SURROGATE BIOMARKERS IN CHRONIC LUNG GRAFT REJECTION
Sean Michael Studer
Newark Beth Israel Medical Center, Newark, Nj 07112
Grant 5K23HL083096-02 from National Heart, Lung, And Blood Institute
Abstract: The primary goal of this proposal is to provide a framework for my scientific development and facilitate my transition to becoming an independent investigator. The Clinical Research Training Program (CRTP) and the Lung Translational Genomics Center at the University of Pittsburgh combine to provide me with the ideal environment to obtain and apply the necessary skills for the study of novel surrogate blood biomarkers in chronic lung allograft rejection (OB/OS). OB/BOS is the main impediment to long-term survival in lung transplant recipients (LTRs) and its etiology and pathogenesis are largely unknown. Currently, OB/BOS diagnosis requires either a lung biopsy, which is invasive, costly and of limited sensitivity, or a decline in spirometric lung function, which represents irreversible loss of greater than 20% of lung function. The central hypothesis of this proposal is that airway remodeling, which characterizes OB/BOS, requires a shift in the inflammatory environment from a predominantly IFN-gamma response (antifibrotic milieu) to a profibrotic response characterized by induction of cytokines such as TGF-beta. Targeted secreted protein and global gene expression profiles in the peripheral blood of LTRs will demonstrate this shift allowing identification of combinatorial biomarkers that will be indicative of risk, progression and outcome of OB/BOS. Sequential, paired peripheral blood and bronchoalveolar lavage specimens will be obtained from 100 lung transplant recipients, which will then be studied via the following specific aims (1) Identify changes in plasma profibrotic cytokines and growth factors in LTRs that predict the development of OB/BOS; (2) Identify temporal changes in gene expression profiles in peripheral blood mononuclear cells (PBMC) that are predictive of favorable long-term response versus those predictive of subsequently developing OB/BOS; While Aim 1 investigates a shift in circulating proteins, Aim 2 evaluates the genes induced in blood cells by this antifibrotic to profibrotic cytokine shift. (3) Determine gene expression and targeted secreted protein patterns in bronchoalveolar lavage fluid (BAL) to identify lung OB/BOS biomarkers that may coincide with those surrogates observed in blood or provide a graft-localized biomarker signal. Through regular interaction with the senior faculty of the CRTP and the experienced investigators who comprise my mentorship committee, I anticipate building the necessary foundation for a successful independent academic career. (End of )
Keywords: Acute; Address; Allografting; Alveolar; Biopsy; Blood; Blood Cells; Blood Plasma; Body Tissues; Bone-Derived Transforming Growth Factor; Bronchial Lavage Fluid; Bronchioalveolar Lavage; Bronchiolitis; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; C-C CKR-5 Gene; C-C Chemokine Receptor Type 5 Gene; CC-CKR-5 Gene; CCCKR5 Gene; CCL2; CCL2 gene; CCR-5 Gene; CCR5; CCR5 gene; CD195 Antigen Gene; CD4 Positive T Lymphocytes; CD4 T cells; CD4 lymphocyte; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; CHEMR13 Gene; CKR-5 Gene; CKR5 Gene; CMKBR5 Gene; CXC-R4; CXCR-4; CXCR4; CXCR4 gene; Causality; Cause of Death; Cell Communication and Signaling; Cell Signaling; Cells, CD4; Characteristics; Chemokine (C-C) Receptor 5 Gene; Chronic; Clinical; Clinical Research; Clinical Study; Co-Stimulator; Collection; Costimulator; Cytokine Receptors; Cytokines, Chemotactic; D2S201E; Data; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disorder; Douching, other