MULTIPLE CIRCADIAN OSCILLATORS: REGULATION OF A NEUROENDOCRINE RHYTHM
J Sandra
University Of Kentuckycity: Lexington country: United States (us)
Grant 5R01NS055228-05 from National Institute Of Neurological Disorders And Stroke
Abstract: Principal Investigator/Program Director (Last, first, middle) Duncan, Marilyn, J. RESEARCH & RELATED Other Project Information 1. * Are Human Subjects Involved? m Yes l No 1.a. If YES to Human Subjects Is the IRB review Pending? m Yes m No IRB Approval Date Exemption Number 1 2 3 4 5 6 Human Subject Assurance Number 2. * Are Vertebrate Animals Used? l Yes m No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? m Yes l No IACUC Approval Date 07-21-2006 Animal Welfare Assurance Number A3336-01 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain 5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators? 5.b. If yes, identify countries 5.c. Optional Explanation 6. * Project Summary/ 1913-COF_A2_.pdf Mime Type application/pdf 7. * 7763-COF_A2_Project_Narrative_(relevaMnicmee).pTdyfpe application/pdf 8. Bibliography & References Cited 8724-COF_A2_References.pdf Mime Type application/pdf 9. Facilities & Other Resources 1191-Facilities.pdf Mime Type application/pdf 10. Equipment 1420-Equipment.pdf Mime Type application/pdf Tracking Number Other Information Page 5 OMB Number 4040-0001 Expiration Date 04/30/2008 Principal Investigator/Program Director (Last, first, middle) Duncan, Marilyn, J. Exciting recent studies have demonstrated autonomous circadian oscillators in many regions outside of the suprachiasmatic nucleus (SCN), the
Keywords: ing; Acute; Address; Affect; Animal Welfare; Animals; Area; Barbiturates; barbituric acid salt; Bibliography; Biological Assay; Blood specimen; Brain; Budgets; Calendar; Categories; Circadian Rhythms; cost; Country; Critiques; Data; design; Distal; Effectiveness; Environment; Environmental Impact; Equipment; Estradiol; expiration; GABA-A Receptor; Genes; Hamsters; human subject; IACUC; Immunohistochemistry; Injection of therapeutic agent; Institutional Review Boards; International; Lead; Lesion; Measurement; Measures; Medial; Messenger RNA; Microdialysis; mRNA Expression; Neurons; Neuropeptides; Neurosciences; Neurosecretory Systems; neurotransmitter release; Norepinephrine; organum vasculosum of the lamina terminalis; Outcome; Peptides; Phenobarbital; Preoptic Areas; prevent; Principal Investigator; professor; programs; Proteins; Protocols documentation; Published Comment; Rattus; Recovery; Regulation; research study; Resources; Role; Site; suprachiasmatic nucleus; Synapses; Third ventricle structure; Time; Translating; Vasopressins; Vertebrates; Wages
Project start date: 2007-12-15
Project end date: 2012-11-30
Budget start date: 1-DEC-2011
Budget end date: 30-NOV-2012
5R01NS055228-05 (2012): $314859
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to J Sandra
MODELS FOR THE GENETIC EPIDEMIOLOGY OF CHRONIC DISEASE
J Sandra, Associate Professor
University Of Utahcity: Salt Lake City country: United States (us)
Grant 5R01HD017463-25 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: This is a competing continuation application for years 21-25 of a project to develop and implement models and methodology for the likelihood analysis of pedigree data and to distribute the resultant software to the research community. Each aspect of the proposal involves PAP (Pedigree Analysis Package). Parametric genetic analysis, the primary strength of PAP, should play a role in the multi-pronged approach needed to tackle the difficult task of characterizing and localizing genes for complex diseases, which result from complicated interactions of multiple genes and environmental factors. Non-parametric linkage analysis will also become available in PAP upon completion of extensions proposed in this application. Although there exist a number of other software packages for the analysis of family data, matches the versatility of PAP. The extension of PAP more efficiently produces software for diverse genetic analysis than does the development of new software for that purpose. In