R35NS127253

Ataxin-2 Complex Proteins in Neurodegeneration - Project Summary/Abstract

This R35 proposal builds on experiments supported by a Javits R37 and a U01 Create Bio award and the longstanding success of the Principal Investigator's group. They have led from mechanistic discoveries in spinocerebellar ataxias and translation to novel treatments, one of which is now in a Phase 1 human trial (BIIB105). The proposal's unifying theme is a focus on RNA-binding proteins (RBPs) in the ATXN2-complex of proteins that direct several aspects of RNA metabolism and that are prone to phase-separation and aggregation.

Building on recent discoveries in polyglutamine-mediated neurodegeneration and neuronal Staufer-1 (STAU1) overabundance, the researchers will apply multi-dimensional approaches to define novel pathogenic mechanisms in their intersections with autophagy, the unfolded protein response (UPR), and with RNA metabolism and transport. They postulate that these responses, while compensatory in the short term, become maladaptive with sustained stress. They believe that an RBP network response leads to progressive deterioration of autophagic flux and amplification of apoptotic signaling.

The researchers have established a broad suite of innovative tools and unique models in an exceptional research environment with established local and national collaborators. They have shared resources with these collaborators over many years. Their approach has been to characterize cerebellar degeneration at multiple time points using genome-wide transcriptomic, proteomic, morphologic, physiologic, and behavioral techniques.

These foundations will allow them to rapidly progress from cellular to animal models, modifying dosage of specific genes in vitro and in vivo. They will now extend this approach from Purkinje cells to spinal motor neurons, enabling them to address fundamental issues of broad relevance to inherited and sporadic neurodegenerative diseases. These topical issues include the role of cytoplasmic RBPs, especially ATXN2 and STAU1, in response to nutrient, chemical, and mutant protein stress. They will also investigate their regulation and interplay with each other, and key proteins determining autophagic flux and the UPR. Additionally, they will study their overall effect on neuronal death and their promise as therapeutic targets using small molecules and RNA-directed therapies.

R35 funding will allow them to identify novel functions of proteins in the ATXN2-complex in neurodegeneration and define shared features across different neurodegenerative diseases. This research has particular relevance not only to inherited, but also to sporadic forms of ataxia and motor neuron disease. The broad scope of their proposed studies will enable participation of scientists with diverse backgrounds in a laboratory and departmental culture of inclusivity and diversity. With their established commitment to reproducibility of animal models and gene targeting approaches, the novel mechanistic insights hold promise for translation into developing novel treatments for neurodegenerative disorders.

University Of Utah

(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]

Salt Lake City, Utah 841121103 United States

Single Zip Code

Research Program Award (R35 Clinical Trial Optional) (RFA-NS-21-020)

Amendment Since initial award the total obligations have increased 297% from $930,250 to $3,693,093.