R01ES037626

NICKEL EXPOSURE DISRUPTS SP1/ZEB1-DEPENDENT TRANSCRIPTIONAL REGULATION - PROJECT SUMMARY NICKEL (NI) COMPOUNDS ARE OCCUPATIONAL AND ENVIRONMENTAL TOXICANTS. ALTHOUGH NI OCCURS NATURALLY, INDUSTRIAL PROCESSES INCLUDING FOOD PROCESSING, MINING, AND REFINING, AS WELL AS EXTENSIVE USE OF NI-CONTAINING PRODUCTS (E.G., STAINLESS STEEL, BATTERIES, AND MEDICAL DEVICES) HAVE SIGNIFICANTLY INCREASED ITS LEVELS IN THE ENVIRONMENT. NI EXPOSURE IS ASSOCIATED WITH CHRONIC INFLAMMATORY LUNG DISEASES SUCH AS ASTHMA, FIBROSIS, BRONCHITIS, EMPHYSEMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). EXPOSURE TO ENVIRONMENTAL LEVELS OF NI HAS BEEN ASSOCIATED WITH DECREASED PULMONARY FUNCTION, AND AMBIENT NI EXPOSURE IN CHILDREN HAS BEEN SHOWN TO CAUSE ALVEOLAR INFLAMMATION. AN ASSOCIATION BETWEEN BLOOD NI CONCENTRATIONS AND DECREASED LUNG FUNCTION HAS ALSO BEEN IDENTIFIED RECENTLY. MOREOVER, EPIDEMIOLOGICAL STUDIES SHOW THAT NI EXPOSURE IS ASSOCIATED WITH LUNG AND NASAL CANCERS. HOWEVER, THE MOLECULAR BASIS OF NI-INDUCED DISEASES REMAINS POORLY UNDERSTOOD. THE OVERARCHING GOAL OF THIS GRANT IS TO UNCOVER THE MECHANISMS UNDERLYING NI EXPOSURE-ASSOCIATED LUNG DISEASES. OUR PRELIMINARY RESULTS SHOW THAT NI EXPOSURE CAUSED GENE SILENCING, WHICH PERSISTED EVEN AFTER THE TERMINATION OF EXPOSURE. NOTABLY, WE FOUND PERSISTENT DOWNREGULATION OF THE GENES INVOLVED IN CELL ADHESION AND EXTRACELLULAR MATRIX ORGANIZATION, INCLUDING E-CADHERIN (CDH1), LEADING TO EPITHELIAL-MESENCHYMAL TRANSITION (EMT), A KEY PROCESS IN NI-INDUCED LUNG DISEASES MENTIONED ABOVE. OUR RESULTS ALSO REVEALED PERSISTENT DOWNREGULATION OF MANY TUMOR SUPPRESSOR GENES FOLLOWING NI EXPOSURE. THESE RESULTS SUGGEST THAT NI-INDUCED GENE SILENCING PLAYS A SIGNIFICANT ROLE IN DISEASE PATHOGENESIS. OUR INVESTIGATION OF THE PERSISTENTLY DOWNREGULATED CDH1 GENE SUGGESTED DISPLACEMENT OF SP1, A TRANSCRIPTIONAL ACTIVATOR, FROM ITS PROMOTER AS KEY FOR ITS NI-INDUCED SILENCING. INTERESTINGLY, SP1 DISPLACEMENT WAS ACCOMPANIED BY RECRUITMENT OF ZEB1, A TRANSCRIPTIONAL REPRESSOR, TO THE SAME LOCUS. MOREOVER, WE ALSO FOUND COLOCALIZATION OF SP1 AND ZEB1 BINDINGSEQUENCES AT HUNDREDS OF NI-DOWNREGULATED GENE PROMOTERS. THIS SUGGESTS THAT SP1 AND ZEB1 BINDING CONSTITUTE A GENE REGULATORY SWITCH, WHICH IS DISRUPTED BY NI EXPOSURE. SP1 AND ZEB1 ARE WELL-KNOWN CHROMATIN MODIFIERS. BASED ON OUR PRELIMINARY RESULTS, WE HYPOTHESIZE THAT NI EXPOSURE DISRUPTS THE SP1- ZEB1 GENE REGULATORY SWITCH, ALTERING THE EPIGENOMIC LANDSCAPE AND RESULTING IN ABERRANT GENE SILENCING. IN AIM 1, WE WILL CHARACTERIZE THE NI-INDUCED ALTERATIONS TO SP1-BINDING ACROSS THE GENOME AND THE RESULTANT CHANGES TO THE EPIGENOMIC LANDSCAPE. IN AIM 2, WE WILL INVESTIGATE THE ROLE OF ZEB1 IN NI-INDUCED PERSISTENT GENE SILENCING. IN AIM 3, WE WILL EXAMINE THE CONSEQUENCES OF NI-INDUCED DISRUPTION OF SP1-ZEB1 REGULATORY SWITCH IN VIVO. THE OVERALL IMPACT OF OUR STUDY WILL BE A COMPREHENSIVE UNDERSTANDING OF THE MECHANISMS UNDERLYING NI-INDUCED LUNG DISEASES.

