R01AG068155

The Role of Tissue Non-Specific Alkaline Phosphatase in Brain Endothelial Cell Homeostasis - Project Summary

The objective of this application is to determine how tissue non-specific alkaline phosphatase (TNAP) enzymatic activity maintains cerebrovascular function within the neurovascular unit (NVU). Brain microvascular endothelial cells (BMECs) comprise the cerebral microvasculature and serve as the structural foundation of the blood-brain barrier (BBB). Increased permeability and diminished integrity of BMECs are two common mechanisms through which cerebrovascular function is compromised in human disease. TNAP is a highly enriched enzyme in cerebral microvessels whose function in brain BMECs is poorly understood.

Our preliminary data demonstrate that TNAP activity stimulates a novel signaling mechanism which protects against the loss of cerebral microvascular integrity and permeability. These intriguing findings led us to propose the central hypothesis that TNAP maintains NVU homeostasis during cerebral ischemia by preserving BBB integrity.

We will utilize mice with a VE-cadherin-Cre driven conditional deletion of TNAP in endothelial cells (VECKO) and its wild type littermates to interrogate the role of TNAP in BMECs. We will compare responses in young (4-5 months) and aged (18-20 months) mice to assess the age-dependent effects of brain endothelial TNAP on indices of brain endothelial barrier permeability combined with vascular network analysis and functional behavioral outcomes.

Aim 1 will elucidate the contribution of brain endothelial cell TNAP to NVU dysfunction in ischemic stroke in young mice. We will employ the transient middle artery occlusion model to assess quantitative differences in cerebrovascular outcomes and behavioral indices.

Aim 2 will determine the impact of brain endothelial cell TNAP on age-dependent impairment of the NVU. This aim will assess the impact TNAP on BMEC function in aging and the putative age-dependent interactions in ischemic stroke.

Aim 3 will determine how the TNAP-Rho associated kinase (ROCK) pathway regulates the barrier function and whether pharmacological inhibition of the ROCK pathway protects against the loss of barrier integrity and functional deficits associated with ischemic stroke in both young and aged mice.

Taken together, the studies in this proposal will delineate a novel mechanism through which brain endothelial cell TNAP enzyme activity preserves NVU function in ischemic stroke and improves functional recovery post-stroke. The overall results will contribute to our limited understanding of the basic biology of TNAP's role at the BBB and its contribution to NVU homeostasis in human health and disease.

West Virginia University Research Corporation

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE 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. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH 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 on Aging (NIA) [HHS - NIH]

Morgantown, West Virginia 26505 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 464% from $541,783 to $3,056,287.