Not listed COMPUTATIONAL DRUG REPOSITIONING FOR ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION - ABSTRACT DESPITE ADVANCES IN KIDNEY TRANSPLANTATION (KT) WITH IMPROVED 1-YEAR GRAFT SURVIVAL TO >90%, KT ATTRITION IS UNCHANGED DUE TO PERSISTENT ANTIBODY MEDIATED REJECTION (ABMR). GIVEN LIMITED ABMR TREATMENT OPTIONS, THE OUTCOME IS PERSISTENT KT INFLAMMATION AND ACCELERATED KT LOSS. AS SUBTYPES OF REJECTION ARE DIVERSE IN THEIR PATHOGENESIS AND TREATMENT RESPONSE, THE NEED FOR PRECISE TREATMENTS BASED ON MOLECULAR BASIS OF REJECTION IS WELL-FOUNDED. WE PROPOSE TO DEVELOP AND APPLY A DRUG REPURPOSING PIPELINE TO ABMR EXPRESSION PROFILES TO QUERY PUBLICLY AVAILABLE DRUG-GENE EXPRESSION DATABASES, TO IDENTIFY SINGLE AND COMBINATION DRUG REPURPOSING CANDIDATES FOR ABMR (AIM 1). OUR PRELIMINARY, PUBLISHED STUDIES SUPPORT THE SUCCESSFUL ANALYSES FOR ABMR WITH IDENTIFICATION OF PUBLICALLY AVAILABLE HISTOLOGICAL AND MOLECULAR STABLE (CONTROL) AND ABMR RENAL ALLOGRAFT DATASETS, TO BE INTEGRATED WITH SINGLE-CELL RNASEQ ANALYSIS EXPERIMENTS THAT WILL BE CONDUCTED ON CURATED ABMR RENAL ALLOGRAFT BIOPSIES. WE WILL USE TRANSCRIPTOMIC-BASED COMPUTATIONAL DRUG-REPURPOSING TO IDENTIFY POTENTIAL NEW SINGLE AGENT AND COMBINATION THERAPEUTICS FOR THE TREATMENT OF ABMR, BASED ON EXPRESSION REVERSAL, LEVERAGING PUBLIC AND NEWLY GENERATED SINGLE CELL DATA. WE WILL FURTHER DETERMINE THE KINETICS AND THE MECHANISM OF ACTION OF PROMISING DRUGS OR DRUG COMBINATIONS IN HUMAN CELLS AND ABMR TISSUE, EX VIVO (AIM 2). PROMISING SINGLE AGENT AND COMBINATION AGENTS WILL BE FURTHER VALIDATED FOR EFFICACY FOR TREATMENT OR PREVENTION OF ABMR IN VIVO, IN A PRE-CLINICAL, ESTABLISHED, RODENT RENAL ALLOGRAFT MODEL OF ABMR (AIM 3). OUR APPROACH IS HIGHLY SIGNIFICANT BECAUSE WE WILL INVESTIGATE UNIQUE AND NOVEL CELL-SPECIFIC TRANSCRIPTOMIC PROFILES, UNDERLYING BIOLOGICAL PROCESSES AND SIGNALING PATHWAYS IN ABMR AND THESE DATA WILL BE ANALYZED WITH A DRUG REPURPOSING PIPELINE TO DISCOVER NOVEL SINGLE AGENTS AND COMBINATION THERAPIES THAT CAN BE USED AS A PERSONALIZED APPROACH TO MANAGEMENT OF ABMR. THE IN VIVO EXPERIMENTS WILL TAKE THESE STUDIES TO VALIDATION OF COMPOUND OR COMBINATION OF COMPOUND EFFICACY FOR REVERSING OR PREVENTING ABMR. THE SUCCESSFUL COMPLETION OF THESE STUDIES CAN PROPOSE NEW, FDA APPROVED DRUGS, THAT COULD BE REPURPOSED FOR IMPROVING LONG TERM OUTCOMES IN KIDNEY TRANSPLANT RECIPIENTS, BY REDUCING ABMR INJURY, EXTEND GRAFT AND PATIENT SURVIVAL. $797.9k 5/8/26 