to neuronal damage. 3) To measure, in conjunction with the above studies, cerebral blood flow and relative concentrations of brain high energy phosphates and lactates. These measurements will address the relationship between brain tissue alkalosis, and CBF and metabolic changes in the tissue. It is proposed that post ischemic brain pH changes will be closely coupled to ultimate tissue viability, and that the studies will therefore highlight the potential diagnostic significance of chronic pH measurements in stroke patients.
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0.907 |
1995 |
Chopp, Michael |
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 Icam 1 Antobody Treatment After McA Occlusion @ Henry Ford Health System
Ischemic brain injury evokes an endogenous brain parenchymal cell damage as well as an exogenous inflammatory response, which includes infiltration and accumulation of polymorphonuclear leukocytes and monocytes/macrophages, and microvascular proliferation. The migration and accumulation of neutrophils into the ischemic tissue after reperfusion is not only associated with tissue repair processes, but also may result in injury to potentially viable tissue. We propose to reduce ischemic cell damage after middle cerebral artery (MCA) occlusion in the rat by selectively blocking the intercellular adhesion molecule 1 (ICAM-1), a glycoprotein expressed on endothelial cells that facilitates leukocyte adhesion. Three specific aims and hypotheses will be tested. Aim 1: The effect of administration of a monoclonal antibody to the rat ICAM-1 on reducing ischemic cell damage will be investigated in rats subjected to transient (2 hours) and permanent MCA occlusion. Ischemic cell damage will be measured as a function of dose and time of antibody administration. Hypothesis: A monoclonal antibody reactive with the ICAM-1 glycoprotein reduces ischemic cell damage after transient MCA occlusion. Aim 2: We will measure the temporal profiles of expression of ICAM-1 and ICAM-1 mRNA in brain after transient MCA occlusion. Hypothesis: MCA occlusion results in an increase of both ICAM-1 message and protein in ischemic brain. Aim 3: Mechanisms by which the anti-ICAM-1 reactive antibody reduces ischemic cell damage will be investigated. 3(a): We will measure and correlate the temporal profile of the extent of neutrophil infiltration into the ischemic tissue with ischemic cell damage. Hypothesis: Anti-ICAM-1 antibody causes a reduction of neutrophils in the ischemic tissue. Infiltration of neutrophils into the ischemic tissue precedes or is concomitant with ischemic cell damage, and contributes to ischemic cell damage after transient focal cerebral ischemia. We will perform quantitative autoradiographic measurements of local cerebral blood flow at time points after transient MCA occlusion. Hypothesis: Neutrophils may contribute to ischemic cell damage in reperfusion injury by reducing local cerebral blood flow (CBF) and extending the duration of ischemia. Our long term objective is to develop a therapeutic intervention (anti- ICAM-1 antibody) to be employed after the onset of ischemic stroke.
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0.907 |
1995 — 2011 |
Chopp, Michael |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Center For Stroke Research @ Henry Ford Health System
DESCRIPTION (Applicant's Abstract): The applicants propose a highly integrated application focused on preclinical and clinical studies to investigate and develop treatment of stroke with an anti-platelet aggregation agent alone, and in combination with thrombolysis using recombinant tissue plasminogen activator (rtPA). Permeating this Program is the development and application of MRI to enhance the management of the stroke patient. Three interdependent Projects and two Cores constitute this grant application. Project 1, Anti-Platelet Aggregation Therapy for Embolic Stroke, will investigate the mechanisms promoting secondary thrombosis after embolic stroke and treatment with rtPA in rat, and will test, in a controlled experimental model, treatment of embolic stroke with an antibody against the GPIIb/IIIa receptor. This receptor binds the platelet to fibrin and is responsible for platelet aggregation and therefore, platelet mediated thrombosis. This project leads into Project 2, MR Assessment of Transient Cerebral Ischemia, which develops and applies a multi-parameter MRI model to experimental embolic stroke in rats. The goals of this Project are to develop and test the application of the multi-parameter MRI model to identify candidates for therapy and to exclude candidates from therapy after embolic stroke. In addition, the MRI response to thrombolysis with rtPA and rtPA in combination with an antagonist to platelet aggregation will be tested. Projects 1 and 2 form the preclinical support for a Phase II Pilot Clinical Trial of treatment of stroke with an anti-platelet aggregation agent, abciximab. This Project will test activity of treatment of the stroke patient with abciximab and will identify an MRI based surrogate marker for activity and accrue MR data to select patients for anti-platelet aggregation therapy. Core A is an Administrative and Biostatistical Core. Core B, the MRI core, services all three Projects. The Program Project provides an integrated highly coherent effort to enhance management and therapeutic intervention in the treatment of acute stroke.
