INTEGRIN AVB3 TARGETED DRUG DESIGN, DELIVERY, AND IMAGING
Nouri Neamati
University Of Southern California, Department Of Contracts And Grants, Los Angeles, Ca 90033
Grant 5R01CA120188-04 from National Cancer Institute
Abstract: We hypothesize that selective targeting of integrin ?v?3 by a small-molecule antagonist and an RGD-paclitaxel conjugate will have safety and efficacy profiles suitable for clinical studies. The purposes of this study are to (A) develop AV38, our highly selective integrin ?v?3 receptor antagonist as a novel anti-neoplastic agent for non-small cell lung cancer (NSCLC) alone and in combination with paclitaxel; (B) conjugate AV38 to paclitaxel and use this conjugate as well as our recently described RGD-paclitaxel as a selective delivery mechanism to ?v?3 receptor-positive cancer cells; and (C) monitor these processes by multimodality imaging techniques such as positron emission tomography (PET), bioluminescence imaging (BLI), and microCT. The rationale behind this proposal comes from the following observations (A) integrin ?v?3 is overexpressed in cancer cells and in the malignant neovascular endothelium; (B) lung cancer cells are highly metastatic and the adhesion, invasion of cells into the matrix of metastatic organs, and subsequent tumoral angiogenesis is mediated, in part, by ?v?3; (C) combination of targeted therapy with conventional chemotherapy increase the efficacy of therapy without additional toxicity; and (D) several antagonists of ?v?3 are entering into clinical and preclinical studies in a variety of disease models but their potential in NSCLC has yet to be studied. To test our overarching hypothesis more specifically we propose Specific Aim 1 To develop an RGD-paclitaxel conjugate with optimal receptor affinity and cytotoxicity. We hypothesize that integrin targeted delivery of paclitaxel allows preferential cytotoxicity to lung cancer cells depending on integrin expression levels. Specific Aim 2 To develop AV38, a novel small-molecule integrin antagonist as a single agent, in combination with paclitaxel, and as a paclitaxel-conjugate. We hypothesize that non-peptide integrin antagonists are efficient for integrin specific delivery of paclitaxel due to their relatively high metabolic stability and ease of synthesis. Specific Aim 3 To evaluate the integrin-targeted delivery efficacy and in vivo pharmacokinetics of the paclitaxel conjugates developed in Aims 1 and 2. We hypothesize that in vivo pharmacokinetics and pharmacodynamics of paclitaxel conjugates are highly correlated with in vitro receptor affinity and cytotoxicity as well as other characters such as molecular size, hydrophilicity, metabolic stability, and molecular charge. Specific Aim 4 To evaluate the anti-tumor effect of the paclitaxel conjugates by means of tumor size monitoring, histopathology and non- invasive molecular imaging. We will test the hypothesis that tumor delivery of the paclitaxel conjugate is most effective to integrin positive lung cancer. We have developed a novel drug conjugate system to deliver maximum dose to both tumor cells and tumor vasculature with dual anti-tumor effects. This new treatment regimen has its greatest potential in patients with tumors that overexpress integrin ?v?3. These tumors are usually highly metastatic as in non-small cell lung cancer (NSCLC). Because most solid tumors are angiogenesis dependent and express integrin on their cell surface, drugs developed in this project are also applicable to many other tumor types such as brain, breast, ovarian, prostate, and colon cancer
