R35NS122209

Mitochondrial Integrated Stress Response in Neurological Diseases

Mitochondria play essential roles in cell biology because they are central hubs of most metabolic pathways. They are not only essential for energy conversion, but also for the biosynthesis and catabolism of virtually all cell constituents. Mitochondrial dysfunction causes havoc in all cells, but especially in those cell types that are highly dependent on mitochondrial energetic and metabolic functions, such as neurons and glia.

Genetic alterations of the mitochondrial proteome, which includes more than 1000 proteins, encoded by both the nuclear and the mitochondrial genomes, result in primary mitochondrial disorders. These diseases, for which there is currently no effective treatment, result in severe and often fatal neurodegeneration. Mitochondrial dysfunction also plays a role in the pathogenesis of many age-related neurodegenerative disorders, such as Alzheimer's and Parkinson's disease and ALS. Therefore, addressing therapeutically the consequences of mitochondrial dysfunction could have a profound impact on the treatment of many human disorders.

A major challenge in devising effective treatments for mitochondrial encephalopathies is our limited understanding of the ramifications of the effects of mitochondrial dysfunction. The conventional view that these disorders are caused simply by energy failure is inadequate, as it is becoming increasingly clear that mitochondrial dysfunction affects much more than just ATP generation and leads to an extensive rewiring of cell metabolism.

An exciting new development in the field is the observation that various types of mitochondrial dysfunction activate transcriptional and metabolic responses that involve multiple stress signaling pathways. We and others have identified a "Mitochondrial Integrated Stress Response" (MTISR) in diverse genetic forms of mitochondrial disorders, suggesting that MTISR is strongly associated with mitochondrial diseases and a potential pathogenic common denominator. We postulate that, while in the short term these responses may be compensatory, if sustained and unresolved, they become maladaptive and cause imbalances of key metabolites, which may be more detrimental than the energy defect itself.

While we now fully appreciate these maladaptive mechanisms in peripheral tissues, such as muscle and heart, very little is known about them in the CNS affected by mitochondrial encephalopathies. A deeper knowledge of the characteristics and the consequences of the MTISR in the CNS is needed to understand its pathogenic significance and develop targeted therapeutic strategies.

Our research group has a long-standing commitment to investigating the pathogenic mechanisms of mitochondrial diseases, and we have accumulated over two decades of expertise in studying the mechanisms of mitochondrial encephalopathies and mitochondrial dysfunction in neurodegeneration. In this R35 application, we focus on fundamental gaps in knowledge on the MTISR in mitochondrial encephalopathies by studying disease models that recapitulate human diseases. We will use a series of approaches, both established and technologically innovative, to generate a blueprint of the metabolic rewiring in the diseased CNS and identify targets potentially responsive to therapeutic modulation.

Weill Medical College Of Cornell 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.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

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

New York, New York 100654805 United States

Single Zip Code

Research Program Award (R35 Clinical Trial Optional) (RFA-NS-20-030)

Amendment Since initial award the total obligations have increased 449% from $998,006 to $5,477,228.