than vaginal; Environment; Epidermal Thymocyte Activating Factor; Equilibrium; Etiology; Evaluation; Expression Profiling; Expression Signature; FB22; Faculty; Foundations; Future; GDCF-2; GDCF-2 HC11; GFAC; Gamma interferon; Gene Expression; Gene Expression Profile; Genes; Genomics; Goals; Graft Rejection; Grafting, Lung; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; HC11; HIV-1 Fusion Co-Receptor Gene; HM89; HSY3RR; Histology; Homologous Chemotactic Cytokines; IFN; IFN-Gamma; IFN-g; IFNG; IL-2; IL2; IL2 Protein; INFLM; Inflammation; Inflammatory; Intercrines; Interferon Gamma; Interferon Type II; Interferon gamma (human lymphocyte protein moiety reduced); Interferon, Immune; Interferon-gamma; Interferons; Interleukin 2; Interleukin 2 Precursor; Interleukin II; Interleukin-2; Interleukine 2; Interleukine 2 Precursor; Interleukine II; Intracellular Communication and Signaling; Investigation; Investigators; Irrigation; Irrigation, other than vaginal; LAP3; LCR1; LESTR; Lavage; Lavage Fluids, Alveolar; Lavage, Bronchopulmonary; Link; Lung; Lung Function Tests; Lung Lavage; Lung Lavage Fluid; Lung Transplantation; Lung diseases; Lymphocyte Mitogenic Factor; MCAF; MCP-1; MCP1; MGC9434; MIP; MIP-1; Macrophage Inflammatory Protein-1; Macrophage Inflammatory Proteins; Mentorship; Milk Growth Factor; Mitogenic Factor; Molecular Fingerprinting; Molecular Profiling; Monitor; Morbidity; Morbidity - disease rate; NPY3R; NPYR; NPYRL; NPYY3R; Nonvaginal irrigation; Nonvaginal lavage; Outcome; PBMC; Pathogenesis; Patients; Pattern; Peripheral Blood Cell; Peripheral Blood Mononuclear Cell; Plasma; Platelet Transforming Growth Factor; Proteins; Publishing; Pulmonary Diseases; Pulmonary Disorder; Pulmonary function tests; Receptors, Cytokine; Reliance; Reporting; Research Personnel; Research Specimen; Research Training; Researchers; Respiratory Disease; Respiratory Disorder; Respiratory Function Tests; Respiratory System Disease; Respiratory System Disorder; Respiratory System, Lung; Respiratory physiology; Reticuloendothelial System, Blood; Reticuloendothelial System, Serum, Plasma; Risk; SCYA2; SIS cytokines; SMC-CF; Sampling; Screening procedure; Sensitivity and Specificity; Series; Serum, Plasma; Signal Transduction; Signal Transduction Systems; Signaling; Specimen; T cell growth factor; T-Cell Growth Factor; T-Cell Stimulating Factor; T-Cells; T-Lymphocyte; T4 Cells; T4 Lymphocytes; TGF B; TGF-beta; TGFbeta; Testing; Therapeutic; Thymocyte Stimulating Factor; Thymus-Dependent Lymphocytes; Time; Tissues; Training Programs; Transforming Growth Factor beta; Transplant Recipients; Transplant Rejection; Transplantation; Transplantation Rejection; Universities; ing; airway remodeling; balance; balance function; base; biological signal transduction; biomarker; bronchopulmonary lavage therapy; career; chemoattractant cytokine; chemokine; combinatorial; cytokine; disease causation; disease etiology; disease/disorder; disease/disorder etiology; disorder etiology; experience; falls; gene expression signature; gene product; helper T cell; improved; insight; irrigation therapy; lFN-Gamma; lavage therapy; lung allograft; lung disorder; lung function; molecuar profile; molecular signature; novel; peripheral blood; prospective; pulmonary; respiratory function; response; screening; screenings; skills; thymus derived lymphocyte; transcriptome; transplant; transplant patient
Project start date: 2008-06-04
Project end date: 2013-05-31
Budget start date: 1-JUN-2009
Budget end date: 31-MAY-2010
PFA/PA: PA-05-143
5K23HL083096-02 (2009): $151881