addition, PAP has a track record for having been wellsupported over the years. During the previous funding period, a graphical user interface in Java was developed to facilitate the use of PAP. During the remaining year of funding the conversion of the source code will be completed, thereby making PAP very portable and convenient to install while maintaining all the analysis versatility. Nevertheless, PAP remains impractical for multipoint linkage analysis, because of the memory and computer time requirements. Therefore, this application proposes to remedy that shortcoming by implementing Markov chain Monte Carlo (MCMC) methods for the analysis of multi-locus marker data. MCMC methods sample, rather than exhaustively enumerate, the possible combinations of genotypes within a pedigree, therefore effecting an enormous saving of computer time. With the availability of MCMCproduced probabilities, multipoint linkage analysis will become feasible for either variance components models or using any of the extensive selection of major gene models already available in PAP. Nevertheless, the current application also proposes to develop new genetic models of disease risk, including a mode-of-inheritance free method. In addition, this application proposes to implement changes to increase computational speed, allow data exploration, and facilitate data handling and analysis, while continuing to distribute and support PAP
Keywords: Affect; Analysis, Data; Chronic Disease; chronic disease/disorder; chronic disorder; Chronic Illness; Communities; Complex; computer program/software; Computer Programs; Computer software; Computers; Data; Data Analyses; Development; Disease; disease risk; disease/disorder; Disorder; disorder risk; drug/agent; Drugs; Environment; Environmental Factor; environmental risk; Environmental Risk Factor; Family; family based linkage study; Funding; Genes; Genetic analyses; genetic analysis; genetic epidemiology; genetic linkage analyses; genetic linkage analysis; Genetic Models; genetic pedigree; Genotype; graphic user interface; Graphical interface; graphical user interface; Imagery; improved; Investigators; Java; linkage analyses; Linkage Analysis; Linkage Disequilibrium; Linkage Disequilibriums; Markov Chains; Markov Process; Medication; Memory; Method LOINC Axis 6; Methodology; Methods; Modeling; Monte Carlo Method; Pedigree; pedigree structure; Pharmaceutic Preparations; Pharmaceutical Preparations; Play; Probability; Procedures; programs; Programs (PT); Programs [Publication Type]; Research; Research Personnel; Researchers; Role; Sampling; simulation; social role; Software; Source Code; Speed; Speed (motion); Time; trait; usability; Visualization; Writing
Project start date: 1999-09-15
Project end date: 2012-03-31
Budget start date: 1-APR-2009
Budget end date: 31-MAR-2012
5R01HD017463-25 (2009): $192679
FUNCTIONAL STUDY OF MUCIN MUC1
J Sandra, Professor
Mayo Clinic Arizonacity: Scottsdale country: United States (us)
Grant 5R01CA064389-17 from National Cancer Institute
Abstract: MUC1 is a tumor-associated antigen involved in oncogenesis, regulation of cellular signaling and transcription and protection of epithelial surfaces. In addition to the widespread expression on epithelia, MUC1 is also found on hematopoietic cells; however, the function of MUC1 in these cells is still fairly unknown. We have found that the lack of Muc1 in primary myeloid progenitors from the C57BL/6 Muc1-/- (KO) mice resulted in an increased expansion of CD11b+Gr1+ cells under GM-CSF and IL-4 signaling, as compared to the wild type (WT) C57BL/6 mice. The CD11b+Gr1+ cells that were expanded in vitro from the KO bone marrow suppressed T cell proliferation in vitro while those from the WT did not, suggesting that these KO CD11b+Gr1+ cells were myeloid derived suppressor cells (MDSCs). MDSCs contribute to the immune suppression frequently seen in cancer; however, the mechanism by which they differentiate from myeloid progenitors is still relatively unknown. Most intriguingly, Muc1 KO mice were able to better tolerate allogeneic tumor growth, with an accumulation of