Keywords: Adhesions; Affinity; After Care; After-Treatment; Aftercare; Anzatax; Apoptosis; Apoptosis Pathway; Arg-Gly-Asp; Arginine-Glycine-Aspartic Acid Cell Adhesion Domain; Asotax; Avidity; Binding; Binding (Molecular Function); Biological; Bioluminescence; Brain; Breast; Bristaxol; Cancer Treatment; Cancer of Lung; Carcinoma, Non-Small-Cell Lung; Cell Death, Programmed; Cell surface; Cells; Charge; Clinical; Clinical Research; Clinical Study; Colon Cancer; Colon Carcinoma; Colonic Carcinoma; Complex; Disease model; Dose; Drug Design; Drug Kinetics; Drugs; Encephalon; Encephalons; Endothelium; Extracellular Matrix, Integrins; Genital System, Male, Prostate; Histologic; Histologically; Histopathology; Human Prostate; Human Prostate Gland; IC50; Image; Imaging Procedures; Imaging Techniques; In Vitro; Inhibitory Concentration 50; Integrins; Ligands; Lytotoxicity; Malignant; Malignant - descriptor; Malignant Cell; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Tumor of the Lung; Malignant neoplasm of lung; Mammals, Mice; Measures; Mediating; Medical Imaging, Positron Emission Tomography; Medication; Metabolic; Methods and Techniques; Methods, Other; Mice; Modeling; Molecular; Molecular Interaction; Monitor; Murine; Mus; NSCLC; NSCLC - Non-Small Cell Lung Cancer; Nervous System, Brain; Non-Small Cell Lung Cancer; Non-Small-Cell Lung Carcinoma; Organ; Ovarian; PET; PET Scan; PET imaging; PETSCAN; PETT; Paclitaxel; Paclitaxel (Taxol); Patients; Peptides; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacodynamics; Pharmacokinetics; Positron Emission Tomography Scan; Positron-Emission Tomography; Praxel; Process; Property; Property, LOINC Axis 2; Prostate; Prostate Gland; Prostatic Gland; Protocols, Treatment; Proton Magnetic Resonance Spectroscopic Imaging; Pulmonary Cancer; Pulmonary malignant Neoplasm; RGD; RGD (peptide); RGD (sequence); RGD Cell Adhesion Domain; RGD Domain; RGD Motif; RGD Tripeptide Sequence; RGD tripeptide; RGM; Rad.-PET; Receptor Cell; Receptor Protein; Regimen; Safety; Solid Neoplasm; Solid Tumor; Specificity; Structure; System; System, LOINC Axis 4; Taxol; Taxol (Old NSC); Taxol A; Taxol Konzentrat; Technics, Imaging; Techniques; Testing; Toxic effect; Toxicities; Treatment Efficacy; Treatment Protocols; Treatment Regimen; Treatment Schedule; Tumor Angiogenesis; Tumor Burden; Tumor Cell; Tumor Load; Xenograft Model; angiogenesis; anticancer therapy; arginyl-glycyl-aspartic acid; base; cancer cell; cancer therapy; chemotherapy; cytotoxicity; density; disorder model; drug/agent; hydrophilicity; imaging; in vitro activity; in vivo; lung cancer; molecular imaging; molecular size; multimodality; neoplasm blood supply; neoplasm vascular supply; neoplastic; neoplastic cell; neovascular; nonsmall cell lung cancer; novel; overexpression; pharmacophore; preclinical study; receptor; site targeted delivery; small molecule; targeted delivery; therapeutic efficacy; therapeutically effective; tumor; tumor blood supply; tumor growth; tumor vascular supply
Project start date: 2007-09-30
Project end date: 2012-07-31
Budget start date: 27-AUG-2010
Budget end date: 31-JUL-2011
PFA/PA: PA-07-070
5R01CA120188-04 (2010): $213288
Sponsored Links Excellgen http://Excellgen.com
INTEGRIN AVB3 TARGETED DRUG DESIGN, DELIVERY, AND IMAGING
Nouri Neamati, Associate Professor
University Of Southern California, Department Of Contracts And Grants, Los Angeles, Ca 90033
Grant 5R01CA120188-03 from National Cancer Institute
Abstract: We hypothesize that selective targeting of integrin ?v?3 by a small-molecule antagonist and an RGD-paclitaxel conjugate will have safety and efficacy profiles suitable for clinical studies. The purposes of this study are to (A) develop AV38, our highly selective integrin ?v?3 receptor antagonist as a novel anti-neoplastic agent for non-small cell lung cancer (NSCLC) alone and in combination with paclitaxel; (B) conjugate AV38 to paclitaxel and use this conjugate as well as our recently described RGD-paclitaxel as a selective delivery mechanism to ?v?3 receptor-positive cancer cells; and (C) monitor these processes by multimodality imaging techniques such as positron emission tomography (PET), bioluminescence imaging (BLI), and microCT. The rationale behind this proposal comes