Not listed COMPUTATIONAL DRUG REPOSITIONING FOR ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION - ABSTRACT DESPITE ADVANCES IN KIDNEY TRANSPLANTATION (KT) WITH IMPROVED 1-YEAR GRAFT SURVIVAL TO >90%, KT ATTRITION IS UNCHANGED DUE TO PERSISTENT ANTIBODY MEDIATED REJECTION (ABMR). GIVEN LIMITED ABMR TREATMENT OPTIONS, THE OUTCOME IS PERSISTENT KT INFLAMMATION AND ACCELERATED KT LOSS. AS SUBTYPES OF REJECTION ARE DIVERSE IN THEIR PATHOGENESIS AND TREATMENT RESPONSE, THE NEED FOR PRECISE TREATMENTS BASED ON MOLECULAR BASIS OF REJECTION IS WELL-FOUNDED. WE PROPOSE TO DEVELOP AND APPLY A DRUG REPURPOSING PIPELINE TO ABMR EXPRESSION PROFILES TO QUERY PUBLICLY AVAILABLE DRUG-GENE EXPRESSION DATABASES, TO IDENTIFY SINGLE AND COMBINATION DRUG REPURPOSING CANDIDATES FOR ABMR (AIM 1). OUR PRELIMINARY, PUBLISHED STUDIES SUPPORT THE SUCCESSFUL ANALYSES FOR ABMR WITH IDENTIFICATION OF PUBLICALLY AVAILABLE HISTOLOGICAL AND MOLECULAR STABLE (CONTROL) AND ABMR RENAL ALLOGRAFT DATASETS, TO BE INTEGRATED WITH SINGLE-CELL RNASEQ ANALYSIS EXPERIMENTS THAT WILL BE CONDUCTED ON CURATED ABMR RENAL ALLOGRAFT BIOPSIES. WE WILL USE TRANSCRIPTOMIC-BASED COMPUTATIONAL DRUG-REPURPOSING TO IDENTIFY POTENTIAL NEW SINGLE AGENT AND COMBINATION THERAPEUTICS FOR THE TREATMENT OF ABMR, BASED ON EXPRESSION REVERSAL, LEVERAGING PUBLIC AND NEWLY GENERATED SINGLE CELL DATA. WE WILL FURTHER DETERMINE THE KINETICS AND THE MECHANISM OF ACTION OF PROMISING DRUGS OR DRUG COMBINATIONS IN HUMAN CELLS AND ABMR TISSUE, EX VIVO (AIM 2). PROMISING SINGLE AGENT AND COMBINATION AGENTS WILL BE FURTHER VALIDATED FOR EFFICACY FOR TREATMENT OR PREVENTION OF ABMR IN VIVO, IN A PRE-CLINICAL, ESTABLISHED, RODENT RENAL ALLOGRAFT MODEL OF ABMR (AIM 3). OUR APPROACH IS HIGHLY SIGNIFICANT BECAUSE WE WILL INVESTIGATE UNIQUE AND NOVEL CELL-SPECIFIC TRANSCRIPTOMIC PROFILES, UNDERLYING BIOLOGICAL PROCESSES AND SIGNALING PATHWAYS IN ABMR AND THESE DATA WILL BE ANALYZED WITH A DRUG REPURPOSING PIPELINE TO DISCOVER NOVEL SINGLE AGENTS AND COMBINATION THERAPIES THAT CAN BE USED AS A PERSONALIZED APPROACH TO MANAGEMENT OF ABMR. THE IN VIVO EXPERIMENTS WILL TAKE THESE STUDIES TO VALIDATION OF COMPOUND OR COMBINATION OF COMPOUND EFFICACY FOR REVERSING OR PREVENTING ABMR. THE SUCCESSFUL COMPLETION OF THESE STUDIES CAN PROPOSE NEW, FDA APPROVED DRUGS, THAT COULD BE REPURPOSED FOR IMPROVING LONG TERM OUTCOMES IN KIDNEY TRANSPLANT RECIPIENTS, BY REDUCING ABMR INJURY, EXTEND GRAFT AND PATIENT SURVIVAL. $814.3k 4/14/25 