R01NS119255

The pathogenic role of interneurons in Huntington's disease - Huntington’s disease (HD) is a deadly neurodegenerative disorder whose pathogenesis remains unknown. The disease is caused by aberrant polyglutamine expansion in huntingtin (HTT), a pleiotropic protein with essential functions during development.

Using genetically modified mouse models to temporally regulate gene expression during the developmental period, previous works from Molero et al., revealed that either exposure to mutant HTT, or loss of normal HTT elicits HD during midlife. These findings demonstrate that events taking place during neural development play pathogenic roles in the disease.

Interestingly, both mutant and loss-of-function models exhibit early interneuron deficits. This application presents evidence that the early ontogenic rescue of interneurons delayed disease onset and ameliorated disease progression in a model of HD, which supports the role of interneurons in disease pathogenesis.

The overall objective of this proposal is to define the mechanisms disrupting interneuron production, and the ensuing pathogenic cascade mediated by these cells. Our central hypothesis is that changes in subpallial cell-cycle dynamics and migration dampen the neurogenic output of interneurons, resulting in the disruption of corticostriatal connectivity, circuit maldevelopment, activation of stress responses, and the generation of “metastable” cells with lower reserves to cope with stress.

This hypothesis will be interrogated with three specific aims: (1) elucidate the underpinnings of the deficient interneuron neurogenic output; (2) determine the effects of interneuron deficits on corticostriatal circuit maturation; (3) identify and characterize developmentally vulnerable cells.

The first aim will employ a cell-cycle phase biosensor to define cell-cycle length and checkpoints; organotypic cultures, fate mapping techniques, and time-lapse microscopy to define interneuron migration; and molecular studies to define DNA damage within interneuron germinative domains.

For the second aim, whole-cell patch clamping in acute slides and in-vivo optogenetic techniques will be employed to define the establishment of the thalamocortical feedforward circuit and the functional maturation of the striatum.

Lastly, the third aim will employ a cellular stress reporter system to map “developmentally stressed” cells, define their survival throughout ontogenesis, and determine their molecular signature.

The proposed research is significant because it will elucidate the primary mechanisms underlying developmental deficits with key pathogenic roles in disease occurrence, uncovering a novel window for therapeutic interventions encompassing a potential array of novel disease-relevant targets. Moreover, these studies have important implications for our understanding of HD comorbidities and would provide an original methodological approach to interrogate related neurological disorders, particularly those involving polyglutamine expansions.

The application is innovative because upon confirming our hypothesis, it would shift the focus of current research efforts from mechanistic processes acting on the mature brain to events operating in the earliest incipient stages of the disease prodrome, thereby introducing a paradigm shift in the field.

Albert Einstein College Of Medicine

(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]

Bronx, New York 10461 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 383% from $623,619 to $3,012,470.