R01AG071512

Neuroprotective Actions of Cystathionine G-Lyase through Gasotransmitter Hydrogen Sulfide Signaling - Project Summary

Neuroprotective Actions of Cystathionine -Lyase through Gasotransmitter Hydrogen Sulfide Signaling.

Hydrogen sulfide (H2S) is a gaseous signaling molecule or gasotransmitter which serves key roles in the central nervous system. However, specific targets and mechanisms of H2S action in the brain are obscure. Herein, we propose to elucidate the signaling pathways modulated by H2S in the brain that are neuroprotective to arrive at therapeutics targeting Alzheimer's disease (AD).

H2S is generated from the amino acid cysteine which, in turn, is synthesized by cystathionine -lyase (CSE) via the transsulfuration pathway in the brain. H2S is also synthesized by two other enzymes, cystathionine ss-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST), in the brain. We have demonstrated previously that H2S and cysteine metabolism are dysregulated in AD.

One of the modes by which H2S signals is via a posttranslational modification termed sulfhydration or persulfidation, wherein the reactive –SH group of cysteine residues on target proteins is converted to an –SSH group in a fashion analogous to nitrosylation by nitric oxide (NO), where the –SH groups are converted to –SNO groups. Although sulfhydration and nitrosylation modulate diverse physiological processes ranging from response to inflammation to neuroprotection, the molecular mechanisms by which cysteine and H2S/NO axes of gasotransmitter signaling affect neuronal function are yet to be deciphered.

In Aim 1 of this project, we will monitor expression and activity of the three H2S biosynthetic enzymes, CSE, CBS, and 3-MST, in the mouse brain at various ages. Sulfhydration status in normal as well as mice lacking CSE will be assessed. The specific proteins modified by sulfhydration will be identified, and sites of sulfhydration mapped on them. The interplay of sulfhydration with nitrosylation in neuronal function will be monitored.

In Aim 2, we will analyze the involvement of H2S in stress responses and behavior. In Aim 3, we will identify differentially sulfhydrated proteins in the 3XTG-AD mouse model of AD. By studying the function of CSE and H2S in the brain, we set a goal to better understand signaling mediated by cysteine, H2S, and protein sulfhydration in the context of neuronal signaling in AD.

Understanding the regulation of H2S signaling in the brain helps to determine the basic physiological pathways involved in neuroprotection and pins down the nodes for precision therapeutics and development of biomarkers for AD and other age-related neurodegenerative diseases involving dysregulated H2S signaling.

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]

Baltimore, Maryland 212051832 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 389% from $689,414 to $3,369,852.