RF1NS144499

HIPPOCAMPAL IPSC-DERIVED ASSEMBLOIDS TO MODEL INTERNEURON AND CIRCUIT VULNERABILITY IN GENETICALLY-ENCODED AMNESTIC AND BEHAVIORAL DEMENTIA - FROM HUMAN DEMENTIA BRAINS THAT SUPPORT AN INTERACTION BETWEEN INTERNEURONS, TAU TOXICITY, AND COGNITIVE DECLINE. WE RECENTLY GENERATED HIPPOCAMPAL ASSEMBLOIDS IN WHICH PHYSIOLOGICAL PROPORTIONS OF INTERNEURONS AND EXCITATORY NEURONS — ACHIEVED THROUGH INTERNEURON MIGRATION FROM THE GANGLIONIC EMINENCE — EXHIBIT ELECTROPHYSIOLOGICAL OSCILLATORY AND CONNECTIVITY PROPERTIES THAT MIRROR THOSE OBSERVED IN HUMAN BRAIN RECORDINGS. MUTATIONS IN THE MICROTUBULE-ASSOCIATED PROTEIN TAU (MAPT), SUCH AS R406W AND IVS10+16 C>T, CAUSE FRONTOTEMPORAL DEMENTIA AND RESULT IN A SPECTRUM OF CLINICAL PHENOTYPES, WITH A PREDILECTION FOR TEMPORAL LOBE- DOMINANT SYNDROMES AFFECTING THE HIPPOCAMPUS. HUMAN INDUCED PLURIPOTENT STEM CELLS (IPSCS) EXPRESSING DIFFERENT MAPT MUTATIONS EXHIBIT VARIOUS PHENOTYPES BUT CONVERGE ON ALTERATIONS IN GENES INVOLVED IN TRANSSYNAPTIC SIGNALING, INCLUDING A GROUP OF 11 GENES ENRICHED IN INTERNEURONS. DESPITE THESE OBSERVATIONS, THE INTERACTION BETWEEN MAPT MUTATIONS AND INTERNEURON SUBTYPES REMAINS POORLY UNDERSTOOD, DUE IN PART TO IPSC MODEL SYSTEMS THAT LACK SUFFICIENT NUMBERS OF INTERNEURONS. BY GENERATING HUMAN IPSC-DERIVED HIPPOCAMPAL ASSEMBLOIDS EXPRESSING MAPT MUTATIONS, WE HAVE DEVELOPED A UNIQUE MODEL OF TAU MUTATION-ASSOCIATED TOXIC PHENOTYPES IN A SYSTEM CONTAINING INTERNEURONS, EXCITATORY NEURONS, ASTROCYTES, AND SIMPLE CIRCUITS. THIS MODEL, ONCE VALIDATED, WILL OPEN OPPORTUNITIES TO CONSIDER INTERACTIONS BETWEEN INTERNEURONS, TAU TOXICITY, AND CIRCUIT-RELATED NEURONAL DYSFUNCTION IN MECHANISTIC OR DRUG DEVELOPMENT APPLICATIONS. WE PROPOSE TO VALIDATE THIS SYSTEM AS A MODEL FOR STUDYING THE INTERACTION OF INTERNEURONS WITH MAPT MUTATION - ASSOCIATED TAU TOXICITY AND CIRCUIT-RELATED NEURONAL DYSFUNCTION. WE WILL ACHIEVE THIS THROUGH REPRODUCIBILITY STUDIES, DEEPER MOLECULAR PHENOTYPING, PERTURBATIONS OF TAU MUTANT EXPRESSION, AND BY MAPPING NEW PHENOTYPIC ENDPOINTS ACHIEVED BY OUR MODEL TO MATCH CELLULAR AND PHYSIOLOGICAL DATA FROM HUMAN MAPT MUTATION CARRIERS.

Los Angeles University Of California

(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]

California United States

State-Wide

Development and Validation of Human Cellular Models for Alzheimer's Disease-Related Dementias (ADRD) (R01 - Clinical Trial Not Allowed) (RFA-NS-24-032)