from the following observations (A) integrin ?v?3 is overexpressed in cancer cells and in the malignant neovascular endothelium; (B) lung cancer cells are highly metastatic and the adhesion, invasion of cells into the matrix of metastatic organs, and subsequent tumoral angiogenesis is mediated, in part, by ?v?3; (C) combination of targeted therapy with conventional chemotherapy increase the efficacy of therapy without additional toxicity; and (D) several antagonists of ?v?3 are entering into clinical and preclinical studies in a variety of disease models but their potential in NSCLC has yet to be studied. To test our overarching hypothesis more specifically we propose Specific Aim 1 To develop an RGD-paclitaxel conjugate with optimal receptor affinity and cytotoxicity. We hypothesize that integrin targeted delivery of paclitaxel allows preferential cytotoxicity to lung cancer cells depending on integrin expression levels. Specific Aim 2 To develop AV38, a novel small-molecule integrin antagonist as a single agent, in combination with paclitaxel, and as a paclitaxel-conjugate. We hypothesize that non-peptide integrin antagonists are efficient for integrin specific delivery of paclitaxel due to their relatively high metabolic stability and ease of synthesis. Specific Aim 3 To evaluate the integrin-targeted delivery efficacy and in vivo pharmacokinetics of the paclitaxel conjugates developed in Aims 1 and 2. We hypothesize that in vivo pharmacokinetics and pharmacodynamics of paclitaxel conjugates are highly correlated with in vitro receptor affinity and cytotoxicity as well as other characters such as molecular size, hydrophilicity, metabolic stability, and molecular charge. Specific Aim 4 To evaluate the anti-tumor effect of the paclitaxel conjugates by means of tumor size monitoring, histopathology and non- invasive molecular imaging. We will test the hypothesis that tumor delivery of the paclitaxel conjugate is most effective to integrin positive lung cancer. We have developed a novel drug conjugate system to deliver maximum dose to both tumor cells and tumor vasculature with dual anti-tumor effects. This new treatment regimen has its greatest potential in patients with tumors that overexpress integrin ?v?3. These tumors are usually highly metastatic as in non-small cell lung cancer (NSCLC). Because most solid tumors are angiogenesis dependent and express integrin on their cell surface, drugs developed in this project are also applicable to many other tumor types such as brain, breast, ovarian, prostate, and colon cancer
Keywords: Adhesions; Affinity; After Care; After-Treatment; Aftercare; Anzatax; Apoptosis; Apoptosis Pathway; Arg-Gly-Asp; Arginine-Glycine-Aspartic Acid Cell Adhesion Domain; Asotax; Avidity; Binding; Binding (Molecular Function); Biological; Bioluminescence; Brain; Breast; Bristaxol; Cancer Treatment; Cancer of Lung; Carcinoma, Non-Small-Cell Lung; Cell Death, Programmed; Cell surface; Cells; Charge; Clinical; Clinical Research; Clinical Study; Colon Cancer; Colon Carcinoma; Colonic Carcinoma; Complex; Disease model; Dose; Drug Design; Drug Kinetics; Drugs; Encephalon; Encephalons; Endothelium; Extracellular Matrix, Integrins; Genital System, Male, Prostate; Histologic; Histologically; Histopathology; Human Prostate; Human Prostate Gland; IC50; Image; Imaging Procedures; Imaging Techniques; In Vitro; Inhibitory Concentration 50; Integrins; Ligands; Lytotoxicity; Malignant; Malignant - descriptor; Malignant Cell; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Tumor of the Lung; Malignant neoplasm of lung; Mammals, Mice; Measures; Mediating; Medical Imaging, Positron Emission Tomography; Medication; Metabolic; Methods and Techniques; Methods, Other; Mice; Modeling; Molecular; Molecular Interaction; Monitor; Murine; Mus; NSCLC; NSCLC - Non-Small Cell Lung Cancer; Nervous System, Brain; Non-Small Cell Lung Cancer; Non-Small-Cell Lung