R01NS117179

Novel neurovascular protective mechanisms of PEDF after subarachnoid hemorrhage - Abstract

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating type of hemorrhagic stroke with 50% mortality and long-term morbidity in surviving patients.1-4 Recently, the focus of SAH research has been shifted to early brain injury (EBI) which comprises the acute initial events after SAH, such as elevation of intracranial pressure (ICP), global ischemia, blood brain barrier (BBB) disruption, brain edema formation, neuronal apoptosis, activation of inflammatory and cell death pathways that contribute to delayed neurological deterioration, leading to mortality and morbidity after SAH.5-8

Pigment-epithelium derived factor (PEDF) is a pluripotent glycoprotein expressed in various tissues including the brain.9,14 PEDF reduced apoptosis in various types of cells including neurons,14,18 osteoblasts24 and cardiomyocytes.22 Likewise, PEDF reduced vascular permeability and macular edema in ophthalmologic pathologies.37,41 There have been relatively limited studies on the role of PEDF following stroke. PEDF has been shown to have protective effects on neuronal cell survival in vitro14,18 and attenuated cerebral ischemic injury in rodent models.19-21 PEDF reduced brain edema following cold-induced injury and transient cerebral ischemia in rodent models.20,21,42 However, the role of PEDF following SAH has not been explored. Furthermore, the neurovascular protective mechanisms of PEDF have not been studied.

This proposal will elucidate the neurovascular protective mechanisms of PEDF through anti-apoptotic and BBB protective pathways in a rodent endovascular perforation SAH model. We will sequentially determine the role of endogenous PEDF and then evaluate the therapeutic benefits of intranasal administration of recombinant PEDF against early brain injury after SAH, specifically neuronal apoptosis and BBB disruption will be evaluated. Additionally, we will elucidate the downstream signaling pathways of PEDF receptor (PEDF-R) that contribute to anti-apoptotic and BBB protective mechanisms of PEDF. We propose that PEDF will activate PEDF-R/NPD1/ERK1/2-CREL pathway that reduces neuronal apoptosis with intranasal recombinant PEDF administration. Also, PEDF activation of the PEDF-R/NRF2/HO-1 pathway will contribute to BBB stabilization after SAH. We will knockdown PEDF receptor and inhibit the pathways to elucidate the mechanism of PEDF-R signaling pathway mediated protection.

Overall, this proposal will provide novel insights into neurovascular protective mechanisms of PEDF. Additionally, this proposal will establish the protective efficacy of intranasal administration of PEDF as a potential therapeutic target against early brain injury after SAH.

Loma Linda 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]

California United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 300% from $400,313 to $1,600,477.