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0.907 |
1995 — 2000 |
Chopp, Michael |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Evaluation of Anti-Adhesion Molecule Therapy After McA Occlusion in the Rat @ Henry Ford Health System
Our goals are; to reduce ischemic cell damage after middle cerebral artery (MCA) occlusion in the rat by selectively blocking leukocyte adhesion molecule receptors (CD11b, LFA-1), to investigate mechanisms by which blocking these receptors reduce ischemic cell damage, and to bring to fruition magnetic resonance imaging as a non-invasive method of assessing the response of ischemic tissue to a therapeutic intervention. To accomplish these goals we will employ experiments associated with three Specific Aims. Aim 1: The effect of anti-(CD11b, LFA-1) monoclonal antibodies on reducing ischemic cell damage will be investigated in rats subjected to transient (2 hours) MCA occlusion. Ischemic cell damage will be measured as a function of dose and time of antibody administration. Hypothesis: A monoclonal antibody reactive with an integrin reduces ischemic cell damage will be measured as a function of dose and time of antibody administration. Hypothesis: A monoclonal antibody reactive with an integrin reduces ischemic cell damage after transient MCA occlusion. Aim 2: Mechanisms by which the anti-CD11b and anti-LFA-1 reactive antibodies reduce ischemic cell damage will be investigated. 2(a); We will measure and correlate the temporal profile of the extent of neutrophil infiltration into the ischemic tissue with ischemic cell damage. Hypothesis; Infiltration of leukocytes, primarily neutrophils, into the ischemic tissue precedes or is concomitant with ischemic cell damage, and contributes to ischemic cell damage after transient focal cerebral ischemia. 2 (b). We will perform quantitative autoradiographic measurements of local cerebral blood flow at time points after transient MCA occlusion. Hypothesis; Neutrophils may contribute to ischemic cell damage in reperfusion injury by reducing local cerebral blood flow. 2(c): The permeability of the blood-brain barrier (BBB) will be evaluated at various times after transient MCA occlusion. Hypothesis; Neutrophils may contribute in part to ischemic cell damage by interacting with the capillary endothelium and thereby increasing the permeability of the BBB to water and neurotoxic substances. Aim 3: We will employ NMR methodology (Perfusion Imaging, Diffusion Weighted Imaging (DWI), T1 & T2 Imaging) to assess the physiological changes and efficacy of the anti- integrin therapeutic intervention. Hypothesis: With effective leukocyte anti-adhesion molecule therapy, the temporal profiles and values of the apparent diffusion constant of water (ADC)w) and CBF in the ischemic tissue will be modified, and the volume of the lesion as measured by T2 weighted imaging will be reduced compared to animals without antibody.
