Document text
Principal Investigator: Anne E Carlson
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $477,370
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY
TMEM16A is a calcium-activated chloride channel that is required for numerous physiologic
processes, including regulation of neuronal and cardiac excitability, uterine contractility,
regulation of electrolyte balance, and sensory transduction. Their importance is supported by
the embryonic lethality of TMEM16A knockout mice, and by the association of mutations in this
channel with craniofacial, breast, and pancreatic cancers. In addition to intracellular calcium,
TMEM16A channels are regulated by membrane lipids produced in the body. The long-term
goal of this research is to understand the molecular mechanisms that enable TMEM16A
channels to respond to cellular changes to alter channel activity. The overall objectives of the
experiments outlined in this proposal is to uncover how the membrane phospholipid
phosphatidylinositol 4,5-bisphosphate binds to the channel to enable chloride conduction,
uncover the signaling events that turn on these channels in their native cells, and to delineate
how polyunsaturated fatty acids regulate channel activity. We will ask the following questions: 1)
How does the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) potentiate
TMEM16A channels? 2) How does arachidonic acid and its metabolites inhibit TMEM16A?
Finally, 3) How does fertilization open TMEM16A channels in eggs from the African clawed frog,
Xenopus laevis? The proposed research includes conceptual and technical innovations and is
significant because it is expected to provide detailed mechanisms by which TMEM16A responds
to changing cellular environments. Ultimately, such knowledge has the potential to offer new
opportunities for the development of innovative therapies to treat TMEM16A-associated
diseases.
Terms: <African><Arachidonic Acids><Binding><Blood flow><Breast Cancer><Calcium><Cardiac><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cell Communication and Signaling><Cell Membrane Lipids><Cell Signaling><Cells><Chloride Channels><Chloride Ion Channels><Chlorides><Development><Diet><Disease><Disorder><Electrolyte Balance><Embryo><Embryonic><Environment><Event><Fertilization><Genetic Alteration><Genetic Change><Genetic defect><Goals><Heart Vascular><Human><Innovative Therapy><Inositide Phospholipids><Inositol Phosphoglycerides><Inositol Phospholipids><Intracellular Communication and Signaling><Ion Channel><Ionic Channels><KO mice><Knock-out Mice><Knockout Mice><Knowledge><Lipids><Malignant Breast Neoplasm><Malignant Pancreatic Neoplasm><Malignant neoplasm of pancreas><Mediating><Membrane><Membrane Channels><Membrane Lipids><Modern Man><Molecular><Molecular Interaction><Mutation><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Null Mouse><Organism-Level Process><Organismal Process><PIP2><Pancreas Cancer><Pancreatic Cancer><Pathology><Phosphatides><Phosphatidyl Inositol><Phosphatidylinositol 4,5-Biphosphate><Phosphatidylinositol 4,5-Diphosphate><Phosphatidylinositol-4,5-Bisphosphate><Phosphatidylinositols><Phosphoinositides><Phospholipids><Physiologic><Physiologic Processes><Physiological><Physiological Processes><Platanna><Polyunsaturated Fatty Acids><Process><PtIns 4,5-P2><PtdIns><PtdInsP2><Public Health><Regulation><Research><Sensory><Signal Transduction><Signal Transduction Systems><Signaling><Therapeutic><Xenopus><Xenopus laevis><Xenopus sp.><biological signal transduction><circulatory system><clawed frog><craniofacial><craniofacies><design><designing><developmental><diets><egg><experiment><experimental research><experimental study><experiments><fertilizations><genome mutation><innovate><innovation><innovative><malignant breast tumor><membrane structure><neuronal><neuronal excitability><pancreatic malignancy><uterine contractility>