Another area of research that has supported over the decade is the identification and development of marine natural products (MNPs). One such example is the discovery of brevenal. Researchers supported by a program project grant at the University of North Carolina Wilmington discovered brevenal, a bio-active compound isolated from the secretions of Karenia brevis, a red tide producing dinoflagellate. Brevenal is showing great potential and promise as a novel therapeutic agent in the fight against cystic fibrosis (CF) and other respiratory dysfunctions. A primary and characteristic feature of CF patients is stickier and drier lung mucous due to defective function of sodium channels. Amiloride is a sodium channel blocker that is used to help clear mucous from the lungs of CF patients, in addition to the use of percussion vests to physically assist mucous clearance. This team of investigators used a sheep model comparing brevenal to amiloride and demonstrated brevenal is 1000-fold more effective at reducing bronchoconstriction and mucous clearance than amiloride in the sheep model. NIEHS continues to support brevenal research and development as this is a potentially major drug discovery from the MNPs aspect of its OHH portfolio that may have wide ranging effects on respiratory dysfunction and CF specifically.
The Massachusetts Division of Marine Fisheries and other state agencies monitor Massachusetts Bay shellfish for annual red tide outbreaks. In May 2005, scientific teams supported by the National Science Foundation and NIEHS jointly supported Woods Hole Center for Oceans and Human Health, using newly developed modeling technologies for counting cells and mapping red tide events associated with Alexandrium fundyense, the predominant red tide species in the Gulf of Maine, predicted the largest HAB event in over 20 years in New England coastal waters, allowing for closure of shellfish beds for harvesting. Continued monitoring of the HAB event by these scientists also provided guidance for when harvesting could safely resume. The research activities by these OHH Center scientists protected an untold number of people who may have consumed toxin tainted shellfish harvested in the Gulf of Maine and undoubtedly provided protection against substantial economic losses in the region that could have been attributed to the sale and consumption of contaminated seafood. The Woods Hole Center for Oceans and Human Health focuses on research issues at the intersection of oceanographic, biological and environmental health sciences, such as red tides, harmful algal blooms and other organisms in coastal waters and estuaries that cause human illness and death.
Additional selected highlights of NIEHS supported OHH research as follows:
Detecting the blue green algae toxin, BMAA in the food chain, from fish to humans, as a possible exposure pathway fort the development of ALS, Alzheimers and Parkinsons.
Using particle flow models to investigate the origins of Florida red tide blooms and to identify coastal and offshore nutrient sources.
Detecting the Florida red tide toxin, brevetoxins, in sediments to investigate the historical records of Florida red tides.
Remote Sensing: Using technology from the Remote Sensing Facilities Core to identify Florida red tide blooms off the Central West Florida Shelf.
Developing Luminex technology (used in medical testing) from the Genomics Facilities Core to rapidly screen common HAB organisms.
Genetic analysis of the 2006 Alexandrium bloom gives an unprecedented dataset with which we can evaluate hypotheses about how toxic dinoflagellate blooms form and change.
Models developed in the center gave an accurate prediction of a severe Alexandrium fundyense bloom in New England in 2008, to our knowledge the first-ever successful seasonal forecast of a red tide anywhere in the world.
A portable surface plasmon resonance (SPR) based biosensor system has been developed that can detect the Pseudo-nitzschia toxin domoic acid. Efforts to increase sensitivity and specificity are underway. Lab based studies have identified iron storage strategies in Pseudo-nitzschia that helps explain
its growth and distribution dynamics.
Center researchers have developed molecular fingerprinting techniques to rapidly identify Pseudo nitzschia species and have tracked species diversity signatures under bloom conditions in Puget Sound in field samples.
Feeding experiments demonstrated differential clearance rate of Pseudo-nitzschia and toxin retention times in different species of intertidal invertebrates, including economically important harvest species. Using these data, DA retention is being evaluated using Bayesian based mathematical modeling and statistical analyses.
Completion of studies in the zebrafish model system reveals that both sub-acute and acute DA exposure treatments result in quantifiable changes in gene expression in brain tissue. Findings provide insight into the chronic effects of sub-acute DA exposure.
Center researchers have determined that DA neurotoxicity is due to oxidative stress and is enhanced in mice lacking oxidative stress proliferative pathways (Gclm (-/-) mice). This response has caused oxidative stress-mediated apoptotic cell death. These findings provide a new paradigm of gene environment interaction. Additional results indicate the importance of oxidative stress-activated JNK and p38 MAP kinase pathways in DA-induced apoptosis in cerebellar granule neurons.
A Center funded Pilot Study with the Washington State Department of Health (DOH) exploring seafood exposures among Asian and Pacific Islander communities in the Puget Sound area has revealed important differences in shellfish consumption patterns between high seafood consuming groups. These differences have been evaluated in conjunction with biomarkers for exposure to improve our ability to understand exposure response and additional benefits.
Developed an assay for ciguatoxin (CTX) that is capable of quantifying CTX at concentrations10 times lower than the threshold for clinical symptoms. Collaborating with fishermen, developed a program (and web site) that facilitates the analysis of locally caught fish for CTX. Identified a new sodium-channel neurotoxin that is present in both fish and algae (Gambierdiscus sp.).
Developed an accurate and sensitive assay for β-methylamino Lalanine (BMAA), an excitotoxic neurotoxin that functions as a glutamate agonist that is found in cyanobacteria and has been implicated in the etiology of amyotrophic lateral sclerosis Parkinsonism dementia complex and Alzheimer's Disease.
Screened several hundred extracts for antibacterial and cytotoxicity activity and several dozen in cell-free extracts for MAP kinase and PKC inhibition. Structural elucidations of the active agents are ongoing and have resulted in the identification of several novel compounds with potential pharmaceutical
use.
Identified isolates from marine microbes that have potential for treating infections from several kinds of troublesome viruses.
Demonstrated that Florida red tide toxins (known as brevetoxins) can impact respiratory function and increase respiratory symptoms in patients with asthma. In the normal population, inhaled aerosolized red tide toxins can lead to eye irritation, rhinorrhea, nonproductive cough, and wheezing. This study
showed that red tide toxins may have a greater impact on patients with asthma, who experienced respiratory problems and decreased lung function after just one hour of beach exposure to the toxins.
Provided data suggesting pregnant women should consider avoiding beaches during K. brevis bloom events. An inhalation toxicologist at the Lovelace Respiratory Research Institute, supported by the program project at UNC Wilmington conducted a study of placental transfer of brevetoxins. Pregnant mice were exposed to a radioactive form of brevetoxin- 3, a major component of aerosolized brevetoxins routinely found on beaches after a bloom event. The toxin and its by-products were identified in fetuses and uterine and placental tissues 48 hours later. Pregnant human females exposed to brevetoxins may pass them to their fetuses or babies.
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