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0.907 |
1995 — 1998 |
Chopp, Michael |
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. |
Mab to Leukocyte Adhesion Molecules-Treatment After McAo @ Henry Ford Health System
DESCRIPTION (Investigator's Abstract): Our goal is to determine the efficacy and parameters of application of employing monoclonal antibodies against Ieukocyte adhesion molecules to reduce ischemic cell damage after middle cerebral artery (MCA) occlusion in the rat. Our underlying hypothesis is that leukocytes, primarily neutrophils, contribute to ischemic cell damage after transient MCA occlusion. Therefore, by blocking adhesion molecule binding sites on the Ieukocyte, adhesion of the leukocyte, to the endothelium and subsequent emigration of the leukocyte into the brain parenchyma will be reduced, and concomitantly ischemic cell damage will be reduced. We will test-the effect of administration of three antibodies, anti-CDt t b, anti-CDt 8, and anti-VLA-4 on -ischemic - cell damage. Anti-CDt lb and anti-CDt 8 monoclonal antibodies will block neutrophil and monocyte adherence and emigration, while the anti-VLA-4 antibody will reduce monocytes within the ischemic lesion. A dose-response for antibody administration will be obtained as function of duration of the lVICA. Since the inflammatory response occurs well into the reperfusion period, we will also test the efficacy of administering these antibodies after onset of reperfusion, and identify the longest duration of reperfusion for which- this -intervention is effective in reducing ischemic cell damage. The mechanisms by which these leukocyte anti-adhesion molecule monoclonal antibodies reduce ischemic cell damage will be investigated. For treatment with anti-adhesion molecule antibodies and with isotype matched, controls, leukocytes (neutrophils and monocytesj will be correlated to ischemic cell damage within regions of the ischemic tissue, and neutrophil numbers will be counted using a myeloperoxidase assay. Quantitative autoradiography will be employed to measure cerebral blood flow and the permeability of the blood-brain-barrier (RlSA, AlB), with and without treatment. The proposed studies will optimize treatment of MCA occlusion and define the limits of applicability (duration of ischemia and reperfusion) of this promising therapy.
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0.907 |
1996 — 1998 |
Chopp, Michael |
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-Icam-1 Antibody Treatment After McA Occlusion @ Henry Ford Health System
Ischemic brain injury evokes an endogenous brain parenchymal cell damage as well as an exogenous inflammatory response, which includes infiltration and accumulation of polymorphonuclear leukocytes and monocytes/macrophages, and microvascular proliferation. The migration and accumulation of neutrophils into the ischemic tissue after reperfusion is not only associated with tissue repair processes, but also may result in injury to potentially viable tissue. We propose to reduce ischemic cell damage after middle cerebral artery (MCA) occlusion in the rat by selectively blocking the intercellular adhesion molecule 1 (ICAM-1), a glycoprotein expressed on endothelial cells that facilitates leukocyte adhesion. Three specific aims and hypotheses will be tested. Aim 1: The effect of administration of a monoclonal antibody to the rat ICAM-1 on reducing ischemic cell damage will be investigated in rats subjected to transient (2 hours) and permanent MCA occlusion. Ischemic cell damage will be measured as a function of dose and time of antibody administration. Hypothesis: A monoclonal antibody reactive with the ICAM-1 glycoprotein reduces ischemic cell damage after transient MCA occlusion. Aim 2: We will measure the temporal profiles of expression of ICAM-1 and ICAM-1 mRNA in brain after transient MCA occlusion. Hypothesis: MCA occlusion results in an increase of both ICAM-1 message and protein in ischemic brain. Aim 3: Mechanisms by which the anti-ICAM-1 reactive antibody reduces ischemic cell damage will be investigated. 3(a): We will measure and correlate the temporal profile of the extent of neutrophil infiltration into the ischemic tissue with ischemic cell damage. Hypothesis: Anti-ICAM-1 antibody causes a reduction of neutrophils in the ischemic tissue. Infiltration of neutrophils into the ischemic tissue precedes or is concomitant with ischemic cell damage, and contributes to ischemic cell damage after transient focal cerebral ischemia. We will perform quantitative autoradiographic measurements of local cerebral blood flow at time points after transient MCA occlusion. Hypothesis: Neutrophils may contribute to ischemic cell damage in reperfusion injury by reducing local cerebral blood flow (CBF) and extending the duration of ischemia. Our long term objective is to develop a therapeutic intervention (anti- ICAM-1 antibody) to be employed after the onset of ischemic stroke.
