R01AG066768

Identification of Enteric Juvenile Protective Factors and Their Role in Stimulating Neurogenesis in the Adult and Ageing Enteric Nervous System - Project Summary/Abstract

Intestinal motility is regulated by the enteric nervous system (ENS), which resides entirely within the gut wall and comprises the largest collection of neurons and glial cells outside of the brain.

Previously, we have provided evidence that post-natal development and adult maintenance of the ENS are controlled by distinct fetal-juvenile SOX10-expressing and adult nestin-expressing enteric neural stem cells (ENSC). With maturation, the SOX10-expressing cells lose their neurogenic potential in healthy gut but regain it after specific types of injuries, suggesting that certain juvenile protective factors (JPFS) that allow for SOX10+ cells to generate neurons in juvenile gut are lost in adults, but are re-introduced upon injury in adults.

The continual genesis of neurons throughout life suggests that a consistent loss of neurons during the juvenile or adult life is due to significant insufficiencies in the neurogenic capacity of ENSC active at that time. Aging is associated with significant loss of enteric neurons and associated chronic intestinal dysmotility, suggesting that an insufficiency in neurogenic capacity of adult ENSC is responsible for such disorders and that the key to crafting a long-term cure for the elderly patients rests in finding novel strategies to increase or supplement existing adult neurogenesis to normalize ENS structure and function.

If latent neurogenic capacity of adult SOX10+ cells can be modulated by JPFS, we hypothesize that identifying, recruiting, and re-introducing JPFS into the aging gut would restart neurogenesis from the newly re-invigorated SOX10+ ENSC and that this strategy holds promise for providing lasting relief to elderly suffering from chronic intestinal dysmotility by supplementing insufficient adult nestin+ derived enteric neurogenesis.

Here, we provide significant preliminary data that identifies some putative extrinsic and intrinsic JPFS and test their effect on ENSC behavior. In this proposal, we aim to use next-generation sequencing, large-scale single-cell measurements, integrative cross-platform analyses, and cutting-edge computational tools to identify diverse putative JPFS, describe the regulatory networks through which they act, and functionally validate their ability to modulate neurogenic capacity using our novel biological insight to correct ENS structure and function in animal models of aging.

The Johns Hopkins 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]

Maryland United States

State-Wide

Juvenile Protective Factors and Their Effects on Aging (R01) (PAR-17-126)

Amendment Since initial award the total obligations have increased 393% from $660,586 to $3,254,354.