CD11b+Gr1+ cells in the blood and tumor draining lymph nodes. The expansion of CD11b+Gr1+ MDSCs from KO bone marrow was accompanied by beta-catenin down regulation, and inhibition of beta-catenin down regulation could reverse the expansion of CD11b+Gr1+ MDSCs. Our findings indicate a need for Muc1 in modulating the differentiation of myeloid progenitors into CD11b+Gr1+ MDSCs. We hypothesize that MUC1 plays a critical role as a signal transducer in MDSC differentiation in response to a steady state disturbance. To further characterize the mechanistic and functional role of Muc1 in regulating MDSC differentiation, we propose the following specific aims (1) To determine the mechanism by which Muc1 regulates the differentiation of myeloid progenitors into CD11b+Gr1+ MDSCs, (2) To determine functional significance of MDSCs generated in tumor-bearing Muc1 KO mice by characterizing MDSC populations generated as well as the process by which they develop from the bone marrow and accumulate in the periphery, (3) To determine the effect of a lack of Muc1 in myeloid development during dextran sodium sulfate (DSS)-induced colitis and colitis associated cancer (CAC) by using chimeric mice that lack or have Muc1 in the hematopoietic or non hematopoietic compartment. MUC1 is an especially attractive target for the development of anti-cancer agents, which would be designed to target MUC1 on carcinomas, but could also affect the hematopoietic cells expressing MUC1 and our studies would be useful in continuing to define the role of MUC1 in hematopoiesis. At the same time, furthering our understanding of the signaling pathways involved in MDSC differentiation (MUC1 regulated or otherwise) would enable the targeting of these pathways by drugs in cancer and inflammation more readily. Results from these studies should give us clearer insight into the role of MUC1 in the epithelium and hematopoietic system in both inflammation and cancer signaling pathways. In this proposal we will study the function of MUC1, a cell-associated signaling mucin, in the maturation and expansion of a cell population (myeloid derived suppressor cells, MDSCs) that can suppress the immune system. Although MUC1 is well established as an oncogene in epithelial tissues, it appears to have different roles in hematopoietic tissues. This study will provide novel mechanistic and functional insights into the immunosuppressive microenvironment that can be found in inflammation and tumors. Further understanding of the signaling pathways involved in MDSC differentiation as well as increased insight into the role of MUC1 in the epithelium and hematopoietic systems in inflammation and cancer will enable us to target therapies more knowledgeably
Keywords: Affect; Allogenic; Antineoplastic Agents; B-Lymphocytes; beta catenin; Blood; Bone Marrow; C57BL/6 Mouse; Cancer Vaccines; Carcinoma; Cell Differentiation process; cell growth regulation; Cells; Colitis; colitis associated cancer; Colon Carcinoma; Dendritic Cells; design; Development; Disease; Disease Progression; Down-Regulation; Epithelial; Epithelium; Genetic Transcription; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Hematopoietic; Hematopoietic System; hematopoietic tissue; Immune; Immune system; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; insight; Interleukin-4; ITGAM gene; Knock-out; Knockout Mice; lymph nodes; Malignant Neoplasms; Mediating; Modeling; Molecular; Mucin-1 Staining Method; Mucins; Mus; Myelogenous; Myeloproliferative disease; Natural immunosuppression; Natural Killer Cells; novel; Oncogene Proteins; Oncogenes; Oncogenic; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Play; Population; Process; progenitor; public health relevance; Regulation; Reporting; response; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Sodium Dextran Sulfate; stem; Stem cells; Suppressor-Effector T-Lymphocytes; Surface; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Time; Tissues; Transducers; Transplantation; tumor; Tumor Antigens; tumor growth; tumor progression; tumorigenesis; Wild Type Mouse