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0.907 |
1998 — 2002 |
Chopp, Michael |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Liposome and Bso Enhancement of Photodynamic Therapy
The objective of this proposal is to enhance the treatment of brain tumor with PDT. We have identified two methods to increase the efficacy of PDT to selectively kill brain tumor relative to normal brain. Photofrin administered encapsulated in a liposome and photofrin administered in conjunction with buthionine sulfoximide (BSO) (a glutathione inhibitor) significantly increases the PDT toxicity to tumor cells. In this project, we will develop, implement and optimize these con-PDT treatment methods of enhancing the PDT of brain tumor and investigate biophysical mechanisms responsible for this therapeutic enhancement. Aim A: To measure the relative increase in therapeutic efficacy of photodynamic therapy in experimental brain tumor in rat treated with Photofrin encapsulated in a liposome (Photofrin-liposome) as the photosensitizing agent compared to Photofrin in a dextrose vehicle (Photofrin-dextrose) as the photosensitizing agent. Hypothesis A: The enhancement of PDT in the treatment of brain tumor with Photofrin-liposome when compared to Photofrin-dextrose is attributed to alterations of the pharmacokinetics and the intracellular localization of Photofrin. Aim B: To measure the relative increase in therapeutic efficacy of photodynamic therapy in experimental brain tumor in rat treated with Photofrin by using buthionine sulfoximide (BSO) as an adjuvant to PDT. Hypothesis B: Administration of BSO decreases the level of gluthione in brain tumor tissue and therefore augments the intensity of brain tumor destruction with PDT. We expect that the optimization of these methods of enhancement of PDT destruction of brain tumor will find application in the clinic and may direct augmentation of human brain tumor treatment.
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0.909 |
1999 — 2000 |
Chopp, Michael |
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. |
Antiicam-1 and Rtpa Treatment of Embolic Stroke in Rat @ Henry Ford Health System
Our goals are to extend the therapeutic window and to reduce adverse effects associated with thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) of embolic stroke. To accomplish these goals we will treat embolic stroke in the rat with a combination of rtPA and anti-adhesion molecule therapy using an antibody against the intercellular adhesion molecule (ICAM-1). The fundamental outcome measurements of the combination therapy will be volume of cerebral infarction and net hemorrhage. The mechanistic bases for secondary damage associated with delayed thrombolytic therapy will be investigated using quantitative laser scanning confocal microscopy (LSCM), immunohistochemistry, histology and Western blot analysis. We will quantify secondary embolization, thrombosis and vascular occlusion after embolic stroke, with and without combination therapy. Microvascular perfusion deficits will be measured under experimental conditions, as will adhesion molecule expression and localization of proinflammatory cytokines (IL1beta, TNFalpha) and vascular endothelial growth factor (VEGF). Cytokine and VEGF expression may be modulated by rtPA, and contribute to inflammatory responses and vascular disruption. Astrocytic response to treatment conditions and vascular deficits will also be quantified. The major strengths of our proposed studies are: 1) we focus on an immediate and highly relevant clinical problem, the need to expand access of stroke patients to rtPA treatment and to reduce secondary adverse effects from thrombolytic therapy. 2) the model of embolic stroke that we have developed and characterized closely adheres to the pathophysiological events and the etiology of human thromboembolic stroke. 3) we have novel data and new insights into the mechanisms of secondary rtPA induced damage, e.g. the enhancement of the inflammatory response to stroke evoked by rtPA treatment, the correlation of expression of VEGF and activation on astrocytes, and the reduction of perfusion. 4) we have developed, characterized and employed a novel technology, quantitative LSCM to the study of experimental stroke. This technology and the proposed experiments will enhance our understanding of the mechanisms underlying microvascular dysfunction and occlusion after stroke and thrombolytic treatment.
