R01AG075963

Age-Related Hypertension and Vascular Cognitive Impairment - Abstract

Hypertension is a key risk factor for the development of cerebral small vessel disease, the foremost source of vascular cognitive impairment, which is the second most common cause of dementia after Alzheimer's disease. There is increasing evidence that blood-brain barrier dysfunction and neuroinflammation play a pivotal role in the pathophysiology of hypertension and contribute to the development of vascular cognitive impairment.

While angiotensin II type 1 receptor antagonists are first-line therapy to treat hypertension, they have recently been demonstrated to improve neurocognitive function. Given the annual cost of dementia in the US is expected to double by 2040, the prevalence of hypertension rises from 46% of US adults aged 20-44 to over 78% of US adults above the age of 65, and that hypertension incidence increases dramatically post-menopause, there is a critical public health need for a greater understanding of the mechanistic link(s) between sex, age-dependent hypertension, and vascular cognitive impairment.

This application will test the global hypothesis that normal aging evokes sex-dependent hypertension that drives central microvascular injury and neuroinflammation to cause vascular cognitive impairment, which can be ameliorated by angiotensin II type 1 receptor antagonism. Our aims will be conducted in male and female 3-, 8-, and 16-month-old Sprague-Dawley rats (model of normal aging). The following specific aims will test this hypothesis:

Specific Aim 1: Hypothalamic PVN blood-brain barrier dysfunction and neuroinflammation contribute to age-dependent hypertension via a reversible sex-dependent angiotensin II type 1 receptor mechanism.

Specific Aim 2: Age-dependent hypertension evoked hippocampal microvascular injury and neural circuit dysfunction drive vascular cognitive impairment via a reversible sex-dependent angiotensin II type 1 receptor mechanism.

Our innovative approach is directly aligned with NIA strategic goals that address Alzheimer's disease and its related dementias and is designed to provide novel insights into the basic mechanisms contributing to sex- and age-dependent hypertension-driven vascular cognitive impairment and fully meets the intent of PAR-19-070 and NOT-AG-20-038.

Specific Aim 1 will establish that hypothalamic PVN blood-brain barrier dysfunction and neuroinflammation contribute to the development of age-dependent hypertension, which drives vascular cognitive impairment, via a reversible sex-dependent angiotensin II type 1 receptor mechanism.

Specific Aim 2 will establish that age-dependent hypertension evoked hippocampal microvascular injury and neural circuit dysfunction drive vascular cognitive impairment via a reversible sex-dependent angiotensin II type 1 receptor mechanism.

Our innovative approach will directly investigate the sex-dependent mechanistic sequelae of events and underlying neural dysfunction in both the PVN and hippocampus that is associated with, and perhaps contributing to, age-dependent hypertension-driven vascular cognitive impairment.

Emory University

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]

Atlanta, Georgia 303221119 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-19-070)

Amendment Since initial award the End Date has been extended from 01/31/27 to 01/31/28 and the total obligations have increased 282% from $835,492 to $3,188,327.