Sponsored Links Excellgen http://Excellgen.com
SURROGATE BIOMARKERS IN CHRONIC LUNG GRAFT REJECTION
Sean Michael Studer
Newark Beth Israel Medical Center, Newark, Nj 07112
Grant 5K23HL083096-03 from National Heart, Lung, And Blood Institute
Abstract: The primary goal of this proposal is to provide a framework for my scientific development and facilitate my transition to becoming an independent investigator. The Clinical Research Training Program (CRTP) and the Lung Translational Genomics Center at the University of Pittsburgh combine to provide me with the ideal environment to obtain and apply the necessary skills for the study of novel surrogate blood biomarkers in chronic lung allograft rejection (OB/OS). OB/BOS is the main impediment to long-term survival in lung transplant recipients (LTRs) and its etiology and pathogenesis are largely unknown. Currently, OB/BOS diagnosis requires either a lung biopsy, which is invasive, costly and of limited sensitivity, or a decline in spirometric lung function, which represents irreversible loss of greater than 20% of lung function. The central hypothesis of this proposal is that airway remodeling, which characterizes OB/BOS, requires a shift in the inflammatory environment from a predominantly IFN-gamma response (antifibrotic milieu) to a profibrotic response characterized by induction of cytokines such as TGF-beta. Targeted secreted protein and global gene expression profiles in the peripheral blood of LTRs will demonstrate this shift allowing identification of combinatorial biomarkers that will be indicative of risk, progression and outcome of OB/BOS. Sequential, paired peripheral blood and bronchoalveolar lavage specimens will be obtained from 100 lung transplant recipients, which will then be studied via the following specific aims (1) Identify changes in plasma profibrotic cytokines and growth factors in LTRs that predict the development of OB/BOS; (2) Identify temporal changes in gene expression profiles in peripheral blood mononuclear cells (PBMC) that are predictive of favorable long-term response versus those predictive of subsequently developing OB/BOS; While Aim 1 investigates a shift in circulating proteins, Aim 2 evaluates the genes induced in blood cells by this antifibrotic to profibrotic cytokine shift. (3) Determine gene expression and targeted secreted protein patterns in bronchoalveolar lavage fluid (BAL) to identify lung OB/BOS biomarkers that may coincide with those surrogates observed in blood or provide a graft-localized biomarker signal. Through regular interaction with the senior faculty of the CRTP and the experienced investigators who comprise my mentorship committee, I anticipate building the necessary foundation for a successful independent academic career. (End of )
Keywords: Acute; Address; Allografting; Alveolar; Biopsy; Blood; Blood Cells; Blood Plasma; Body Tissues; Bone-Derived Transforming Growth Factor; Bronchial Lavage Fluid; Bronchioalveolar Lavage; Bronchiolitis; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; C-C CKR-5 Gene; C-C Chemokine Receptor Type 5 Gene; CC-CKR-5 Gene; CCCKR5 Gene; CCL2; CCL2 gene; CCR-5 Gene; CCR5; CCR5 gene; CD195 Antigen Gene; CD4 Positive T Lymphocytes; CD4 T cells; CD4 lymphocyte; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; CHEMR13 Gene; CKR-5 Gene; CKR5 Gene; CMKBR5 Gene; CXC-R4; CXCR-4; CXCR4; CXCR4 gene; Causality; Cause of Death; Cell Communication and Signaling; Cell Signaling; Cells, CD4; Characteristics; Chemokine (C-C) Receptor 5 Gene; Chronic; Clinical; Clinical Research; Clinical Study; Co-Stimulator; Collection; Costimulator; Cytokine