RESEARCH TRAINING IN INFECTIONS AND IMMUNITY
David John Tweardy
Baylor College Of Medicine, 1 Baylor Plaza, Houston, Tx 77030-3498
Grant 5T32AI055413-07 from National Institute Of Allergy And Infectious Diseases
Abstract: This NRSA competing application will allow trainees at Baylor College of Medicine (BCM) to continue to successfully launch clinical research careers in infectious diseases. At this time, ours is the sole NRSA existing within BCM or the Texas Medical Center to pursue clinical research training in non-AIDS infections. Superb training opportunities exist at BCM in a number of areas. Participating projects with a strong record of federal funding and training experience include 1) Innate Immunity and Nosocomial Infections, 2) Novel Drug-, Cell- and Probiotic-based Therapeutics, 3) Viral and Bacterial Gastroenteritis, 4) Viral and Bacterial Pathogenesis and Oncogenesis, 5), Acute Respiratory Pathogens and Pneumonia, 6) Vaccine Development and Evaluation, 7) Tuberculosis, and 8) Prostheses Infections. Total grant support in 2007 for the specific centers and programs participating in this NRSA Program is $19.5M. The structure of the Program contains three components, representing training tracks that can be pursued by trainees 1) laboratory-based clinical research, 2) clinical research trials and 3) clinical epidemiology. All trainees pursuing the laboratory-based track will be required to participate in the Clinical Scientist Training Program (CSTP; K30) at BCM; physician trainees will obtain their MS in Clinical Investigation. Those pursuing the clinical epidemiology track are required to enter the University of Texas-Houston School of Public Health (UTHSPH) and obtain their MPH. Those trainees pursuing the clinical trials track will enter either the CSTP or UTHSPH and obtain their MS or MPH, respectively. The Adult Infectious Diseases Training Program at BCM has shown it can attract highly qualified postdoctoral trainees, over half of them women and close to a quarter under-represented minorities, and provide them with the skills necessary to begin successful careers in infectious diseases clinical research. In the current cycle, this Program has graduated 5 trainees, all of whom were appointed to the Assistant Professor level in a major medical college or university. Altogether, these individuals have published 60 original peer-reviewed manuscripts and have been awarded several prestigious grants and career development awards, totaling $1.6M. This record of success, along with a doubling in the pool of applicants and the participation of 10 new Faculty Mentors/Co-Mentors, is offered as evidence in support of renewal with 3 postdoctoral trainees per year, an increase from 2 trainees in the current cycle
Keywords: Immunity; Infection; Research Training
Project start date: 2003-08-01
Project end date: 2013-07-31
Budget start date: 1-AUG-2009
Budget end date: 31-JUL-2010
PFA/PA: PA-06-468
5T32AI055413-07 (2009): $133024
Sponsored Links Excellgen http://Excellgen.com
RESEARCH TRAINING IN INFECTIONS AND IMMUNITY
David John Tweardy
Baylor College Of Medicine, 1 Baylor Plaza, Houston, Tx 77030-3498
Grant 5T32AI055413-08 from National Institute Of Allergy And Infectious Diseases
Abstract: This NRSA competing application will allow trainees at Baylor College of Medicine (BCM) to continue to successfully launch clinical research careers in infectious diseases. At this time, ours is the sole NRSA existing within BCM or the Texas Medical Center to pursue clinical research training in non-AIDS infections. Superb training opportunities exist at BCM in a number of areas. Participating projects with a strong record of federal funding and training experience include 1) Innate Immunity and Nosocomial Infections, 2) Novel Drug-, Cell- and Probiotic-based Therapeutics, 3) Viral and Bacterial Gastroenteritis, 4) Viral and Bacterial Pathogenesis and Oncogenesis, 5), Acute Respiratory Pathogens and Pneumonia, 6) Vaccine Development and Evaluation, 7) Tuberculosis, and 8) Prostheses Infections. Total grant support in 2007 for the specific centers and programs participating in this NRSA Program is $19.5M. The structure of the Program contains three components, representing training tracks that can be pursued by trainees 1) laboratory-based clinical research, 2) clinical research trials and 3) clinical epidemiology. All