R01NS133998

Using single cell biological approaches to understand CNS TB - project summary

Tuberculosis is a global disease affecting millions of people in primarily developing regions of the world. Central nervous system tuberculosis (CNS-TB) is the most severe extra pulmonary form of the disease, which, despite aggressive therapeutic intervention, can have a fatality rate of up to 80%.

Significant barriers to understanding disease pathogenesis exist, which translates to poor diagnosis and treatment outcomes. Thus, improved insight into neuro-glial-immune cell interactions in CNS TB, and the factors that regulate brain pathology require a global molecular and cellular perspective.

Our long-term goal is to understand the mechanisms associated with the development of CNS-TB, and different CNS-TB outcomes, in order to develop novel, effective, and broadly accessible therapeutics.

Single cell/nucleus RNA sequencing (sc/snRNA-seq) gene expression analysis allows for a large-scale view of the cells and molecular pathways involved in neuropathogenesis, with the potential to identify novel differences between TB diseased states.

In this study, we will investigate transcriptional changes induced by M. tuberculosis infection of the brain under clinical and experimental conditions to determine how CNS-TB starts and progresses to different outcomes. This is made possible by preliminary snRNA-seq data generated during our global brain R21 that we recently completed.

We hypothesize that M. tuberculosis invades the CNS due to the failed generation of an appropriate neuroimmune response in CNS resident and peripherally recruited immune cells. This is strongly supported by our preliminary data from human and rodent snRNA-seq studies.

By exploring the transcriptional differences in cells from normal and diseased states we will be able to identify the cell type-specific molecular and cellular processes that underpin the pathogenesis of CNS-TB, including neuroinflammation and immune system engagement.

Understanding cell type-specific CNS and immune signaling in CNS-TB will enable us to develop novel therapies and improve clinical outcomes.

To test our central hypothesis, we will determine the molecular pathways across CNS and immune cells that define clinical phenotypes in patients with CNS-TB and create a full disease spectrum signaling framework of CNS-TB using multiple mouse models.

In addition to our scientific aims, we will expand the single cell gene expression analysis platform, established at the University of Cape Town (UCT) during our global brain R21 support, to the broader African scientific community. We aim to provide training in project planning, library preparation, and data analysis.

When complete, we will have a novel understanding of the cell type-specific inflammatory signaling events that drive CNS-TB and will be poised to engage novel molecular targets to improve CNS-TB outcomes. Furthermore, UCT will be established as a hub of single cell biology, to launch scientific careers of the next generation of African scientists, and to improve health care across Africa.

Trustees Of Tufts College

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE 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. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER 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.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Boston, Massachusetts 021111817 United States

Single Zip Code

Global Brain and Nervous System Disorders Research Across the Lifespan (R01 Clinical Trials Optional) (PAR-21-311)

Amendment Since initial award the total obligations have increased 193% from $484,125 to $1,419,875.