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0.907 |
2001 — 2002 |
Chopp, Michael |
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. |
Antiicam-1 and Rtpa Treatment of Embolic Stroke @ Henry Ford Health System
Our goals are to extend the therapeutic window and to reduce adverse effects associated with thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) of embolic stroke. To accomplish these goals we will treat embolic stroke in the rat with a combination of rtPA and anti-adhesion molecule therapy using an antibody against the intercellular adhesion molecule (ICAM-1). The fundamental outcome measurements of the combination therapy will be volume of cerebral infarction and net hemorrhage. The mechanistic bases for secondary damage associated with delayed thrombolytic therapy will be investigated using quantitative laser scanning confocal microscopy (LSCM), immunohistochemistry, histology and Western blot analysis. We will quantify secondary embolization, thrombosis and vascular occlusion after embolic stroke, with and without combination therapy. Microvascular perfusion deficits will be measured under experimental conditions, as will adhesion molecule expression and localization of proinflammatory cytokines (IL1beta, TNFalpha) and vascular endothelial growth factor (VEGF). Cytokine and VEGF expression may be modulated by rtPA, and contribute to inflammatory responses and vascular disruption. Astrocytic response to treatment conditions and vascular deficits will also be quantified. The major strengths of our proposed studies are: 1) we focus on an immediate and highly relevant clinical problem, the need to expand access of stroke patients to rtPA treatment and to reduce secondary adverse effects from thrombolytic therapy. 2) the model of embolic stroke that we have developed and characterized closely adheres to the pathophysiological events and the etiology of human thromboembolic stroke. 3) we have novel data and new insights into the mechanisms of secondary rtPA induced damage, e.g. the enhancement of the inflammatory response to stroke evoked by rtPA treatment, the correlation of expression of VEGF and activation on astrocytes, and the reduction of perfusion. 4) we have developed, characterized and employed a novel technology, quantitative LSCM to the study of experimental stroke. This technology and the proposed experiments will enhance our understanding of the mechanisms underlying microvascular dysfunction and occlusion after stroke and thrombolytic treatment.
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0.907 |
2001 — 2002 |
Chopp, Michael |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Antiplatelet Aggregation Therapy For Embolic Stroke @ Henry Ford Health System
There is a compelling need to develop therapies complementary to thrombolysis for the treatment of acute stroke. In this Project, we test the hypothesis that microvascular thrombosis ensues after stroke and that platelet aggregation contributes to progression of the fulminating ischemic lesion. Thus, treatment of embolic stroke with an antagonist to the GPIIb/IIIa receptor, which binds the platelet to fibrinogen and is the terminus of platelet with an antagonist to the GPIIb/IIIa receptor, which binds the platelet to fibrinogen and is the terminus of platelet thrombosis, may enhance cerebral perfusion, reduce thrombosis and complement and enhance thrombolytic therapy of stroke with rtPA. To achieve our goals, we propose four Specific Aims: Specific Aim 1: Rats will be subjected to embolic stroke and the spatiotemporal profiles of tissue perfusion and thrombosis will be measured. Specific Aim 2: Rats will be subjected to embolic stroke and will be treated with rtPA at specific time paints after stroke (2h, 4h, 6h). The volume of cerebral infarction and the spatiotemporal profiles of tissue perfusion and thrombosis will be measured. Specific Aim 3: Rats will be subjected to embolic stroke and will be treated with GP IIb/IIIa receptor antagonist at specific time points before and after stroke. The volume of cerebral infarction and the spatiotemporal profiles of tissue perfusion and thrombosis will be measured. Specific Aim 2: Rats will be subjected to embolic stroke and will be treated with rtPA and specific time points after stroke (2h, 4h, 6h). The volume of cerebral infarction and the spatiotemporal profiles of tissue perfusion and thrombosis will be measured. Specific Aim 3: Rats will be subjected to embolic stroke and will be treated with a GP IIb/IIIa receptor antagonist at specific time points before and after stroke. The volume of cerebral infarction and the spatiotemporal profiles of tissue perfusion and thrombosis will be measured. Specific Aim 4: Rats will be subjected to embolic stroke and will be treated with a combination of GPIIb/IIIa receptor antagonist and fibrinolysis with rtPA at specific time points after stroke. To test our hypotheses, we employ a clinically relevant model of embolic stroke in the rat and state-of-the-art technology, including quantita6tive scanning confocal microscopy and MRI. Our long term objective of developing anti-platelet aggregation therapy in the human is initiated in the Phase II Clinical Trial to be carried out in Project 3. This Project provides the experimental basis for reducing platelet mediated thrombosis secondary to stroke.