Relevance: In this proposal we will study the function of MUC1, a cell-associated signaling mucin, in the maturation and expansion of a cell population (myeloid derived suppressor cells, MDSCs) that can suppress the immune system. Although MUC1 is well established as an oncogene in epithelial tissues, it appears to have different roles in hematopoietic tissues. This study will provide novel mechanistic and functional insights into the immunosuppressive microenvironment that can be found in inflammation and tumors. Further understanding of the signaling pathways involved in MDSC differentiation as well as increased insight into the role of MUC1 in the epithelium and hematopoietic systems in inflammation and cancer will enable us to target therapies more knowledgeably
Project start date: 1994-07-01
Project end date: 2015-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-07-070
5R01CA064389-17 (2011): $361215
CONSTRUCTING A CONDITIONAL SLC7A11 (XCT) NULL MOUSE
J Sandra
Syracuse Universitycity: Syracuse country: United States (us)
Grant 1R21NS074756-01A1 from National Institute Of Neurological Disorders And Stroke
Abstract: Injury to the brain caused by cerebral ischemia is a major public health concern. Studies have determined that the brain damage associated with cerebral ischemia is mediated by over-stimulation of excitatory amino acid receptors, oxidative stress, as well as inflammatory factors. Our laboratory demonstrated - using an in vitro model of the ischemic penumbra - that astrocyte-mediated alterations in system xc- (cystine/glutamate antiporter) contribute to the development and progression of inflammatory (IL-12-mediated) hypoxic neuronal injury. Thus, we believe that system xc- has the potential to be a novel therapeutic target for stroke. However, to validate this hypothesis, our results must be confirmed in vivo. Mice harboring a natural loss of function mutation in the Slc7a11 (sut) gene - which encodes for xCT, the light chain dictating substrate specificity in system xc- - and xCT null mutant mice have been described in the literature. However, these are global knockouts. To date no tissue-specific knockout for this allele exists. Hence, the overall goal of this project is to develop (Aim 1) and characterize (Aim 2) an astrocyte-specific conditional knockout mouse of the Slc7a11 gene for the ultimate use in in vivo. Morbidity associated with cerebral ischemia (stroke) remains a huge emotional and economic burden due in large part to a void in treatment options to protect against secondary injury. It is our contention that successful completion of this application [i.e., the successful generation of a Scla711 (xCT) conditional knockout animal] will allow us to assess the viability of our hypothesis that astrocyte system xc- (cystine/glutamate transporter) is a novel therapeutic target in stroke
Keywords: Alleles; Amino Acid Transporter; Animal Model; Antioxidants; antiporter; Astrocytes; Behavioral; Brain; Brain Injuries; Cell Culture Techniques; Cell membrane; cell type; Cells; Cerebral Ischemia; Chemosensitization; cofactor; Couples; Cyst; Cysteine; Cystine; cytokine; design; Development; driving force; Economic Burden; Emotional; Environment; Enzymes; Excitatory Amino Acid Receptors; Exons; extracellular; Free Radicals; Gene Expression; Generations; Genes; Genetic Transcription; Glutamate Receptor; Glutamate Transporter; Glutamates; Glutathione; glutathione peroxidase; Glycine; Goals; Health; Hour; Hypoxia; in vitro Model; in vivo; Inflammatory; Injury; Interleukin-12; Interleukins; Invaded; Ischemic Penumbra; Knock-out; knockout animal; Knockout Mice; Laboratories; Lead; Light; Literature; loss of function; loss of function mutation; Maintenance; Mediating; Metabolism; Microglia; Morbidity - disease rate; Mus; Mutant Strains Mice; Nerve Degeneration; Neuronal Injury; Neurons; new therapeutic target; Organism; Oxidants; Oxidative Stress; Play; prevent; Prevention; Process; Production; Proteins; public health medicine (field); Recycling; Role; Signal Transduction; Site; stoichiometry; stroke; Substrate Specificity; System; Tissues; Transgenic Mice; Translations; uptake
