overview
Projects
CLEAR-TB Projects 1-4 are assisted by three Core teams. Core impact and interactions are outlines below.
Connect
Impact & Interactions
Administrative Core
Systems Biology Core
Clinical Core
A
TBRU Administrative Core
TBRU is supported by an Administrative Core which coordinates and maintains the unit’s research and development progress, communications, and interactions with internal and external partners and provides problem resolution. The Admin Core is directed by Dr. Jerrold Ellner, Dr. David Alland, and David Hom. It aims to:
Develop and operate an administrative (fiscal, regulatory), operational (scientific, logistics) infrastructure and data management center capable of supporting proposed clinical, animal & translational protocols
Maintain fiscal compliance and site reimbursement procedures per NIH policy
Communicate and work with NIH program staff to monitor study progress and achieve milestones
Coordinate and collaborate with other TBRU programs to leverage expertise
An existing Data Center – Data and Operations Management Center (DOMC) in the Center for Emerging Pathogens (directed by Dr. David Alland) provides a comprehensive Data Management Plan with appropriate systems to organize, coordinate, and validate the collection of clinical data and specimens (MTB strains and blood samples) from the proposed clinical protocols. The DOMC houses experienced staff who have worked alongside the Ugandan and Brazilian teams to implement and manage clinical studies.
B
Systems Biology Core
This overall TBRU Program seeks to understand how both host and bacterial heterogeneity act together to promote TB clinical phenotypes such as transmission, disease progression, and drug tolerance. These two subjects (biological heterogeneity and clinical phenotypes) are emergent properties of intracellular networks and of multicellular interactions, respectively, rendering this overall topic challenging to study by conventional hypothesis-driven research approaches. Systems-level analyses are required to account for the biological complexity imposed by cellular network and multicellular interactions and advanced computational techniques are required to elucidate biological understanding from the increasingly large quantitative datasets generated by modern advanced experimental platforms. The Systems Biology Core is designed to meet both needs, providing advanced bioinformatics, biomedical data science, and network modeling analysis services to support each Project in this Proposal. This Core is led by Drs. William Evan Johnson, Shuyi Ma, and Jason Yang, each with extensive subject-matter expertise in diverse computational and systems biology analytical approaches, and each of whom actively collaborates with other investigators from this TBRU on diverse tuberculosis research projects. The Systems Biology Core aids in the standardized processing and analysis of data from each Project, generation of experimentally testable hypotheses for each Project, and integrative analyses of mechanisms connecting clinical phenotypes across Projects.
Two key strengths of this Core that differentiate it from other computational cores and that enable this TBRU to uniquely study clinical biospecimens are:
The extensive expertise in using biomarker signatures such as PREDICT29 to detect incipient and subclinical TB disease, expanding the range of clinical Mtb strains and host cells that can be studied
The extensive expertise in multiscale cellular network modeling and interpretable machine learning, expanding the breadth and precision of biological hypotheses that can be generated from each set of experimental data
Investigators in this TBRU have uniquely developed Mtb gene regulatory and metabolic network models, which will be used by this Systems Biology Core to form condition-specific models of host and Mtb cell physiology corresponding to experimental samples for each Project. These models will not only enable the Core to deconvolve the large experimental datasets generated in this Program but will also enable the Core to directly predict causal gene regulatory and metabolic gene and pathway mechanisms that underlie each of the key clinical phenotypes studied from these clinical samples: TB transmission, disease progression and drug tolerance. These models and analyses will enable direct integration between Projects, allowing this TBRU to determine how these clinical phenotypes may be mechanistically linked. The Systems Biology Core will synergize with each Project to mechanistically bridge host and pathogen heterogeneity with clinical outcomes.
C
TBRU Clinical Core
The Clinical Core holds responsibility for all human subjects’ studies in the TBRU protocols and works closely with the Administrative Core to coordinate approved protocols and unit-wide scientific activities in concert with the scientific decisions of the TBRU. It is co-led by Dr. Christopher Whalen and Emily Douglass. The primary objective of the Clinical Core is to ensure the implementation and conduct of the clinical research studies align with the scientific and translational aims of the TBRU projects and scientific cores by providing support for:
Protocol Development
Implementation and Operations
Quality Assurance and Control
Sample Banking and Inventory
Data Collection
Epidemiological and Statistical Analysis
The Clinical Core monitors the clinical operations, sample collection, processing, and data collection from study initiation through close-out. The Clinical Core ensures that all activities are conducted in compliance with local and international regulations and ethical standards. Under the direction of the Principal Investigators, the Clinical Core coordinates efforts with the Administrative Core and the Systems Biology Core. Their objective is to implement clinical protocols for projects 1 and 2 at the collaborating sites in Brazil and Uganda; and to establish an inventory of human clinical specimens, isolates of Mtb and clinical epidemiological data to be utilized across projects 1, 2, 3 and 4.