Not listed COMPUTATIONAL DRUG REPOSITIONING FOR ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION - ABSTRACT DESPITE ADVANCES IN KIDNEY TRANSPLANTATION (KT) WITH IMPROVED 1-YEAR GRAFT SURVIVAL TO >90%, KT ATTRITION IS UNCHANGED DUE TO PERSISTENT ANTIBODY MEDIATED REJECTION (ABMR). GIVEN LIMITED ABMR TREATMENT OPTIONS, THE OUTCOME IS PERSISTENT KT INFLAMMATION AND ACCELERATED KT LOSS. AS SUBTYPES OF REJECTION ARE DIVERSE IN THEIR PATHOGENESIS AND TREATMENT RESPONSE, THE NEED FOR PRECISE TREATMENTS BASED ON MOLECULAR BASIS OF REJECTION IS WELL-FOUNDED. WE PROPOSE TO DEVELOP AND APPLY A DRUG REPURPOSING PIPELINE TO ABMR EXPRESSION PROFILES TO QUERY PUBLICLY AVAILABLE DRUG-GENE EXPRESSION DATABASES, TO IDENTIFY SINGLE AND COMBINATION DRUG REPURPOSING CANDIDATES FOR ABMR (AIM 1). OUR PRELIMINARY, PUBLISHED STUDIES SUPPORT THE SUCCESSFUL ANALYSES FOR ABMR WITH IDENTIFICATION OF PUBLICALLY AVAILABLE HISTOLOGICAL AND MOLECULAR STABLE (CONTROL) AND ABMR RENAL ALLOGRAFT DATASETS, TO BE INTEGRATED WITH SINGLE-CELL RNASEQ ANALYSIS EXPERIMENTS THAT WILL BE CONDUCTED ON CURATED ABMR RENAL ALLOGRAFT BIOPSIES. WE WILL USE TRANSCRIPTOMIC-BASED COMPUTATIONAL DRUG-REPURPOSING TO IDENTIFY POTENTIAL NEW SINGLE AGENT AND COMBINATION THERAPEUTICS FOR THE TREATMENT OF ABMR, BASED ON EXPRESSION REVERSAL, LEVERAGING PUBLIC AND NEWLY GENERATED SINGLE CELL DATA. WE WILL FURTHER DETERMINE THE KINETICS AND THE MECHANISM OF ACTION OF PROMISING DRUGS OR DRUG COMBINATIONS IN HUMAN CELLS AND ABMR TISSUE, EX VIVO (AIM 2). PROMISING SINGLE AGENT AND COMBINATION AGENTS WILL BE FURTHER VALIDATED FOR EFFICACY FOR TREATMENT OR PREVENTION OF ABMR IN VIVO, IN A PRE-CLINICAL, ESTABLISHED, RODENT RENAL ALLOGRAFT MODEL OF ABMR (AIM 3). OUR APPROACH IS HIGHLY SIGNIFICANT BECAUSE WE WILL INVESTIGATE UNIQUE AND NOVEL CELL-SPECIFIC TRANSCRIPTOMIC PROFILES, UNDERLYING BIOLOGICAL PROCESSES AND SIGNALING PATHWAYS IN ABMR AND THESE DATA WILL BE ANALYZED WITH A DRUG REPURPOSING PIPELINE TO DISCOVER NOVEL SINGLE AGENTS AND COMBINATION THERAPIES THAT CAN BE USED AS A PERSONALIZED APPROACH TO MANAGEMENT OF ABMR. THE IN VIVO EXPERIMENTS WILL TAKE THESE STUDIES TO VALIDATION OF COMPOUND OR COMBINATION OF COMPOUND EFFICACY FOR REVERSING OR PREVENTING ABMR. THE SUCCESSFUL COMPLETION OF THESE STUDIES CAN PROPOSE NEW, FDA APPROVED DRUGS, THAT COULD BE REPURPOSED FOR IMPROVING LONG TERM OUTCOMES IN KIDNEY TRANSPLANT RECIPIENTS, BY REDUCING ABMR INJURY, EXTEND GRAFT AND PATIENT SURVIVAL. $78.5k 9/5/24 