Relevance: Morbidity associated with cerebral ischemia (stroke) remains a huge emotional and economic burden due in large part to a void in treatment options to protect against secondary injury. It is our contention that successful completion of this application [i.e., the successful generation of a Scla711 (xCT) conditional knockout animal] will allow us to assess the viability of our hypothesis that astrocyte system xc- (cystine/glutamate transporter) is a novel therapeutic target in stroke
Project start date: 2011-07-15
Project end date: 2013-06-30
Budget start date: 15-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-10-069
1R21NS074756-01A1 (2011): $147000
EXCITOTOXICITY AND INFLAMMATION
J Sandra, Professor
University Of Connecticut Sch Of Med/dntcity: Farmington country: United States (us)
Grant 5R01NS036812-13 from National Institute Of Neurological Disorders And Stroke
Abstract: Injury to the brain caused by cerebral ischemia (i.e. stroke) is a major public health concern. Studies have determined that the brain damage associated with cerebral ischemia is mediated by over-stimulation of excitatory amino acid receptors, oxidative stress, as well as inflammatory factors. Preliminary results obtained during the last/current grant period as well as supporting data from the literature demonstrate a link between leukocyte-type 12/15 lipoxygenase (L-12/15 LO) activation in cerebral ischemic neuronal injury in vivo and oxidative stress-induced neuronal injury in vitro. Thus, the objectives of this following 5 yr research plan of study are as follows 1) To determine the extent to which L-12/15 LO is involved in cerebral ischemic injury. Animals genetically null for L-12/15 LO and those genetically engineered to over-express L-12/15 LO will be used to determine its contribution to cerebral ischemic damage over a detailed time course. 2) To determine whether the decreased susceptibility of L-12/15 LO null mutants to cerebral ischemic damage results from a change in cerebrovasculature function and/or a reduction in glutamate receptor-mediated damage. To assess the former, relative and absolute regional cerebral blood flow changes occurring during and at end-stage cerebral ischemia will be measured to determine whether L-12/15 LO animals (null mutants and over-expressers) sustain a similar intra-ischemic insult as compared to wild-type mice. To assess the latter, a comparison of the damage induced by direct microinjection of NMDA into brain parenchyma between L- 12/15 LO animals and wild-type controls will be made. 3) To identify an orally active, pharmacological inhibitor of the L-12/15-LO pathway for the treatment cerebral ischemic damage. Using structurally distinct, proprietary lipoxygenase inhibitors developed by Onconova Therapeutics, studies will be undertaken to identify compounds that effectively prevent injury induced by middle cerebral artery occlusion (MCAo) and/or direct hippocampal injection of NMDA as well as to elucidate their therapeutic time window. Results from this study will elucidate the contribution of L-12/15 LO to cerebral ischemic damage and could aid in the development of a novel stroke therapeutic. Morbidity associated with stroke remains a huge emotional and economic burden due in large part to a void in treatment options to protect against secondary injury. It is our contention that successful completion of this proposal will advance and refine our knowledge about an important new therapeutic target (L-12/15 LO) that complements other ongoing efforts to reduce injury following cerebral ischemic insult