trainees pursuing the laboratory-based track will be required to participate in the Clinical Scientist Training Program (CSTP; K30) at BCM; physician trainees will obtain their MS in Clinical Investigation. Those pursuing the clinical epidemiology track are required to enter the University of Texas-Houston School of Public Health (UTHSPH) and obtain their MPH. Those trainees pursuing the clinical trials track will enter either the CSTP or UTHSPH and obtain their MS or MPH, respectively. The Adult Infectious Diseases Training Program at BCM has shown it can attract highly qualified postdoctoral trainees, over half of them women and close to a quarter under-represented minorities, and provide them with the skills necessary to begin successful careers in infectious diseases clinical research. In the current cycle, this Program has graduated 5 trainees, all of whom were appointed to the Assistant Professor level in a major medical college or university. Altogether, these individuals have published 60 original peer-reviewed manuscripts and have been awarded several prestigious grants and career development awards, totaling $1.6M. This record of success, along with a doubling in the pool of applicants and the participation of 10 new Faculty Mentors/Co-Mentors, is offered as evidence in support of renewal with 3 postdoctoral trainees per year, an increase from 2 trainees in the current cycle
Keywords: Immunity; Infection; Research Training
Project start date: 2003-08-01
Project end date: 2013-07-31
Budget start date: 1-AUG-2010
Budget end date: 31-JUL-2011
PFA/PA: PA-06-468
5T32AI055413-08 (2010): $134074
Grants awarded to David John Tweardy
STAT3 PROBES THAT TARGET BREAST CANCER STEM CELLS
David John Tweardy
Baylor College Of Medicine, 1 Baylor Plaza, Houston, Tx 77030-3498
Grant 1R21CA149783-01 from National Cancer Institute
Abstract: Conventional chemotherapy is effective initially in controlling and reversing tumor growth. However, residual cancers will invariably re-grow. Our recent data from paired human breast cancer samples indicates that standard therapy eliminates dividing daughter cells while enriching the residual tumor for CD44?/low putative breast "cancer stem cells" (CSCs) that have the ability to self-renew in mammosphere (MS) cultures, and to give rise to tumors upon xenograft transplantation. We have identified a cancer stem cell signature within these CD44?/low, MS-forming cells that features Stat3. Using virtual ligand screening (VLS), we developed lead chemical probes that target the Src homology (SH) 2 domain of Stat3 and that competitively and selectively inhibited Stat3 activation. 3-D pharmacophore analysis was performed using the most active lead compound (Cpd188) and a Life Chemicals compound library; the top scoring compounds identified were tested for inhibition of Stat3 binding to its phosphopeptide ligand by surface plasmon resonance (SPR). All but six of 39 compounds tested have measurable IC50s, with 17 having IC50 values equal to or less than Cpd188. One compound (Cpd188-15) has an IC50 value in MS formation inhibition assays that is one log lower than Cpd188. We have developed 2 highly focused SPECIFIC AIMS to directly test the hypothesis that small- molecule inhibitors of Stat3 can specifically target breast cancer stem cells. AIM 1. To develop third (3rd) generation Stat3 chemical probes with increased binding affinity and inhibitory activity. We propose using the most active 2nd generation probe, Cpd188-15, as a scaffold for making 3rd generation probes. Modifications planned are based on the results of a structure-activity relationship (SAR) analysis performed on 2nd generation probes and center around the straightforward synthesis of sulfamides from panels of sulfonyl chlorides and amides. Each novel sulfamide compound will be examined in the SPR assay, in a high throughput fluorescence microscopy (HTFM) assay that will test inhibition of IL-6-stimulated cytoplasmic-to-nuclear translocation and for their selectivity for Stat3 vs. Stat1. AIM 2. To determine whether suppression of the Stat3 pathway can improve existing cancer therapies in preclinical MS assays and human xenograft models. We will determine whether Stat3 inhibition by the most active 3rd generation probes will improve efficacy of conventional therapy in vitro and in vivo, using MS formation inhibition