R01AI167570

Comparative Systems Biology of Apicomplexan Cell Division - Summary

Apicomplexan parasites have major impacts on human health, e.g. Plasmodium falciparum causes malaria, whereas Toxoplasma gondii and Babesia spp. cause opportunistic infections. Although this close-knit group shares their obligate intracellular lifestyles, they display a wide variety of asexual cell division modes. These differ between parasites as well as between different life stages within a single parasite species, but the start- and end-point is always a host cell invasion competent 'zoite'.

The number of zoites made per division round varies dramatically (from 2-90,000) and can unfold in several different ways by reshuffling the functional modules of 1) mother cytoskeleton disassembly, 2) DNA synthesis and chromosome segregation (D&S), 3) karyokinesis, and 4) zoite assembly (budding).

Distinct cell division modes across Apicomplexa arise from variations in the order and sequence of the modules as well as the number of module repetitions. In the current model, cell division progresses in transcriptional waves mediated transcription factors that act on target genes that in turn bundle into the functional modules. However, little is known of the composition, regulators, and wiring of the different modules, and how this leads to the diversity of cell division modes in Apicomplexa.

The research team hypothesizes that these questions can be answered by a comparative systems biology approach, starting with parasites representing different diverse and 'exotic' division cell division modes wherein particular modules are amplified, or combined differently: Babesia divergens binary fission, P. falciparum schizogony, Sarcocystis neurona endopolygeny without karyokinesis, T. gondii asexual endodyogeny, and T. gondii pre-sexual endopolygeny with karyokinesis in the definitive host.

This approach takes advantage of the single-cell sequencing revolution combined with computational network analysis approaches. Firstly, single-cell transcriptomic and epigenomic maps of the five cell division modes will be generated and analyzed to define the effectors contained in each specific module. A subset of uncharacterized effectors in the poorly characterized karyokinesis and cytoskeleton disassembly modules will be experimentally validated by gene knock-downs.

Secondly, chemical and genetic perturbations combined with single-cell sequencing will enable the assembly of causal gene regulatory networks (GRNs) across all division modes. Candidate module controllers in these GRNs will be validated by reprogramming and/or genetic perturbation experiments: changing (parts of) the division mode in specific parasites. This work will answer elusive questions regarding apicomplexan-specific biology within barely studied functional modules, as well as how apicomplexan cell division flexibility is wired.

Thirdly, the proposed work will produce extensive community resources comprising single expression and chromatin accessibility atlases across five different cell division modes and parasite species. Moreover, datasets will be searchable across systems in real-time for any biological feature of interest by web-based apps that will be incorporated in VeupathDB and enable querying the data for biological questions beyond cell division.

Trustees Of Boston College

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]

Chestnut Hill, Massachusetts 024673800 United States

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

Amendment Since initial award the total obligations have increased 285% from $1,413,826 to $5,447,470.