P01AI150585

Molecular Mechanisms of the Dysregulated Immune Response to Ebola Virus - Overall: Project Summary/Abstract

The central hypothesis of the proposed P01 program is that Ebola virus infection leads to cell-type specific transcriptional, posttranscriptional, and posttranslational alterations that create aberrant counterproductive responses of immune cells, leading to a dysregulated immune response, which paradoxically produces "immune paralysis" and hyperinflammation.

To address the hypothesis, three research projects are proposed. Research Project 1 focuses on pathogenic mechanisms at the transcriptional level, while Research Project 2 focuses on posttranscriptional events, and Research Project 3 focuses on posttranslational modifications, each contributing to the dysregulated immune response to Ebola virus. The dysregulated immune response is responsible for most of the pathogenesis observed in Ebola virus disease.

All projects require the BSL-4 Core (Core B), which will be responsible for performing infections of human immune and nonimmune cells, nonhuman primates, and the initial steps of experiments that involve infectious virus. Importantly, Core B will provide each of the research projects samples from the same experimental samples, ensuring that data from each project can be compared directly. This is a unique feature of this P01 program.

The Proteogenomics Core (Core C) will be responsible for massive parallel sequencing and mass spectrometry-based studies. The Bioinformatics and Modeling Core (Core D) is critical for generating tools employed in the experimental designs, including statistical help for omics experiments, analyzing omics data, and integrating omics data into networks that model the behavior of various cell populations infected with EBOV. The work done in Core D will synthesize a model to explain how transcriptional, posttranscriptional, and posttranslational responses of individual cell populations lead to immune dysregulation.

The comprehensive picture painted by this collaborative effort will revolutionize our understanding of the immunopathogenesis of severe acute viral infections (e.g., immune imbalance seen in COVID-19). The Administrative Core (Core A) will be responsible for strategic planning, continual evaluation, and communication and coordination of activities among the various components of the project according to a detailed management plan.

The expected outcomes will contribute substantially to our knowledge of the fundamental mechanisms of the immunopathogenesis of EBOV infections toward the development of effective countermeasures. The expected outcomes will include (1) detailed knowledge of transcriptional mechanisms leading to the dysregulated immune response to EBOV, (2) elucidation of the role of posttranscriptional mechanisms in the dysregulated immune response to EBOV, (3) elucidation of the role of posttranslational mechanisms in the dysregulated immune response to EBOV, and (4) experimental validation of the identified pathogenic mechanisms and their targeting.

The proposed tightly coordinated and comprehensive analysis has not been done before for any virus.

University Of Texas Medical Branch At Galveston

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Galveston, Texas 775555302 United States

Single Zip Code

NIAID Investigator Initiated Program Project Applications (P01 Clinical Trial Not Allowed) (PAR-20-072)

Amendment Since initial award the total obligations have increased 402% from $2,258,675 to $11,342,672.