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Assistant ProfessorPhone: (601) 984-1858
In chronic and heavy drinkers, alcohol slows the beating of lung airway cilia resulting in poor mucociliary clearance. This leaves the alcoholic highly prone to recurring lung infections, pneumonia and permanent lung disease. The molecular targets in cilia that are altered in "Alcohol-Induced Ciliary Dysfunction" (AICD) are unknown.
Figure 1: Eukaryotic cilia conservation. Cross-sections through a Chlamydomonas cilium (left) and a human respiratory cilium (middle show the structures are virtually identical. A schematic (right) shows the 9 outer doublets (1-9), the central pair (CP), radial spokes (RS), nexin links and inner and outer dynein arms. The CP, RS and nexin links are critical axoneme structures involved in regulation of ciliary dynein motor function.
Cilia are highly conserved organelles found on nearly every differentiated cell and play vital motile and signaling roles in the adult human body and during development. Key cilia cytoskeletal structures involved in regulation of ciliary motility include the central pair (CP), radial spokes (RS) and nexin links. These structures anchor highly conserved signaling molecules that function to transmit mechanochemical signals from the central pair to the dynein arm motors. Within the cilium, multiple dynein motors work in a coordinated manner to generate complex ciliary bends and precise ciliary beat frequencies.
Genetic defects (gene mutations) or acquired defects (alcohol) in cilia and the ciliary dyneins which drive their movement can lead to a wide range of diseases and syndromes called "the ciliopathies." Cilia dysfunction results in widespread pathologies in fetal development and function of nearly every organ system in the adult body.
My lab uses Chlamydomonas reinhardtii as a model experimental organism to determine the ciliary targets of alcohol and to reveal fundamental mechanisms for regulation of dynein motor function and ciliary motility. "Chlamy" is a unicellular green algae with 2 cilia that are used for locomotion. Chlamydomonas offers exceptional experimental advantages for the study of cilia and the dynein motors that drive their movement, including genetic, ultrastructural, molecular and biochemical approaches.
Our recent work has demonstrated that alcohol (ethanol) exposure reduces ciliary beat frequencies by targeting the outer dynein arm (ODA) ciliary motor. Moreover, we have shown that alcohol reduces phosphorylation of DCC1, a component of the ODA-docking complex - a heterotrimeric complex that "docks' the ODA to the ciliary microtubule axoneme.
In addition, my lab collaborates with Dr. Kristine Willett (University of Mississippi, Oxford) to study the effects of alcohol on development in zebrafish - a powerful model for testing the effect of chemicals on fetal development.
Alcohol consumption during pregnancy results in a range of developmental defects including severe developmental and intellectual delays, central nervous system abnormalities, abnormal facial features and severe heart defects. Babies exposed to alcohol during development can manifest some or all of these conditions, which are collectively referred to as Fetal Alcohol Syndrome (FAS). The underlying mechanism of how alcohol consumption results in these significant health issues is largely unknown.
Of particular interest are the congenital heart defects associated with FAS. A prominent feature of vertebrate development is the establishment of the left and right sides of the body, which dictates the proper placement of the internal organs of the chest and abdomen including the leftward tilt of the heart. Proper formation of the left and right sides of the body are critical for normal heart development and recent evidence has established a role for cilia in these important embryonic events. During vertebrate development, motile cilia in the embryonic node create a directional flow of extra-embryonic fluid that triggers signaling events in an asymmetric manner across the LR axis of the developing embryo. Defective motility of nodal cilia leads to abnormal LR axis specification and consequent heart development, resulting in ciliopathies such as Primary Ciliary Dyskinesia (PCD), situs defects or embryonic lethality due to congenital heart defects.
Using the zebrafish model, we are testing the idea that alcohol consumption during fetal development reduces the beating of embryonic cilia leading to defective left-right axis specification and consequent congenital heart disease.
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