R01AG081841

The effect of circadian rhythm disruptions on the angiogenic response to hypoperfusion in the AD brain - project summary/abstract.

Although the pathophysiology of Alzheimer's disease (AD) is complex and multifactorial, vascular comorbidities and cerebrovascular insufficiency occur in almost two-thirds of AD patients. However, how cerebrovascular insufficiency interacts with and contributes to AD remains poorly understood.

Recently, the brain vasculome (i.e. transcriptome profiles of cerebral endothelial cells and pericytes) has been proposed as a conceptual framework to investigate vascular mechanisms in CNS diseases. In response to RFA-AG-23-014 (Mechanisms of Brain Hypoperfusion in AD/ADRD), we propose to test the hypothesis that cerebrovascular insufficiency perturbs the AD brain vasculome, eventually leading to cognitive impairment.

The normal brain compensates for hypoperfusion by inducing endogenous vascular remodeling and angiogenesis. The presence of AD interferes with endogenous angiogenesis and vascular recovery in response to hypoperfusion, and this exacerbates AD progression and worsens the AD brain vasculome.

Because circadian rhythms and circadian genes are known to regulate angiogenesis, we further hypothesize that AD disrupts circadian homeostasis in the brain vasculome, thus interfering with the endogenous angiogenic response to hypoperfusion.

The importance of investigating these interactions between AD, vascular responses, and circadian rhythms is emphasized by our pilot data. For example, we show a greater difference in transcriptome profiles of cerebral endothelial cells and pericytes of wild-type vs AD mice when tested during the active (awake) phase compared to the inactive (sleep) phase.

For testing our hypotheses, we propose three integrated aims. Aim 1 will show that AD brains exhibit a lower capacity of compensatory angiogenesis in response to hypoperfusion, and Aim 2 will show that circadian rhythms are disrupted in AD brains and that disrupted circadian rhythms suppress angiogenic response. And finally, Aim 3 will examine whether re-normalizing circadian rhythms improves the brain vasculome and promotes angiogenesis after hypoperfusion in AD mice.

Whether and how AD brains lose compensatory angiogenesis capacity after cerebral hypoperfusion is unknown. Therefore, we have designed a multi-disciplinary multi-lab project to fill this gap of knowledge by examining how perturbations in circadian rhythms disrupt the brain vasculome and worsen hypoperfusion in AD.

The General Hospital 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]

Charlestown, Massachusetts 02129 United States

Single Zip Code

Mechanisms of Brain Hypoperfusion in AD/ADRD (R01 Clinical Trial Not Allowed) (RFA-AG-23-014)

Amendment Since initial award the total obligations have increased 292% from $775,852 to $3,037,977.