Receptors; Cytokines, Chemotactic; D2S201E; Data; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disorder; Douching, other than vaginal; Environment; Epidermal Thymocyte Activating Factor; Equilibrium; Etiology; Evaluation; Expression Profiling; Expression Signature; FB22; Faculty; Foundations; Future; GDCF-2; GDCF-2 HC11; GFAC; Gamma interferon; Gene Expression; Gene Expression Profile; Genes; Genomics; Goals; Graft Rejection; Grafting, Lung; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; HC11; HIV-1 Fusion Co-Receptor Gene; HM89; HSY3RR; Histology; Homologous Chemotactic Cytokines; IFN; IFN-Gamma; IFN-g; IFNG; IL-2; IL2; IL2 Protein; INFLM; Inflammation; Inflammatory; Intercrines; Interferon Gamma; Interferon Type II; Interferon gamma (human lymphocyte protein moiety reduced); Interferon, Immune; Interferon-gamma; Interferons; Interleukin 2; Interleukin 2 Precursor; Interleukin II; Interleukin-2; Interleukine 2; Interleukine 2 Precursor; Interleukine II; Intracellular Communication and Signaling; Investigation; Investigators; Irrigation; Irrigation, other than vaginal; LAP3; LCR1; LESTR; Lavage; Lavage Fluids, Alveolar; Lavage, Bronchopulmonary; Link; Lung; Lung Function Tests; Lung Lavage; Lung Lavage Fluid; Lung Transplantation; Lung diseases; Lymphocyte Mitogenic Factor; MCAF; MCP-1; MCP1; MGC9434; MIP; MIP-1; Macrophage Inflammatory Protein-1; Macrophage Inflammatory Proteins; Mentorship; Milk Growth Factor; Mitogenic Factor; Molecular Fingerprinting; Molecular Profiling; Monitor; Morbidity; Morbidity - disease rate; NPY3R; NPYR; NPYRL; NPYY3R; Nonvaginal irrigation; Nonvaginal lavage; Outcome; PBMC; Pathogenesis; Patients; Pattern; Peripheral Blood Cell; Peripheral Blood Mononuclear Cell; Plasma; Platelet Transforming Growth Factor; Proteins; Publishing; Pulmonary Diseases; Pulmonary Disorder; Pulmonary function tests; Reliance; Reporting; Research Personnel; Research Specimen; Research Training; Researchers; Respiratory Disease; Respiratory Disorder; Respiratory Function Tests; Respiratory System Disease; Respiratory System Disorder; Respiratory System, Lung; Respiratory physiology; Reticuloendothelial System, Blood; Reticuloendothelial System, Serum, Plasma; Risk; SCYA2; SIS cytokines; SMC-CF; Sampling; Screening procedure; Sensitivity and Specificity; Series; Serum, Plasma; Signal Transduction; Signal Transduction Systems; Signaling; Specimen; T cell growth factor; T-Cell Growth Factor; T-Cell Stimulating Factor; T-Cells; T-Lymphocyte; T4 Cells; T4 Lymphocytes; TGF B; TGF-beta; TGFbeta; Testing; Therapeutic; Thymocyte Stimulating Factor; Thymus-Dependent Lymphocytes; Time; Tissues; Training Programs; Transforming Growth Factor beta; Transplant Recipients; Transplant Rejection; Transplantation; Transplantation Rejection; Universities; ing; airway remodeling; allograft rejection; balance; balance function; base; biological signal transduction; biomarker; bronchopulmonary lavage therapy; career; chemoattractant cytokine; chemokine; combinatorial; cytokine; disease causation; disease etiology; disease/disorder; disease/disorder etiology; disorder etiology; experience; falls; gene expression signature; gene product; helper T cell; improved; insight; irrigation therapy; lFN-Gamma; lavage therapy; lung allograft; lung disorder; lung function; molecuar profile; molecular signature; novel; peripheral blood; prospective; pulmonary; respiratory function; response; screening; screenings; skills; thymus derived lymphocyte; transcriptome; transplant; transplant patient
Project start date: 2008-06-04
Project end date: 2013-05-31
Budget start date: 1-JUN-2010
Budget end date: 31-MAY-2011
PFA/PA: PA-05-143
5K23HL083096-03 (2010): $151881