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0.907 |
2001 — 2002 |
Chopp, Michael |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Core--Biostatistics @ Henry Ford Health System
The Administrative and Biostatistics Core will: promote high quality collaborative research in cerebral vascular disease by providing a supportive academic environment in which investigators can carry out scientific projects, facilitate the interaction of projects and cores, oversee the administration and financial aspects of the knowledge towards an understanding of the mechanisms and management of cerebrovascular disease. The role of the Biostatistics Core in the Stroke Project is to support the clinical and laboratory based research. This includes a high-level data management, collaboration with investigators in the design and conduct of research studies, statistical modeling, hypothesis formulation and data analyses. There are four major activities: 1) consultation and collaboration in the planning, conduct, analysis and reporting of the pilot clinical trial; 2) consultation and collaboration with research investigators in developing an MRI based model to stage ischemic tissue and to integrate MRI measurements into the evaluation of therapeutic intervention with a platelet aggregation inhibitor and thrombolysis with rtPA; 3) evaluation of the prognostic significance of risk factors and MRI biological markers, based on the presence/absence of quantitative levels to identify non-response subjects, 4) coordination on project conduct, responsibility for data management and data quality.
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0.907 |
2003 — 2007 |
Chopp, Michael |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Treatment of Neural Injury With Mscs @ Henry Ford Health System
DESCRIPTION (provided by applicant): The underlying hypothesis of this Program Project application is that bone marrow stromal cells (MSCs) delivered to brain via an intravenous route can be employed to improve functional outcome after neural injury, specifically, stroke and traumatic brain injury. Three complementary projects and two supporting cores are proposed: Project 1 Treatment of Stroke with MSCs; Project 2/Treatment of Traumatic Brain Injury with MSCs; Project 3/Analysis of MSC Interaction with Tissue. Core A provides the administrative and biostatistical support for the Program Project, and Core B provides the outcome measures of function and behavior after stroke and trauma, measures of cellular and molecular responses to injury and treatment, and the preparation of cells to be employed for treatment. Projects 1 and 2, will determine the optimal means of applying MSC therapy to experimental models in the rat and the mouse of stroke (young and old animals, male, female) and traumatic brain injury (young male), respectively, with safety as an overriding consideration. The hypothesis to be tested is that MSCs in brain evoke the production of trophic factors that alter injured brain to promote functional benefit. Marrow stromal ceils administered to animals intravenously find their way to ischemic or damaged cerebral tissue and foster functional improvement. Thus, under the clinically relevant conditions of intravenous administration, Projects 1 (stroke) and 2 (traumatic brain injury) will optimize and define the boundaries of therapeutic intervention, measure specific neurotrophic factors and structural and morphological changes in treated brain and clarify how the injured brain responds to MSC treatment. Project 3, will employ antibodies, and genetically modified mice and an array of novel technologies to investigate the mechanisms by which treatment of stroke and trauma with MSCs provides functional improvement. A specific set of neurotrophic factors i.e. VEGF, bFGF and BDNF are identified (in Projects I and 2) as key mediators of MSC therapeutic benefit. In Project 3, these factors are manipulated in the MSC treated mouse to determine their roles in MSC therapy of stroke and trauma, with an emphasis on how these factors induced in injured tissue by MSC treatment, promote plasticity and neuroprotection. The long-term goal of this Program Project application is to translate our finding of therapeutic benefit after treatment of experimental stroke and traumatic brain injury with MSCs to the patient.
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0.907 |
2003 — 2007 |
Chopp, Michael |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Core--Biostatistical @ Henry Ford Health System
This core will: promote high quality collaborative research by providing a supportive academic environment in which investigators can carry out scientific projects, facilitate the interaction of projects and cores, oversee the administration and financial aspects of the Program Project, interact with core facilities effectively, foster new research projects, and contribute new knowledge towards an understanding of marrow stromal cell therapy of stroke and traumatic brain injury. The role of the Biostatistics Core is to support the preclinical and laboratory based research. This includes a high-level data management, collaboration with investigators in the design and conduct of research studies, statistical modeling, hypothesis formulation and data analyses.
