R01NS123456

Region-Specific Vulnerability of the Lewy Body Dementia's Brain - Region-Specific Vulnerability of the Lewy Body Dementia’s Brain Project Summary.

Lewy Body Dementia (LBD) is a progressive neurodegenerative disorder characterized by aggregation of the α-synuclein (A-Syn) into intracellular inclusions called Lewy bodies (LB) and Lewy neurites (LN). This form of dementia belongs to a class of neurodegenerative diseases termed “synucleinopathies.” LBD is the most common neurodegenerative dementia after Alzheimer’s disease.

In LBD, dementia usually proceeds to the onset of Parkinsonian motor symptoms with neurobehavioral symptoms that may be accompanied by both cognitive and motoric dysfunction. While various misfolded oligomers, primarily constituted of A-Syn, are associated with the development of dementia along with neuronal loss, there is still insufficient understanding of the pathogenesis process.

Especially, particular brain areas such as the limbic system and neocortex are more vulnerable than other regions. Researchers have considered that the answer to this question will provide a key clue to understanding the pathogenesis mechanism.

Inter-cellular crosstalk of neurons, microglia, and astrocytes results in complex physiologies and cellular behaviors, potentially leading to neuronal loss. Moreover, there is brain region-specific heterogeneity in cellular populations of neurons, microglia, and astrocytes that can contribute to the region-specific vulnerability of the LBD brain. Therefore, information on cell-type-specific and single-cell-specific proteome and transcriptome over multiple brain regions is indispensable for understanding this complex mechanism.

To study this complex mechanism, the selection of the right animal model that best recapitulates the human LBD pathogenesis process is crucial. The mouse model that recapitulates the Braak hypothesis would serve as the best animal model, and we recently have generated this mouse model (Gut-Brain A-Syn model) successfully by injecting A-Syn to the gut.

To study the regional vulnerability of LBD using the mouse model, we propose:

1) To study region- and cell-type-specific proteome of the brain of the Gut-Brain A-Syn model using BONCAT and XMD,

2) To study region- and single-cell-specific transcriptome of the brain of the Gut-Brain A-Syn model using HIF-SNRNASEQ,

3) To perform integrative bioinformatic analysis and validate the affected pathways found in the mouse models using the human brain.

Cell-type-specific proteome analysis and single-cell transcriptome analyses over multiple brain regions of the Gut-Brain A-Syn model proposed in this application will enable us to identify region- and cell-type-specific signaling pathways that are involved in region-specific vulnerabilities to pathological A-Syn. This novel information will contribute to a better understanding of LBD pathogenesis. Furthermore, these approaches can be expanded to studying pathogenesis mechanisms of other neurodegenerative diseases.

The Johns Hopkins University

(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.

93.866 - Aging Research

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

National Institute on Aging (NIA) [HHS - NIH]

Baltimore, Maryland 212051832 United States

Single Zip Code

Mechanisms of Selective Vulnerability in LBD and FTD (R01 Clinical Trial Not Allowed) (RFA-NS-21-007)

Amendment Since initial award the total obligations have increased 436% from $664,314 to $3,557,900.