Not listed COMPUTATIONAL DRUG REPOSITIONING FOR ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION - ABSTRACT DESPITE ADVANCES IN KIDNEY TRANSPLANTATION (KT) WITH IMPROVED 1-YEAR GRAFT SURVIVAL TO >90%, KT ATTRITION IS UNCHANGED DUE TO PERSISTENT ANTIBODY MEDIATED REJECTION (ABMR). GIVEN LIMITED ABMR TREATMENT OPTIONS, THE OUTCOME IS PERSISTENT KT INFLAMMATION AND ACCELERATED KT LOSS. AS SUBTYPES OF REJECTION ARE DIVERSE IN THEIR PATHOGENESIS AND TREATMENT RESPONSE, THE NEED FOR PRECISE TREATMENTS BASED ON MOLECULAR BASIS OF REJECTION IS WELL-FOUNDED. WE PROPOSE TO DEVELOP AND APPLY A DRUG REPURPOSING PIPELINE TO ABMR EXPRESSION PROFILES TO QUERY PUBLICLY AVAILABLE DRUG-GENE EXPRESSION DATABASES, TO IDENTIFY SINGLE AND COMBINATION DRUG REPURPOSING CANDIDATES FOR ABMR (AIM 1). OUR PRELIMINARY, PUBLISHED STUDIES SUPPORT THE SUCCESSFUL ANALYSES FOR ABMR WITH IDENTIFICATION OF PUBLICALLY AVAILABLE HISTOLOGICAL AND MOLECULAR STABLE (CONTROL) AND ABMR RENAL ALLOGRAFT DATASETS, TO BE INTEGRATED WITH SINGLE-CELL RNASEQ ANALYSIS EXPERIMENTS THAT WILL BE CONDUCTED ON CURATED ABMR RENAL ALLOGRAFT BIOPSIES. WE WILL USE TRANSCRIPTOMIC-BASED COMPUTATIONAL DRUG-REPURPOSING TO IDENTIFY POTENTIAL NEW SINGLE AGENT AND COMBINATION THERAPEUTICS FOR THE TREATMENT OF ABMR, BASED ON EXPRESSION REVERSAL, LEVERAGING PUBLIC AND NEWLY GENERATED SINGLE CELL DATA. WE WILL FURTHER DETERMINE THE KINETICS AND THE MECHANISM OF ACTION OF PROMISING DRUGS OR DRUG COMBINATIONS IN HUMAN CELLS AND ABMR TISSUE, EX VIVO (AIM 2). PROMISING SINGLE AGENT AND COMBINATION AGENTS WILL BE FURTHER VALIDATED FOR EFFICACY FOR TREATMENT OR PREVENTION OF ABMR IN VIVO, IN A PRE-CLINICAL, ESTABLISHED, RODENT RENAL ALLOGRAFT MODEL OF ABMR (AIM 3). OUR APPROACH IS HIGHLY SIGNIFICANT BECAUSE WE WILL INVESTIGATE UNIQUE AND NOVEL CELL-SPECIFIC TRANSCRIPTOMIC PROFILES, UNDERLYING BIOLOGICAL PROCESSES AND SIGNALING PATHWAYS IN ABMR AND THESE DATA WILL BE ANALYZED WITH A DRUG REPURPOSING PIPELINE TO DISCOVER NOVEL SINGLE AGENTS AND COMBINATION THERAPIES THAT CAN BE USED AS A PERSONALIZED APPROACH TO MANAGEMENT OF ABMR. THE IN VIVO EXPERIMENTS WILL TAKE THESE STUDIES TO VALIDATION OF COMPOUND OR COMBINATION OF COMPOUND EFFICACY FOR REVERSING OR PREVENTING ABMR. THE SUCCESSFUL COMPLETION OF THESE STUDIES CAN PROPOSE NEW, FDA APPROVED DRUGS, THAT COULD BE REPURPOSED FOR IMPROVING LONG TERM OUTCOMES IN KIDNEY TRANSPLANT RECIPIENTS, BY REDUCING ABMR INJURY, EXTEND GRAFT AND PATIENT SURVIVAL. $78.5k 9/5/24 