Carcinoma; Organ; Ovarian; PET; PET Scan; PET imaging; PETSCAN; PETT; Paclitaxel; Paclitaxel (Taxol); Patients; Peptides; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacodynamics; Pharmacokinetics; Positron Emission Tomography Scan; Positron-Emission Tomography; Praxel; Process; Property; Property, LOINC Axis 2; Prostate; Prostate Gland; Prostatic Gland; Protocols, Treatment; Proton Magnetic Resonance Spectroscopic Imaging; Pulmonary Cancer; Pulmonary malignant Neoplasm; RGD; RGD (peptide); RGD (sequence); RGD Cell Adhesion Domain; RGD Domain; RGD Motif; RGD Tripeptide Sequence; RGD tripeptide; RGM; Rad.-PET; Receptor Cell; Receptor Protein; Regimen; Safety; Solid Neoplasm; Solid Tumor; Specificity; Structure; System; System, LOINC Axis 4; Taxol; Taxol (Old NSC); Taxol A; Taxol Konzentrat; Technics, Imaging; Techniques; Testing; Toxic effect; Toxicities; Treatment Efficacy; Treatment Protocols; Treatment Regimen; Treatment Schedule; Tumor Angiogenesis; Tumor Burden; Tumor Cell; Tumor Load; Xenograft Model; angiogenesis; anticancer therapy; arginyl-glycyl-aspartic acid; base; cancer cell; cancer therapy; chemotherapy; cytotoxicity; density; disorder model; drug/agent; hydrophilicity; imaging; in vitro activity; in vivo; lung cancer; molecular imaging; molecular size; multimodality; neoplasm blood supply; neoplasm vascular supply; neoplastic; neoplastic cell; neovascular; nonsmall cell lung cancer; novel; overexpression; pharmacophore; preclinical study; receptor; site targeted delivery; small molecule; targeted delivery; therapeutic efficacy; therapeutically effective; tumor; tumor blood supply; tumor growth; tumor vascular supply
Project start date: 2007-09-30
Project end date: 2012-07-31
Budget start date: 1-AUG-2009
Budget end date: 31-JUL-2010
PFA/PA: PA-07-070
5R01CA120188-03 (2009): $213984
5R01CA120188-02 (2008): $214048
Grants awarded to Nouri Neamati
Integrin Avb3 Targeted Drug Design, Delivery, And Imaging
Nouri Neamati, Assistant Professor
Pharmacology And Pharmaceutical Scisuniversity Of Southern California
department Of Contracts And Grants
los Angeles, Ca 90033
Grant 1R01CA120188-01A2 from National Cancer Institute IRG: DMP
Abstract: We hypothesize that selective targeting of integrin ?v?3 by a small-molecule antagonist and an RGD-paclitaxel conjugate will have safety and efficacy profiles suitable for clinical studies. The purposes of this study are to (A) develop AV38, our highly selective integrin ?v?3 receptor antagonist as a novel anti-neoplastic agent for non-small cell lung cancer (NSCLC) alone and in combination with paclitaxel; (B) conjugate AV38 to paclitaxel and use this conjugate as well as our recently described RGD-paclitaxel as a selective delivery mechanism to ?v?3 receptor-positive cancer cells; and (C) monitor these processes by multimodality imaging techniques such as positron emission tomography (PET), bioluminescence imaging (BLI), and microCT. The rationale behind this proposal comes from the following observations (A) integrin ?v?3 is overexpressed in cancer cells and in the malignant neovascular endothelium; (B) lung cancer cells are highly metastatic and the adhesion, invasion of cells into the matrix of metastatic organs, and subsequent tumoral angiogenesis is mediated, in part, by ?v?3; (C) combination of targeted therapy with conventional chemotherapy increase the efficacy of therapy without additional toxicity; and (D) several antagonists of ?v?3 are entering into clinical and preclinical studies in a variety of disease models but their potential in NSCLC has yet to be studied. To test our overarching hypothesis more specifically we propose Specific Aim 1 To develop an RGD-paclitaxel conjugate with optimal receptor affinity and cytotoxicity. We hypothesize that integrin targeted delivery of paclitaxel allows preferential cytotoxicity to lung cancer cells depending on integrin expression levels. Specific Aim 