R01NS125018

RNA Regulatory Networks in Neuronal Cell Type Diversity and Function - Project Summary

The mammalian brain is probably the most complex organ in the body, and its proper function requires coordination of many diverse types of excitatory and inhibitory neurons that form distinct functional circuitries. Characterization of neuronal cell types is fundamental to understand not only how the brain works but also how specific cell types are selectively affected in multiple neuronal disorders and how this process can be reversed.

A large number of neuronal cell types were recently defined based on their gene expression profiles in bulk and single cells, and these cell types are organized into a hierarchical cell taxonomy. Alternative splicing is a mechanism to generate multiple transcript and protein variants with distinct functions, thus providing a major driving force of the molecular diversity in mammals.

The overarching goal of my research group is to understand the contribution of alternative splicing and the underlying RNA-regulatory networks in the brain and brain-related disorders. Previous work from multiple groups, including ours, unambiguously demonstrated that the brain has unique splicing-regulatory programs compared to non-neuronal tissues. Our studies also revealed the establishment of a pan-neuronal splicing program regulated by multiple RNA-binding proteins (RBPs) during neural development and demonstrated the important role of the RBFOX protein family in regulating axonal maturation and neuronal excitability.

However, how alternative splicing contributes to the distinct molecular profiles of diverse neuronal cell types in the cortex is currently poorly understood. We hypothesize that the transcriptome diversity generated by highly regulated alternative exons is a major component that specifies neuronal cell type identity and function.

In this application, we describe our preliminary analysis of neuronal cell type-specific alternative splicing regulation in mouse cortex, which provides strong support for the following specific aims we would like to pursue:

1) Perform systematic analysis of neuronal cell type-specific alternative splicing to identify novel neuronal subclasses and regulators using deep sc-RNA-seq data.

2) Validate our computational predictions and characterize mechanisms of neuronal cell type-specific splicing regulation and function using two complementary model systems: the distinction of two major subclasses of GABAergic interneurons originating from caudal (CGE) and medial (MGE) ganglionic eminences, and a GABAergic neuron-specific microexon in ANK3/ANKYRIN G.

To achieve our goal, we will use a multidisciplinary approach that integrates cutting-edge statistical and machine learning methods and multiple in vitro and in vivo experimental models. This study will generate a global and mechanistic view of precise alternative splicing regulation across diverse neuronal cell types and illuminate its impact on neuronal structural and functional properties.

The Trustees Of Columbia University In The City Of New York

(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]

New York, New York 100323725 United States

Single Zip Code

Promoting Research in Basic Neuroscience (R01) (PAS-18-483)

Amendment Since initial award the total obligations have increased 383% from $624,986 to $3,016,581.