Keywords: 15-Lipoxygenase; 15-Lipoxygenase, Reticulocyte Arachidonate; 15-LOX; Acquired brain injury; ALOX15; Ammon Horn; Animals; Apoplexy; Arachidonate 15-Lipoxygenase; Arachidonate Omega-6 Lipoxygenase; Arachidonate[{..}]oxygen 15-oxidoreductase; Arachidonic Acid 15-Lipoxygenase; base; Biochemical; Blood leukocyte; Brain; brain attack; brain damage; Brain Injuries; brain lesion (from injury); cerebral blood flow; cerebral circulation; Cerebral Ischemia; Cerebral Stroke; cerebral vascular accident; cerebrocirculation; Cerebrovascular accident; Cerebrovascular Apoplexy; Cerebrovascular Circulation; Cerebrovascular Stroke; Cerebrum; Complement; Complement Proteins; Cornu Ammonis; Data; Development; EAA receptor; Economic Burden; Emotional; Encephalon; Encephalons; Engineering; Engineerings; Excitatory Amino Acid Receptors; excitatory aminoacid receptor; excitotoxicity; Glutamate Receptor; Goals; Grant; Health; hippocampal; Hippocampus; Hippocampus (Brain); In Vitro; in vivo; Inflammation; Inflammatory; INFLM; inhibitor; inhibitor/antagonist; Injection of therapeutic agent; Injections; Injury; Ischemic Neuronal Injury; Knowledge; Leukocytes; Link; Lipoxygenase Inhibitors; Literature; Marrow leukocyte; Measures; Mediating; Microinjections; Middle Cerebral Artery Occlusion; Molecular; Morbidity; Morbidity - disease rate; mutant; N methyl D aspartate; N Methyl D aspartic Acid; N-Methyl-D-aspartate; N-Methylaspartate; Nervous System, Brain; neuron injury; Neuronal Injury; new therapeutic target; NMDA; novel; Oxidative Stress; pathway; Pathway interactions; Predisposition; prevent; preventing; Public Health; public health medicine (field); Receptors, Excitatory Amino Acid; Relative; Relative (related person); Research; Reticuloendothelial System, Leukocytes; Staging; Stroke; stroke; Susceptibility; Therapeutic; Therapeutic Studies; Therapy Research; Time; Vascular Accident, Brain; white blood cell; White Blood Cells; white blood corpuscle; White Cell; Wild Animals; Wild Type Mouse
Relevance: Morbidity associated with stroke remains a huge emotional and economic burden due in large part to a void in treatment options to protect against secondary injury. It is our contention that successful completion of this proposal will advance and refine our knowledge about an important new therapeutic target (L-12/15 LO) that complements other ongoing efforts to reduce injury following cerebral ischemic insult
Project start date: 1997-09-01
Project end date: 2013-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
PFA/PA: PA-07-070
5R01NS036812-13 (2011): $369937
7R01NS036812-14 (2011): $283050
IL1 AND HYPOXIC-ISCHEMIC INSULTS
J Sandra, Professor
University Of Connecticut Sch Of Med/dntcity: Farmington country: United States (us)
Grant 5R01NS051445-04 from National Institute Of Neurological Disorders And Stroke
Abstract: Injury to the brain caused by cerebral ischemia (i.e. stroke) is a major public health concern. As much as 50% of the brain damage incurred by stroke occurs outside of the primary focus of damage with the process of tissue destruction continuing for hours to days. It is now apparent that inflammatory factors contribute to this delayed pathophysiology. Specifically, studies demonstrate that the cytokine, interleukin 1¿ (IL-1¿), is upregulated following experimental and clinical stroke while additional studies implicate it in the progression of injury. However, the cellular and molecular pathway(s) by which IL-1¿ contributes to neuronal cell death have yet to be identified. This is largely due to the lack of suitable in vitro models in which to assess these mechanisms. Therefore, we developed a reliable and reproducible in vitro model system utilizing mixed neuronal/astrocyte cortical cell cultures. In this model, endogenous production of IL-1¿ is simulated by exogenous addition of IL IL-1¿ and neuronal injury induced by depriving cells of oxygen. We found that pre-treatment? but not concurrent or post-treatment? with this cytokine dramatically potentiated neuronal cell death induced by depriving mixed murine cortical cell cultures of oxygen. The effect of IL-1¿ was concentration-dependent and could be completely inhibited by the recombinant IL-1 receptor antagonist, indicating that signaling through the IL-1 receptor type I (IL1R1) was involved. Further, we found this IL-1¿ -mediated enhancement of hypoxic-neuronal injury can be completely prevented by pharmacological antagonism of metabotropic glutamate receptor 1 (but not mGluRS). This is in stark contrast to a pure hypoxic neuronal injury which is unaffected by mGluRI receptor