2 To develop AV38, a novel small-molecule integrin antagonist as a single agent, in combination with paclitaxel, and as a paclitaxel-conjugate. We hypothesize that non-peptide integrin antagonists are efficient for integrin specific delivery of paclitaxel due to their relatively high metabolic stability and ease of synthesis. Specific Aim 3 To evaluate the integrin-targeted delivery efficacy and in vivo pharmacokinetics of the paclitaxel conjugates developed in Aims 1 and 2. We hypothesize that in vivo pharmacokinetics and pharmacodynamics of paclitaxel conjugates are highly correlated with in vitro receptor affinity and cytotoxicity as well as other characters such as molecular size, hydrophilicity, metabolic stability, and molecular charge. Specific Aim 4 To evaluate the anti-tumor effect of the paclitaxel conjugates by means of tumor size monitoring, histopathology and non- invasive molecular imaging. We will test the hypothesis that tumor delivery of the paclitaxel conjugate is most effective to integrin positive lung cancer. We have developed a novel drug conjugate system to deliver maximum dose to both tumor cells and tumor vasculature with dual anti-tumor effects. This new treatment regimen has its greatest potential in patients with tumors that overexpress integrin ?v?3. These tumors are usually highly metastatic as in non-small cell lung cancer (NSCLC). Because most solid tumors are angiogenesis dependent and express integrin on their cell surface, drugs developed in this project are also applicable to many other tumor types such as brain, breast, ovarian, prostate, and colon cancer
Project start date: 2007-09-30
Project end date: 2012-07-31
1R01CA120188-01A2 (2007): $229798
INHIBITION OF HIV-1 INTEGRASE-LEDGF/P75 INTERACTIONS
Nouri Neamati, Associate Professor
University Of Southern California, Department Of Contracts And Grants, Los Angeles, Ca 90033
Grant 5R21AI081610-02 from National Institute Of Allergy And Infectious Diseases
Abstract: Our central hypothesis is that the interaction between HIV-1 integrase (IN) and the cellular co-factor LEDGF/p75 is important for efficient viral replication. We further hypothesize that inhibitors of this interaction have antiviral activity, a low chance of inducing antiviral resistance, and should have low toxicity. Designed drugs targeting an essential IN-cofactor hotspot will have a major impact on current treatment regimens. The IN- LEDGF/p75 disrupting drugs would display synergistic interactions with components of HAART cocktails. Because these designed drugs target spots different from the active site, they would also display synergy with other IN inhibitors presently in development, which target the active site of the enzyme. Patients receiving HAART therapy over long periods often develop drug resistant viral strains. Drugs specific for IN-LEDGF/p75 interactions represent a completely different class of compounds, and target different stages in the viral life cycle. Viral strains exhibiting resistance to reverse transcriptase, protease, or even IN inhibitors would still be susceptible to this class of therapeutics. Additionally, the emergence rate of viral strains resistant to potential IN-LEDGF/p75 disrupting drugs would presumably be considerably slower than that to traditional antiviral therapeutics since the interface includes a cellular protein with much lower genetic variability. The study of IN cofactors and the design of potential IN-cofactor disrupting drugs is an emerging field with the potential for major developments. Previously, we created eukaryotic 293T cell lines stably expressing IN and identified LEDGF/p75 as an important cellular co-factor of IN. Recently, we have developed a high throughput assay to screen for inhibitors of the LEDGF/p75-IN interaction and have identified a series of novel inhibitors. In this proposal our goal is to characterize these inhibitors, especially their