RF1NS139970

Vcid center without walls for understanding and leveraging small vessel cerebrovascular disease mechanisms in ADRD - understanding the pathogenesis of cerebral small vessel disease (CSVD) and vascular contributions to dementia (VCID) is increasingly important to help protect the cognitive and mental health of an aging population.

Recent technological advances now permit us to measure thousands of proteins and metabolites simultaneously in body fluids including cerebrospinal fluid (CSF), and single cell and spatial transcriptomics reveal tissue pathology at unprecedented resolution.

Leveraging these new technologies to investigate CSVD and VCID will help to unravel the complex and heterogeneous mechanisms underlying these diseases.

Here we take advantage of three resources led by our institution to best pursue these investigations.

The first resource is a large collection of CSF samples from the Washington University Knight Alzheimer’s Disease Research Center (KNIGHT-ADRC) and Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts.

The second resource is a collection of human brain tissue specimens from these same cohorts.

The third is extensive neuroimaging and analytical pipelines that can identify dissociable patterns of white matter hyperintensities (WMH), which are a key neuroimaging feature of CSVD.

By combining these resources together, our first aim is to identify specific CSF proteins and metabolites related to each of 5 different WMH spatial patterns (i.e., topographies).

This approach is likely to identify both shared and separate molecular correlates for each of the WMH topographies, which differentiate vascular risk factors and Alzheimer’s disease related pathologies.

We will also determine how identified CSF correlates of CSVD relate to the development of cognitive impairment.

Our second aim is to sample 5 regions of the brain, based on each of the different WMH topographies, from KNIGHT-ADRC and ADNI human brain specimens.

These will then undergo single cell and spatial transcriptomics, as well as further analysis using a vessel enrichment technique.

We will relate these transcriptional data to premortem imaging and postmortem histopathology features from each specimen.

The third and last aim is to perform a parallel transcriptomic analysis in rodent models of hypertension and cerebral amyloid angiopathy, both without and with treatment.

Comparing rodent data to the human results will shed light on the validity of these rodent models for understanding CSVD in humans and may potentially reveal specific molecular mechanisms that underlie these diseases.

We intend to use the results from all three aims to identify potential biomarkers and druggable targets.

We are strongly committed to sharing all of the data produced by these efforts openly, and collectively hope that they will lead to a clearer mechanistic understanding of CSVD and VCID.

Washington 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]

Missouri United States

State-Wide

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

Amendment Since initial award the total obligations have increased 48% from $2,954,213 to $4,361,625.