New York University

<P>THE GOALS ARE:</P><UL><LI>TO FOSTER FUNDAMENTAL CREATIVE DISCOVERIES, INNOVATIVE RESEARCH STRATEGIES, AND THEIR APPLICATIONS AS A BASIS FOR ULTIMATELY PROTECTING AND IMPROVING HEALTH;</LI><LI>TO DEVELOP, MAINTAIN, AND RENEW SCIENTIFIC HUMAN AND PHYSICAL RESOURCES THAT WILL ENSURE THE NATION'S CAPABILITY TO PREVENT DISEASE;</LI><LI>TO EXPAND THE KNOWLEDGE BASE IN MEDICAL AND ASSOCIATED SCIENCES IN ORDER TO ENHANCE THE NATION'S ECONOMIC WELL-BEING AND ENSURE A CONTINUED HIGH RETURN ON THE PUBLIC INVESTMENT IN RESEARCH; AND</LI><LI>TO EXEMPLIFY AND PROMOTE THE HIGHEST LEVEL OF SCIENTIFIC INTEGRITY, PUBLIC ACCOUNTABILITY, AND SOCIAL RESPONSIBILITY IN THE CONDUCT OF SCIENCE.</LI></UL><P>IN REALIZING THESE GOALS, THE NIH PROVIDES LEADERSHIP AND DIRECTION TO PROGRAMS DESIGNED TO IMPROVE THE HEALTH OF THE NATION BY CONDUCTING AND SUPPORTING RESEARCH:</P><UL><LI>IN THE CAUSES, DIAGNOSIS, PREVENTION, AND CURE OF HUMAN DISEASES;</LI><LI>IN THE PROCESSES OF HUMAN GROWTH AND DEVELOPMENT;</LI><LI>IN THE BIOLOGICAL EFFECTS OF ENVIRONMENTAL CONTAMINANTS;</LI><LI>IN THE UNDERSTANDING OF MENTAL, ADDICTIVE AND PHYSICAL DISORDERS; AND</LI><LI>IN DIRECTING PROGRAMS FOR THE COLLECTION, DISSEMINATION, AND EXCHANGE OF INFORMATION IN MEDICINE AND HEALTH, INCLUDING THE DEVELOPMENT AND SUPPORT OF MEDICAL LIBRARIES AND THE TRAINING OF MEDICAL LIBRARIANS AND OTHER HEALTH INFORMATION SPECIALISTS.</LI></UL>

93.113 - Environmental Health

National Institute of Environmental Health Sciences (NIEHS) [HHS - NIH]

New York, New York 100102533 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-25-301)