interaction with IN, antiviral activity, and design optimized inhibitors selectively blocking their interactions with IN. More specifically we propose Aim 1. To design novel inhibitors of the LEDGF/p75-IN interaction and Aim 2. To validate our top 10 compounds as bona fide inhibitors of IN-LEDGF/p75 interaction. Successful completion of this study will show that this innovative strategy provides a new target and inhibitor for antiretroviral therapy and for further interrogating the LEDG/p75 pathway. By extension this approach can be exploited in other diseases where protein-protein interactions can be safely inhibited without affecting cellular function. HIV-1 integrase interacts with a series of cellular co-factors and many of these interactions such as with LEDGF/p75 are important for efficient viral replication. Selective inhibition of these interactions provides a unique strategy to design novel and safe drugs with antiviral activity
Keywords: 3-D structure; 3-dimensional structure; 3D structure; AIDS Virus; Active Sites; Affect; Antiretroviral Therapy, Highly Active; Antiviral Agents; Antiviral Drugs; Antiviral resistance; Antiviral resistant; Antivirals; Assay; Bioassay; Biologic Assays; Biological Assay; Biology; Cell Function; Cell Line; Cell Lines, Strains; Cell Process; Cell physiology; CellLine; Cellular Function; Cellular Physiology; Cellular Process; Deoxynucleotide-triphosphate[{..}]DNA deoxynucleotidyltransferase (RNA-directed); Development; Disease; Disorder; Drug Delivery; Drug Delivery Systems; Drug Design; Drug Targeting; Drug Targetings; Drug resistant viral; Drugs; EC 2.7.7.49; Enzymes; Esteroproteases; Exhibits; Fluorescence; Genetic; Goals; HAART; HIV-1; HIV-1 Integrase; HIV-I; HIV1; High Throughput Assay; Highly Active Antiretroviral Therapy; Human immunodeficiency virus 1; Immunodeficiency Virus Type 1, Human; Integrase; Integrase Inhibitors; Libraries; Life Cycle; Life Cycle Stages; Lytotoxicity; Medication; Pathway interactions; Patients; Peptidases; Peptide Hydrolases; Pharmaceutic Preparations; Pharmaceutical Preparations; Programs (PT); Programs [Publication Type]; Proteases; Proteinases; Proteins; Proteolytic Enzymes; Protocols, Treatment; RGM; RNA Transcriptase; RNA-Dependent DNA Polymerase; RNA-Directed DNA Polymerase; Regimen; Resistance; Reverse Transcriptase; Revertase; Series; Spottings; Staging; Structure; Subcellular Process; Testing; Therapeutic; Toxic effect; Toxicities; Treatment Protocols; Treatment Regimen; Treatment Schedule; Viral; anti-retroviral therapy, highly active; anti-viral resistance; anti-viral resistant; antiretroviral therapy; base; cofactor; cultured cell line; cytotoxicity; design; designing; disease/disorder; drug discovery; drug resistant virus; drug/agent; gene product; high throughput screening; human T cell leukemia virus III; human T lymphotropic virus III; inhibitor; inhibitor/antagonist; innovate; innovation; innovative; life course; mutant; novel; p75; p75 transcription factor; pathway; programs; protein protein interaction; public health relevance; resistance to anti-viral; resistance to antiviral; resistant; resistant strain; resistant to anti-viral; resistant to antiviral; small molecule; therapeutic target; three dimensional structure; transcriptional coactivator p75; virtual
Relevance: HIV-1 integrase interacts with a series of cellular co-factors and many of these interactions such as with LEDGF/p75 are important for efficient viral replication. Selective inhibition of these interactions provides a unique strategy to design novel and safe drugs with antiviral activity
Project start date: 2009-07-23
Project end date: 2011-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
PFA/PA: PA-06-181
5R21AI081610-02 (2010): $196250
1R21AI081610-01A1 (2009): $246009
Nouri Neamati, Associate Professor
University Of Southern California, Department Of Contracts And Grants, Los Angeles, Ca 90033
