R01NS131469

Radiographic markers and therapeutic targets of cerebral edema after SAH - project summary/abstract
Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke that affects ~500,000 people annually world- wide and causes significant mortality and long-term disability.
Severe cerebral edema (CE) occurs in ~30-40% of SAH and contributes to poor long-term outcomes.
Although CE has been implicated as an important pathophysiologic process after SAH, CE targeted therapeutics have not been explored.

In this proposal, we address important barriers to the development of therapies targeting CE by 1) using a dual-energy CT (DECT) based method for measuring brain water content (BWC) to develop a validated measure of CE after SAH and 2) identifying the role of MIR-335-3P and MIR-5585-5P in the mechanisms of CE after SAH.
We have previously developed surrogate markers of CE using sulcal effacement measurements on computed tomography (CT) scans [selective sulcal volume (SSV) and the subarachnoid hemorrhage early brain edema score (SEBES)].
Using these markers, combined with miRNA and proteomic analyses, our preliminary data show elevated miRNAs (MIR-335P and MIR-5585) and decreased proteins (including SCARA5, GPNMB, and NTRK2) in SAH patients with severe sulcal effacement.

These miRNAs are predicted to downregulate NA+/K+ATPase (NKATP) expression as well as the proteins found to be decreased after SAH.
NKATP is important for maintenance of cellular membrane potential and has been shown to be downregulated after SAH.
Disruption of NKATP has been shown to cause cellular swelling which can lead to CE.

Our preliminary data shows elevations in MIR-335 and MIR-5585, decreased Na/K ATPase A-1 subunit (an essential subunit of NKATP) and increased cellular edema in an in vitro SAH model.
We also found MIR-335 and MIR-5585 elevations in brain tissue in an in vivo model with associated CE measured by MRI and ex-vivo methods.
Despite the utility of SSV and SEBES, these markers only measure the sulcal spaces in the brain and are indirect measures of CE, limiting their utility.

We have found that CE can be measured in brain parenchyma using DECT.
This measure of brain parenchymal water content will address the limitations of indirect markers.
We will employ a “bed-to-bench” approach, where a combination of DECT BWC techniques, plasma/cerebrospinal fluid samples and in vivo and in vitro models will be used to test the following specific aims.

Aim 1 will test whether BWC is predictive of in-hospital complications and long- term outcomes.
We will test if MIR-335 and MIR-5585 (markers of sulcal effacement) are also markers of BWC and if they are predictive of clinical outcomes.
Aim 2 will investigate the mechanism of MIR-335 and MIR-5585 related CE and if antagonism can ameliorate their detrimental effects in an in vitro and in vivo model.

We will perform the clinical study across two centers: UTHealth Houston and University of Maryland Medical Center.
The completion of our proposal will establish a validated radiographic technique that represents CE and identify miRNA mediated pathways that can be targeted for future clinical trials to improve outcomes.

University Of Texas Health Science Center At Houston

(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]

Houston, Texas 770303870 United States

Single Zip Code

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

Amendment Since initial award the total obligations have increased 98% from $571,202 to $1,128,404.