RF1NS130681

Synergistic White Matter Injury from Diesel Exhaust Particulate and Chronic Cerebral Hypoperfusion Exposures: Interaction between the Nogo/Ngr1 Receptor Pathway and Extravascular Fibrinogen Toxicity - Studies suggest an important role for cerebral hypoperfusion and blood-brain barrier (BBB) permeability in the onset and progression of cognitive impairment and dementia. Ambient air pollution may differentially impact cognitive health in individuals with underlying cerebrovascular disease.

Murine studies demonstrate that particulate matter (PM) exposure and chronic cerebral hypoperfusion (CCH) have supra-additive effects on subcortical white matter injury and neurocognitive deficits. This proposal leverages cell culture studies and a murine bilateral carotid artery stenosis (BCAS) model to assess the effects of diesel exhaust particulate (DEP) in a system that isolates a purely vascular component of cognitive decline and dementia. Potential synergies between axonal growth inhibitors and extravascular fibrinogen deposition are studied as critical regulators of white matter injury and repair.

The specific aims of this project are:

1) Examine the role of the Nogo/Ngr1 pathway in axonal regeneration and white matter repair following DEP exposure.
2) Establish the roles of BBB permeability and extravascular fibrinogen on axonal regeneration and white matter injury following DEP/CCH exposures.
3) Examine Ngr1 and 67kDa laminin receptor (67 LR) binding/internalization as a potential therapeutic strategy to mitigate white matter pathology in the setting of DEP/CCH exposures.

A factorial design will determine the independent and combined effects of DEP and CCH on white matter toxicity and neurocognition. We expect PM exposure to prime the Ngr1 pathway for neurite outgrowth inhibition. We also expect PM exposure to increase plasma fibrinogen levels. Neither of these changes result in substantial white matter injury on their own.

We expect CCH to amplify the PM effects on neurite outgrowth inhibition and white matter toxicity. We hypothesize this will occur through 1) decreased cAMP levels secondary to hypoxia that augment DEP-induced axonal growth inhibition and 2) increased BBB permeability that results in extravascular fibrinogen deposition in the subcortical white matter.

In addition to causing direct white matter toxicity, fibrinogen can impair axonal regeneration through the integrin B3/epidermal growth factor receptor (EGFR) pathway and increased chondroitin sulfate proteoglycan (CSPGs), which can further inhibit white matter repair through the Ngr1 pathway.

We will assess the impact of epigallocatechin-3-gallate (EGCG) administration to mitigate white matter injury following PM and CCH exposure. We expect this to work through a coordinated strategy of Ngr1 and 67LR binding/internalization and cAMP-mediated signaling.

University Of Southern 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.

93.866 - Aging Research

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

National Institute on Aging (NIA) [HHS - NIH]

Los Angeles, California 90033 United States

Single Zip Code

Clinical Relevance of the Linkage between Environmental Toxicant Exposures and Alzheimers Disease and Related Dementias (R01 Clinical Trial Not Allowed) (PAR-22-048)

Amendment Since initial award the End Date has been extended from 08/31/25 to 08/31/27 and the total obligations have increased 67% from $2,351,919 to $3,929,367.