Project: Research project

Project Details


DESCRIPTION (adapted from investigator's abstract): Programmed cell death
(apoptosis) plays an essential role in many processes underlying embryological
development, from formation of the digits to selection of effective
immunological repertoires in Iymphocytes. It is generally believed that loss of
normal onset of apoptosis is involved in the etiology of many cancers.
Increased understanding of the signaling components within cells that control
this process may lead to improved treatments for cancer. The applicant has
identified a critical role in early embryogenesis for the Calcium Modulating
cyclophilin Ligand (CAML). CAML is an integral membrane protein localized at
internal Ca2+ containing vesicles, and appears able to cause release of
intracellular Ca2+ stores when stimulated by physical interaction with cell
surface receptors. Genetic knockout of the CAML gene in mice causes a block in
embryonic development between 4.5 and 6.5 days post coitum. Remarkably,
embryoid bodies derived from CAML-/- ES cells fail to develop a 'proamniotic
cavity," a structure shown by others to arise upon induction of programmed cell
death in a specific area of the inner cell mass. An attractive hypothesis is
that CAML activates a developmentally important programmed cell death pathway
via its ability to release intracellular Ca2+ stores. The overall goal of this
project is to determine how, at the molecular level, the CAML protein regulates
early embryogenesis and lymphopoiesis in the mouse. Experiments will focus on
determining the mechanism of action of CAML, by identifying its functional
domains, and identifying protein contacts that mediate its action. Chimeric
experiments in mice will allow the identification of other developmental steps
that require CAML function. In vitro experiments examining the function of CAML
in embryoid body formation will further delineate its mechanism of action in
contributing to apoptosis. Lastly, the role of CAML in development and function
of Iymphocytes will be determined in chimeric mice.
StatusNot started


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