antagonism. Finally, we found that the enhancement of injury induced by IL-1¿ was dependent on astrocytic expression of IL1R1 whereas loss of signaling in neurons had no effect. Thus, the objectives of this five year research plan are to 1) determine the molecular mechanism(s) by which IL1p signaling functionally synergizes with mGluRI signaling to enhance hypoxic neuronal injury; 2) to determine the astrocytic factor or factors responsible for mediating the IL-1¿ enhancing effect; and 3) to assess whether removal of IL-1¿ signaling can effectively prevent/ameliorate hippocampal injury in vivo induced by direct hippocampal injection of NMDA and/or middle cerebral artery occlusion. Improved definition of these events could lead to the development of new therapeutic strategies designed to attenuate the progression of neuronal destruction following stroke
Keywords: Abscission; Acquired brain injury; Address; After Care; After-Treatment; Aftercare; Ammon Horn; Apoplexy; Astrocytes; Astrocytus; Astroglia; Attenuated; Biochemical; Biological Models; biological signal transduction; Brain; brain attack; brain damage; Brain Injuries; brain lesion (from injury); Cell Communication and Signaling; Cell Culture Techniques; cell damage; cell injury; Cell Signaling; cell type; Cells; Cellular injury; Cerebral Ischemia; Cerebral Stroke; cerebral vascular accident; Cerebrovascular accident; Cerebrovascular Apoplexy; Cerebrovascular Stroke; Clinical; Cornu Ammonis; cytokine; design; designing; Development; Dysfunction; EAA receptor; Encephalon; Encephalons; Event; Evolution; Excision; Excitatory Amino Acid Receptors; excitatory aminoacid receptor; excitotoxicity; experiment; experimental research; experimental study; Extirpation; Foundations; Functional disorder; Glutamate Receptor; Glutamate Receptor, Metabotropic 1; Goals; Grant; GRM1; heavy metal lead; heavy metal Pb; hippocampal; Hippocampus; Hippocampus (Brain); Hour; Hypoxia; Hypoxic; IL-1; IL1; IL1 Receptors; IL1R; IL1R1; IL1R1 gene; IL1RA; improved; in vitro Model; in vivo; infarct; Infarction; Inflammation; Inflammation Mediators; Inflammatory; INFLM; Injection of therapeutic agent; Injections; Injury; Interleukin I; Interleukin-1; Interleukin-1 Receptors; Interleukins; Intracellular Communication and Signaling; Ischemia; Ischemic Penumbra; Lead; Ligands; lymphocyte activating factor; Lymphocyte-Stimulating Hormone; Macrophage Cell Factor; Mammals, Mice; Mediating; metabotropic glutamate receptor type 1; MGLUR1; Mice; Middle Cerebral Artery Occlusion; Model System; Modeling; Models, Biologic; Molecular; Murine; Mus; N methyl D aspartate; N Methyl D aspartic Acid; N-Methyl-D-aspartate; N-Methylaspartate; Nerve Cells; Nerve Unit; Nervous System, Brain; Neural Cell; Neurocyte; neuron cell death; neuron injury; neuron loss; neuronal; neuronal cell death; Neuronal Injury; neuronal loss; Neurons; neurotrophic factor; neurotrophin; neutrophin; new therapeutics; next generation therapeutics; NMDA; novel therapeutics; O element; O2 element; Oxygen; Oxygen Deficiency; pathophysiology; pathway; Pathway interactions; Pb element; Physiopathology; Predisposition; prevent; preventing; Production; Public Health; public health medicine (field); receptor; receptor expression; Receptor Protein; Receptors, Excitatory Amino Acid; Receptors, IL-1; Receptors, Interleukin-1; Recombinants; Removal; Research; research study; resection; Signal Transduction; Signal Transduction Systems; Signaling; Simulate; stroke; Stroke; Surgical Removal; Susceptibility; synergism; System; System, LOINC Axis 4; T Helper Factor; tissue processing; unspecified interleukin; Vascular Accident, Brain
Project start date: 2006-07-18
Project end date: 2011-04-30
Budget start date: 1-MAY-2009
Budget end date: 30-APR-2011
5R01NS051445-04 (2009): $344641
J Sandra, Senior Vice President
Stanford Universitycity: Stanford country: United States (us)
