R01AI169648

Functional Investigation of a Novel and Essential Subcellular Compartment in Plasmodium falciparum Transmission Stage Parasites - Project Summary

Malaria is an important cause of illness and death worldwide, with most of these deaths resulting from Plasmodium falciparum infection. Successful completion of the P. falciparum life cycle and infection of a new human host requires transmission. During the asexual blood stage in human red blood cells, a small population of parasites differentiates into transmission forms known as gametocytes. These gametocytes can complete the sexual stage of the parasite life cycle following ingestion by a mosquito.

Gametocyte maturation in human red blood cells occurs over 10-12 days and is associated with major changes in cellular morphology and rigidity. A newly discovered protein, PFBLEB (for Baso-lateral Expansion Boundary), is essential for mature gametocyte formation. In asexual parasites, PFBLEB is part of the basal complex, a ring-like multi-protein complex at the leading edge of the inner membrane complex. While PFBLEB is dispensable for both asexual replication and gametocyte commitment, it is essential for gametocyte development. PFBLEB-knockdown or knockout gametocytes arrest during maturation and are non-transmissible. Furthermore, the PFBLEB-deficient gametocytes have gross morphologic changes with defects in major cytoskeletal features of the maturing transmission-stage parasite, including the inner membrane complex and subpellicular microtubules.

In gametocytes with normal PFBLEB expression, PFBLEB defines a new subcellular compartment within the parasite, demarcating the regions of the parasite plasma membrane that are devoid of the underlying inner membrane complex. The PFBLEB-compartment is essential for gametocyte development, but the function and protein constituents of this newly discovered subcellular compartment remain unknown.

The goal of the current application is to define and genetically evaluate the protein components of the PFBLEB compartment and to understand the functional defects in PFBLEB-deficient gametocytes. The first aim will utilize proximity labeling and reverse genetics to explore the PFBLEB-containing compartment. The second aim will utilize multiple imaging and microfabrication techniques to gain a functional understanding of what processes are abnormal in PFBLEB-deficient gametocytes.

Together, the proposed studies will add a new layer to our molecular understanding of gametocyte development in P. falciparum.

Children's Hospital Corporation

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]

Boston, Massachusetts 021155724 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 373% from $775,289 to $3,663,262.