R01AI170840

mRNA Alternative Polyadenylation in B Cell Development - Project Summary:

The vast majority of mammalian genes produce alternatively processed mRNAs through alternative splicing and alternative polyadenylation (APA). Different mRNA isoforms produced from the same gene can encode distinct proteins and/or they may be differentially regulated. Recent studies have revealed essential roles of mRNA alternative processing in many biological processes, and mis-regulation of alternative splicing and APA has been causally linked to a wide range of diseases, including cancer and neurodegenerative diseases. However, the mechanism and functions of alternative mRNA processing remain poorly understood.

Antibody secretion by B cells is a major component of our immune response, and mis-regulated antibody response underlies many autoimmune diseases. B cell activation and differentiation require a sophisticated gene regulation cascade. Previous works, including ours, have provided insights into the transcriptional regulation mechanisms governing this process. However, it is clear that post-transcriptional gene regulation, such as alternative splicing and APA, also play an important role.

In 1980, several landmark studies reported the first example of alternative RNA processing: the immunoglobulin M (IgM) heavy chain gene (IGHM) produces two APA isoforms, which encode a membrane-bound and a secreted IgM respectively. Additionally, the IGHM APA is developmentally regulated. Subsequent studies, however, have failed to provide a consistent mechanistic model for this APA switch. Furthermore, it remains unknown how widespread the APA regulation network is and what the functional impact of APA regulation is during B cell activation and differentiation.

In our preliminary studies, we provided evidence that transcription factors, core mRNA 3' processing factors, and RNA-binding proteins regulate IGHM APA. In addition, we discovered that B cell activation leads to a significant change in the APA patterns of approximately 900 genes, including those encoding key cell fate regulators and signaling proteins. Based on these preliminary results, we hypothesize that the APA of IGHM and a large gene network are regulated at multiple levels and that APA regulation plays an important role in B cell functions.

To test these hypotheses, we have designed the following specific aims:

1) Identify regulators of B cell activation-induced IGHM APA switch using a biochemical and genetic approach.
2) Systematically characterize the mechanisms of B cell activation-induced IGHM APA switch.
3) Determine the role of APA regulation in B cell activation and differentiation.

Successful completion of the proposed studies will provide fundamental insights into APA regulation and function. More importantly, our results will reveal the role of post-transcriptional gene regulation in B cell development and B cell-mediated immune response, which will pave the way for better strategies for developing vaccines and treatment for autoimmune diseases.

Irvine University Of California

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]

Irvine, California 926970001 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 314% from $793,986 to $3,286,818.