Abstract: Autologous hematopoietic cell transplantation (AHCT) is the standard treatment for the most common type of non-Hodgkin´s lymphoma, diffuse large B-cell (DLBCL), that recurs or is primarily refractory to induction therapy, and the application of AHCT following induction therapy for mantle cell lymphoma (MCL) has been shown to prolong diseas´e remission. Despite excellent cytoreduction, relapse occurs continuously in MCL and in about half of DLBCL cases. The idiotype unique to each B-cell lymphoma is a specific target that we have successfully pursued for vaccination. In Aim 1, we plan to vaccinate with idiotype-pulsed dendritic cells after AHCT in MCL, building upon our experience in developing and using these cells after transplantation (IND #11227), together with administration of primed T-cells, in order to optimize the likelihood of an effective, durable immune response. We will measure the effects of vaccination by molecular assessment of tumor burden in the peripheral blood and by determination of the immune response. In Aim 2, we will take advantage of advances in functional imaging with FDG-PET that allow the distinction of DLBCL patients with a very high rate of relapse after standard AHCT. Utilizing existing systems for central PET review at Stanford University, we will define very high risk DLBCL patients on the basis of PET-positive disease after salvage chemotherapy and plan post-AHCT immunotherapy on the basis of genetic randomization. In high risk DLBCL patients with HLA matched donors (Aim 2.1), we will pursue non- myeloablative allogeneic HCT utilizing a novel conditioning regimen consisting of total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) developed in Project 4 and translated in Project 1 of this Program Project Grant. Our experience with this regimen suggests that graft versus tumor effects are retained but the incidence of acute graft versus host disease (GVHD) and treatment-related mortality is reduced. For those PET-positive patients without an available donor (Aim 2.2), we plan to study cytokine-induced killer (CIK) cells as a post-AHCT immunotherapy, building on our previous experience with CIK cells in Project 3, which has been translated in the autologous setting in this Project. The unifying hypothesis in Project 2 is that lymphoma-specific immunotherapy applied after cytoreduction and tumor control is established with conventional AHCT will improve event-free survival in patients with lymphoma at high risk of recurrence. Our goals are to develop such immune-based strategies to reduce the risk of disease relapse after AHCT that could be broadly applied to non-Hodgkin´s lymphoma patients. Project 2 interacts with Projects 1, 3, 4, 6, and 8 and is supported by all of the Cores of this Program Project Grant
Keywords: Acute Graft Versus Host Disease; Allogenic; Antithymoglobulin; Autologous; Autologous Transplantation; B-Cell Lymphomas; B-Lymphocytes; base; Biology; Bone Marrow Transplantation; Cell Transplantation; Cells; chemotherapy; Clinic; Clinical Investigator; conditioning; cytokine; Dendritic Cells; Development; Diffuse; Disease; Disease remission; Disease-Free Survival; disorder control; disorder risk; Exclusion; experience; fluorodeoxyglucose positron emission tomography; Functional Imaging; Genetic; Goals; Graft-Versus-Tumor Induction; Hematopoietic; high risk; Immune; Immune response; Immune Targeting; Immunoglobulin Idiotypes; Immunotherapy; improved; Incidence; Killer Cells; Laboratories; leukemia/lymphoma; Lymphatic Irradiation; Lymphoma; Malignant lymphoma, lymphocytic, intermediate differentiation, diffuse; Measures; Mediating; Molecular; Morbidity - disease rate; Mortality Vital Statistics; Neoadjuvant Therapy; Non-Hodgkin`s Lymphoma; novel; novel therapeutics; older patient; Patients; peripheral blood; Physiologic pulse; Positron-Emission Tomography; Pre-Clinical Model; Principal Investigator; Program Research Project Grants; Randomized; Recurrence; Recurrent disease; Refractory; Regimen; Relapse; Residual Tumors; Risk; rituximab; standard care; System; T-Lymphocyte; tositumomab; Toxic effect; Translating; Transplantation; tumor; Tumor Burden; Universities; Vaccinated; Vaccination; Vaccines
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5P01CA049605-23_0002 (2011): $396263