assays and human breast cancer xenograft models. In addition to establishing the contribution of Stat3 to breast cancer stem cell survival and self-renewal, these preclinical studies may inform the design of future clinical trials and determine whether suppressing stem cell self-renewal and treatment resistance pathways can improve existing breast cancer therapies in patients. A small proportion of breast cancer cells fail to respond to the usual treatments and cause relapsing disease. This proposal outlines chemical and biological studies designed to develop small molecule probes that target these therapy-resistant cells. If these studies are successful, these small molecule probes may be combined with current treatments for breast cancer thereby preventing cancer relapse and resulting in a cure
Keywords: 3-D; 3-Dimensional; Affinity; Amides; Assay; Binding; Binding (Molecular Function); Binding Sites; Bioassay; Biologic Assays; Biological; Biological Assay; Breast Cancer Cell; Breast Cancer Treatment; Cancer Patient; Cancer Relapse; Cancer Treatment; Cancer of Breast; Cancer stem cell; Cell Communication and Signaling; Cell Signaling; Cell Survival; Cell Viability; Cells; Chemicals; Chemistry, Pharmaceutical; Chloride; Chloride Ion; Chlorides; Cl- element; Clinical Trials; Clinical Trials, Unspecified; Combining Site; Data; Data Set; Dataset; Docking; Drugs; FLR; Failure (biologic function); Fluorescence Microscopy; Future; Gene Expression; Generalized Growth; Generations; Goals; Growth; Heterograft; Human; Human Breast Cancer Cell; Human, General; IC50; IFN; Immunocompromised; Immunocompromised Host; Immunocompromised Patient; Immunosuppressed Host; In Vitro; Inhibitory Concentration 50; Interferons; Intracellular Communication and Signaling; L-tyrosine, dihydrogen phosphate (ester); Lead; Libraries; Life; Ligands; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Tumor of the Breast; Malignant neoplasm of breast; Man (Taxonomy); Man, Modern; Measurable; Medication; Medicinal Chemistry; Microscopy, Fluorescence; Microscopy, Light, Fluorescence; Modification; Molecular Interaction; Mother Cells; Nuclear Translocation; Parents; Pathway interactions; Patients; Pb element; Peptides; Pharmaceutic Chemistry; Pharmaceutic Preparations; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phosphopeptides; Phosphorylation; Phosphotyrosine; Population; Progenitor Cells; Protein Phosphorylation; Reactive Site; Recurrent disease; Relapse; Relapsed Disease; Research Design; Residual Cancers; Residual Tumors; Resistance; Role; SCID Beige; SCID Beige Mouse; SH2 Domains; Sampling; Screening procedure; Signal Transduction; Signal Transduction Systems; Signaling; Site; Stem cells; Structure; Structure-Activity Relationship; Study Type; Surface Plasmon Resonance; Testing; Time; Tissue Growth; Transplantation; Transplantation, Heterologous; Tumorigenicity; Tumors, Residual; Tyrosine-O-phosphate; Xenograft; Xenograft Model; Xenograft procedure; Xenotransplantation; anticancer therapy; base; biological signal transduction; cancer therapy; chemical structure function; chemotherapy; clinical investigation; conventional therapy; daughter cell; design; designing; drug/agent; failure; heavy metal Pb; heavy metal lead; immunosuppressed patient; improved; in vivo; inhibitor; inhibitor/antagonist; malignant breast neoplasm; novel; ontogeny; pathway; pharmacophore; pre-clinical; preclinical; preclinical study; prevent; preventing; public health relevance; residual disease; resistance to therapy; resistant; resistant to therapy; scaffold; scaffolding; screening; screenings; self-renewal; small molecule; social role; src Homology Region 2 Domain; structure function relationship; study design; therapy resistant; transplant; tumor; tumor growth; tumorigenic; virtual
Relevance: NARRATIVE A small proportion of breast cancer cells fail to respond to the usual treatments and cause relapsing disease. This proposal outlines chemical and biological studies designed to develop small molecule probes that target these therapy-resistant cells. If these studies are successful, these small molecule probes may be combined with current treatments for breast cancer thereby preventing cancer relapse and resulting in a cure
Project start date: 2010-07-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
PFA/PA: PA-08-165
1R21CA149783-01 (2010): $200318