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0.907 |
2007 — 2011 |
Chopp, Michael |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Administration @ Henry Ford Health System |
0.907 |
2011 — 2015 |
Chopp, Michael |
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. |
Mscs Induce Brain Plasticity Via Tpa @ Henry Ford Health System
DESCRIPTION (provided by applicant): Cell-based therapies have shown enormous promise in reducing neurological deficits associated with stroke. One of the most effective of these therapies is bone marrow stromal cells (MSCs), that has been demonstrated to be highly neurorestorative. In this application, we will investigate the mechanisms by which MSCs produce this neurorestorative effect. Our preliminary data strongly indicate that MSC treatment of stroke promotes neurite remodeling of brain. We propose that when administered after stroke, MSCs activate tissue plasminogen activator (tPA) within parenchymal cells, and tPA mediates neurite remodeling leading to improvement in neurological function. Therefore, the following three hypotheses are tested: Hypothesis 1: a) MSCs increase tPA activity in parenchymal cells; b) Increased tPA activity increases neurite remodeling; c) Increased neurite remodeling contributes to improvement of functional outcome after stroke. Hypothesis 2: a) MSCs up-regulate tPA activity in astrocytes, neurons and endothelial cells via the Shh signaling pathway; b) MSCs down-regulate TGF-¿1/PAI-1 via the Shh signaling pathway and thereby increase tPA activity. Hypothesis 3: tPA activity increased by MSCs promotes neurite remodeling via plasmin-dependent proteolytic cleavage of pro-neurotrophins: pro-nerve growth factor (pro-NGF) to NGF, pro-brain derived neurotrophic factor (pro-BDNF) to BDNF These hypotheses dissect the interactions of exogenous MSCs and endogenous parenchymal cells and their affect on tPA activity, neurite remodeling and neurological function after stroke. Our studies employ genetically modified tPA-/-, Plg-/-mice as well as an array of novel and well-established experimental techniques in our laboratory. To our knowledge, our work is the first to investigate tPA activity as a key unifying factor to amplify beneficial actions of exogenous cells in the CNS. This project is a coherent and highly interwoven effort to elucidate the molecular and cellular pathways by which injured brain can be remodeled by cell-based therapies. Our ultimate goal is to delineate the mechanistic underpinnings of cell-based therapy in the restorative treatment of stroke. The therapeutic implications of our studies for all neurological disease and injury are evident. PUBLIC HEALTH RELEVANCE: Our study will provide essential insight into how the injured brain is remodeled and neurological function improved using a cell-based therapy. Restorative therapy using exogenously administered cells is not limited by a narrow therapeutic window and can be administered to all stroke patients. Our goal to identify how these administered cells interact with the endogenous brain cells will likely bring to fruition restorative cell-based therapy for the treatment of stroke and neural injury.
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0.907 |
2015 — 2019 |
Chopp, Michael |
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. |
Mir-17-92 Exosome Treatment of Stroke @ Henry Ford Health System
? DESCRIPTION (provided by applicant): Exosomes, small lipid microvesicles (30-150 nm), are active biological containers, which transport regulatory genes and proteins between cells and form a major biological communication conduit, facilitating a plethora of biological responses. The regulatory molecules contained in the exosomes include microRNAs (miRNAs), short (22-25 nt) non-coding RNAs which regulate gene translation and play primary roles in mediating a vast range of biological functions. In this proposal, based on strong preliminary data, we propose to manufacture a distinct exosome population which contains increased levels of the miR-17-92 cluster as a proof-of-principle and a mechanistic demonstration of a new method of treating stroke and possibly other neurological diseases and injury. We test the premise, that by modulating their miRNA content, exosomes can be designed to enhance plasticity of axons and thereby further promote neurological recovery post stroke. Success of this novel approach may lead to a new designer-based paradigm for the treatment of stroke and neurological disease. The following Specific Aims and associated Hypotheses are proposed: Specific Aim 1: To employ exosomes derived from multipotent mesenchymal stromal cells (MSCs) to treat stroke in order to enhance neurovascular remodeling and thereby, functional recovery post stroke. Hypothesis: Exosomes, derived from MSCs when administered to rats after stroke promote neurovascular remodeling which improves functional outcome. Specific Aim 2: To alter specific miRNAs contained within exosomes generated by MSCs as a means to enhance axonal plasticity and neurological recovery post stroke. Hypothesis: Administration of exosomes with increased miR-17-92 cluster to rats post stroke promotes axonal remodeling and enhances functional outcome. There are multiple layers of innovation in our application: we generate biological exosome carriers tailored for specific miRNAs; we use these exosomes to treat stroke, without the administration of exogenous cells; we employ electrophysiological methods, laser capture, fiber track tracing, a battery of neurological tests, and an array of novel approaches, e.g. microfluidic chambers, and ex vivo slice cultures, to mechanistically determine the molecular pathways of the target exosomes which mediate axonal outgrowth. Development of this designer exosome-based therapy, also serves as a prototype for capitalizing on the characteristics of exosomes to transport specific miRNAs and for the manufacture of designer exosomes. Developing a therapy for stroke that is exosome-based, opens up a wide variety of means to deliver targeted regulatory genes to enhance multifaceted aspects of central nervous system (CNS) plasticity and to amplify neurological recovery for neural injury and neurodegenerative diseases.
