RF1NS139972

Defining the molecular spectrum of white matter vascular lesions - This project will define the molecular spectrum of white matter vascular lesions that drive vascular cognitive impairment and dementia (VCID).

Cerebral small vessel disease (CSVD) is a spectrum that begins in the vessel but progresses to include brain-wide changes in inflammation, dysregulated cell-cell communication, and cortical disconnection, ultimately leading to VCID.

The goal of this research proposal is to develop a VCID center with out walls (CWOW) that will advance a mechanistic understanding of the molecular pathways driving VCID while testing the efficacy of multiple VCID therapeutics.

Converging evidence indicates that white matter vascular lesions resulting from CSVD modulate the location, severity, and progression of neuroinflammation, tauopathy, and neurodegeneration in AD-ADRD conditions.

However, a key knowledge gap is the precise identification of molecular pathways both within cerebral small vessels and in brain networks at-large that mediate the cognitive impairment and dementia associated with white matter vascular lesions.

Recent work and preliminary data from our group points to distinct molecular pathways driving inflammatory signaling and disrupted cellular communication in white matter endothelial cells, that produce disordered signaling in the microenvironment of cells around white matter vessels (the neurovascular niche), which leads to white matter axonal damage and then cortical disconnection acting through molecular pathways linking CSVD and AD.

This vessel inflammation-to-cognitive impairment progression will be characterized using sophisticated viral, genetic, Brain Initiative imaging technology, and human-to-rodent data alignment.

Further, we will test three candidate therapeutics, developed by the PI’s, that interdict this vessel inflammation to brain disconnection progression.

We will test this hypothesis using an unparalleled combination of prodromal, isolated, recurrent, and mixed ADRD rodent models of CSVD.

We will use mechanistic studies aimed at identifying and validating molecular systems regulating white matter inflammation (SA1) as well as cortical dysfunction (SA2), and by developing a unique human single-cell sequencing dataset and applying translational VCID imaging biomarkers to rodent models of VCID to exploit regional differences in brain resilience (SA3).

End point metrics will include: I) Inflammatory vessel signaling cascades shared across prodromal CSVD models (aging, obesity, hypertension, and AD backgrounds); II) Inter-regional and inter-hemispheric measures of cortical disconnection that vary across lesion type and neurodegenerative comorbidity; III) Cellular, molecular, and imaging correlates of regional brain resilience to white matter vascular lesions; and IV) Therapeutic efficacy of three novel VCID therapeutics targeting these pathways.

This project and its research team leverages recognized leaders in VCID with relevant technical expertise to advance a VCID CWOW framework that will accelerate the identification of new therapeutic targets and diagnostic strategies to VCID.

Los Angeles University Of 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

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

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

Los Angeles, California 900957334 United States

Single Zip Code

VCID Center Without Walls for Understanding and Leveraging Small Vessel Cerebrovascular Disease Mechanisms in ADRD (R01 - Clinical Trial Not Allowed) (RFA-NS-24-027)