Not listed COMPUTATIONAL DRUG REPOSITIONING FOR ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION - ABSTRACT DESPITE ADVANCES IN KIDNEY TRANSPLANTATION (KT) WITH IMPROVED 1-YEAR GRAFT SURVIVAL TO >90%, KT ATTRITION IS UNCHANGED DUE TO PERSISTENT ANTIBODY MEDIATED REJECTION (ABMR). GIVEN LIMITED ABMR TREATMENT OPTIONS, THE OUTCOME IS PERSISTENT KT INFLAMMATION AND ACCELERATED KT LOSS. AS SUBTYPES OF REJECTION ARE DIVERSE IN THEIR PATHOGENESIS AND TREATMENT RESPONSE, THE NEED FOR PRECISE TREATMENTS BASED ON MOLECULAR BASIS OF REJECTION IS WELL-FOUNDED. WE PROPOSE TO DEVELOP AND APPLY A DRUG REPURPOSING PIPELINE TO ABMR EXPRESSION PROFILES TO QUERY PUBLICLY AVAILABLE DRUG-GENE EXPRESSION DATABASES, TO IDENTIFY SINGLE AND COMBINATION DRUG REPURPOSING CANDIDATES FOR ABMR (AIM 1). OUR PRELIMINARY, PUBLISHED STUDIES SUPPORT THE SUCCESSFUL ANALYSES FOR ABMR WITH IDENTIFICATION OF PUBLICALLY AVAILABLE HISTOLOGICAL AND MOLECULAR STABLE (CONTROL) AND ABMR RENAL ALLOGRAFT DATASETS, TO BE INTEGRATED WITH SINGLE-CELL RNASEQ ANALYSIS EXPERIMENTS THAT WILL BE CONDUCTED ON CURATED ABMR RENAL ALLOGRAFT BIOPSIES. WE WILL USE TRANSCRIPTOMIC-BASED COMPUTATIONAL DRUG-REPURPOSING TO IDENTIFY POTENTIAL NEW SINGLE AGENT AND COMBINATION THERAPEUTICS FOR THE TREATMENT OF ABMR, BASED ON EXPRESSION REVERSAL, LEVERAGING PUBLIC AND NEWLY GENERATED SINGLE CELL DATA. WE WILL FURTHER DETERMINE THE KINETICS AND THE MECHANISM OF ACTION OF PROMISING DRUGS OR DRUG COMBINATIONS IN HUMAN CELLS AND ABMR TISSUE, EX VIVO (AIM 2). PROMISING SINGLE AGENT AND COMBINATION AGENTS WILL BE FURTHER VALIDATED FOR EFFICACY FOR TREATMENT OR PREVENTION OF ABMR IN VIVO, IN A PRE-CLINICAL, ESTABLISHED, RODENT RENAL ALLOGRAFT MODEL OF ABMR (AIM 3). OUR APPROACH IS HIGHLY SIGNIFICANT BECAUSE WE WILL INVESTIGATE UNIQUE AND NOVEL CELL-SPECIFIC TRANSCRIPTOMIC PROFILES, UNDERLYING BIOLOGICAL PROCESSES AND SIGNALING PATHWAYS IN ABMR AND THESE DATA WILL BE ANALYZED WITH A DRUG REPURPOSING PIPELINE TO DISCOVER NOVEL SINGLE AGENTS AND COMBINATION THERAPIES THAT CAN BE USED AS A PERSONALIZED APPROACH TO MANAGEMENT OF ABMR. THE IN VIVO EXPERIMENTS WILL TAKE THESE STUDIES TO VALIDATION OF COMPOUND OR COMBINATION OF COMPOUND EFFICACY FOR REVERSING OR PREVENTING ABMR. THE SUCCESSFUL COMPLETION OF THESE STUDIES CAN PROPOSE NEW, FDA APPROVED DRUGS, THAT COULD BE REPURPOSED FOR IMPROVING LONG TERM OUTCOMES IN KIDNEY TRANSPLANT RECIPIENTS, BY REDUCING ABMR INJURY, EXTEND GRAFT AND PATIENT SURVIVAL. $722.0k 6/27/24