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0.907 |
2021 |
Chopp, Michael |
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. |
Diabetic Stroke Cardiac Dysfunction; Treatment With Cd133+Exosomes @ Henry Ford Health System
Cardiovascular complications are primarily responsible for the high morbidity and mortality in people with stroke and diabetes mellitus (DM). Cardiovascular diseases are roughly three times higher in patients with neurological deficits than in patients without neurological diseases. DM is a prominent risk factor for cardiovascular diseases and cerebral ischemic stroke. Our preliminary data show that ischemic stroke and type two DM (T2DM) each induces cardiac dysfunction, while T2DM animals subjected to ischemic stroke exhibit profound cardiac dysfunction compared to non-stroke T2DM mice or non-T2DM stroke mice. Therefore, there is a compelling need to develop therapeutic approaches specifically designed not only to reduce neurological deficits, but also to decrease cardiac dysfunction after stroke with diabetes. Our preliminary data indicate that treatment of stroke in T2DM mice with exosomes derived from human umbilical cord blood isolated CD133+/KDR+ cells (CD133+Exo) 3 days after stroke not only improves neurological and cognitive outcome, but also significantly improves cardiac function and increases heart microRNA (miR)126 and miR29b expression. In a novel and clinically relevant approach, based on our robust preliminary data, we propose to investigate the underlying cardioprotective therapeutic mechanisms of CD133+Exo treatment of stroke in T2DM mice, and we will test the hypothesis that miR126 and miR29b mediate CD133+Exo-induced cardiac protective effects in male and female mice in vitro and in vivo. Two Aims are proposed. Aim 1: To investigate the effect of cerebral ischemic stroke and stroke-related factors (age, sex and T2DM) on cardiac and neurological function in mice. To test the therapeutic effects of CD133+Exo treatment of T2DM-stroke in male, female and aged mice, time window, dose response, multiple doses and combination with anti-diabetic drug (Metformin) studies will be performed. Aim 2: To investigate the mechanism of CD133+Exo induced cardiac protective effects in male and female T2DM-stroke mice in vitro and in vivo. We will focus on miR126 and miR29b, and will test: 1) whether CD133+Exo treatment of T2DM-stroke increases heart and serum miR126 or miR29b levels; 2) whether increasing miR126 or/and miR29b expression in heart or/and serum mediates the CD133+Exo induced cardiac beneficial effects in male and female T2DM-stroke mice; 3) whether the miR126/Spred-1 and/or the miR29b/DPP4 signaling pathways mediate CD133+Exo treatment induced myocardiocyte protection of cultured cardiomyocytes. A major significance of our investigations is that it opens up important and novel ways to understand how exogenously administered CD133+Exo communicate with and alter heart cells by means of miR delivery to thereby activate endogenous cardiac protective events. This proposal is highly clinically relevant and if successful, it will significantly impact the treatment of stroke, diabetes, and cardiac dysfunction. Importantly, this proposal will elucidate novel mechanisms of action and generate therapeutic targets for CD133+Exo treatment of cardiac dysfunction after stroke with T2DM in male, female and aged mice.
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0.907 |