Abstract: Core C Analytic The Analytical Core, under the direction of Dr. Nouri Neamati, Assistant Professor of Pharmaceutical Sciences, will process, bank, and analyze all tissues and appropriate samples for research purposes for use in this Program Project. The tissues as well as fluid, specimens including blood, serum, and urine will be collected where needed for individual investigators with hypothesis driven translational research. The Analytical Core will provide the following services where appropriate 1) Macroarray analysis of 100 highly relevant customized genes using SuperArray platform. 2) Real-Time PCR for selected genes. 3) Mass Spectrometry including MALDI and MS/MS analysis for selected samples. 4) Progesterone and metabolite analysis by Gas Chromatograph with Mass Selective Detector utilizing Electron Impact ionization, and 5) Quantitative analysis of progesterone and metabolites by radioimmunoassays
Keywords: AD model; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer`s; Alzheimer`s Disease; Alzheimer`s disease model; Alzheimers Dementia; Alzheimers disease; Ammon Horn; Animals; Antihormone Agents; Banking, Tissue; Bio-Informatics; Bioinformatics; Blood; Blood Plasma; Blood Serum; Body Tissues; Brain; Brain region; Cataloging; Catalogs; Change of Life, Female; Chemotherapy-Hormones/Steroids; Cluster Analyses; Cluster Analysis; Cognitive Discrimination; Common Rat Strains; Cornu Ammonis; Corpus Luteum Hormone; Custom; Delta4-pregnene-3, 20-dione; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Discrimination; Discrimination (Psychology); Electrons; Encephalon; Encephalons; Endocrine Gland Secretion; Ensure; Future; Gases; Gene Expression; Genes; Genital System, Female, Uterus; Hippocampus; Hippocampus (Brain); Hormone Antagonists; Hormones; Immunologic, Radioimmunoassay; Individual; Investigators; Liquid substance; MALD-MS; MALDI; MALDI-MS; Mammals, Mice; Mammals, Rats; Mass Spectrum; Mass Spectrum Analysis; Menopause; Mice; Modeling; Murine; Mus; Negative Beta Particle; Negatrons; Nervous System, Brain; Pathway interactions; Pattern; Pattern Recognition; Pattern Recognition/Display/Analysis; Perimenopausal; Perimenopause; Pharmaceutical Agent; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Photometry/Spectrum Analysis, Mass; Plasma; Pregn-4-ene-3, 20-dione; Pregnenedione; Primary Senile Degenerative Dementia; Process; Progesterone; Programs (PT); Programs [Publication Type]; Proteins; RIA; RNA Metabolism[{..}] Processing and Transport; RNA Processing; RT-PCR; RTPCR; Radioimmunoassay; Rat; Rattus; Research; Research Personnel; Research Specimen; Researchers; Reticuloendothelial System, Blood; Reticuloendothelial System, Serum, Plasma; Reverse Transcriptase Polymerase Chain Reaction; Sampling; Science; Serum; Serum, Plasma; Services; Solutions; Specimen; Spectrometry, Mass; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spectroscopy, Mass; Spectroscopy, Mass, Matrix-Assisted Laser Desorption-Ionization; Spectrum Analyses, Mass; Spectrum Analysis, Mass; Therapeutic Hormone; Therapeutic Progesterone; Time; Tissue Banking; Tissue Banks; Tissue Collection; Tissue Sample; Tissue/Specimen Collection; Tissues; Translational Research; Translational Research Enterprise; Translational Science; Urinary System, Urine; Urine; Uterus; aging brain; brain tissue; computational chemistry; dementia of the Alzheimer type; detector; experiment; experimental research; experimental study; fluid; gene product; hippocampal; hormone inhibitor; hormone metabolism; inhibitor; inhibitor/antagonist; ionization; liquid; matrix assisted laser desorption ionization; member; menopausal; pathway; primary degenerative dementia; professor; programs; research study; reverse transcriptase PCR; senile dementia of the Alzheimer type; translation research enterprise; womb
Budget start date: 1-JUN-2009
Budget end date: 31-MAY-2010
5P01AG026572-04_9002 (2009): $209308