Mammalian Target of Rapamycin Signaling and the Suprachiamatic Circadian Clock

Project Summary
The objective of the proposed research is to understand physiological functions of the mammalian target of
rapamycin (mTOR) signaling pathway in the brain circadian (~24 h) clock, the hypothalamic suprachiasmatic
nucleus (SCN). To be synchronized with the external and internal environment, gene expression in the SCN
clock is regulated by an intracellular signaling network. A major gap exists in our understanding of the key
signaling events that couple extracellular and intracellular signals to regulate protein synthesis (mRNA
translation). mTOR is a master regulator of mRNA translation. It forms two functionally distinct branches, mTORC
(mTOR complex) 1 and mTORC2. Based on our published work and unpublished preliminary data, our overall
hypothesis is that mTORC1 controls mRNA translation and SCN cell synchrony, whereas mTORC2
controls circadian cytoskeleton reorganization, both of which are critical for the SCN clock function. To
test the hypothesis, activities of specific mTOR components will be manipulated by genetic and pharmacological
approaches. The circadian clock functions will be assessed at the molecular, cellular and animal behavioral
levels using a multidisciplinary approach. Aim 1 will define the functions of the mTORC1 translation effectors
S6Ks in the SCN. We hypothesize that S6Ks regulate the photic clock resetting by regulating mRNA translation.
Aim 2 will assess a role for mTORC1 in mediating photoperiodic regulation of SCN cell synchrony. We
hypothesize that mTORC1 mediates the regulation of SCN synchrony by photoperiods. Aim 3 will identify a role
for mTORC2 in the circadian clock. We hypothesize that mTORC2 regulates SCN properties by controlling
circadian cytoskeleton reorganization. The proposed work is innovative because it utilizes our latest mouse
genetic models to address conceptually novel questions regarding the role of mTOR in the brain clock. The
contributions of the proposed work are expected to be significant, because it will elucidate fundamental
mechanisms whereby mTOR regulates the function of the circadian clock. Aberrant mTOR activities in the brain
are identified in neurological and psychiatric diseases, which are often accompanied by disrupted daily rhythms
in patients. FDA-approved mTOR inhibitors can cause sleep problems. The proposed research will generate
new knowledge that is essential for a mechanistic understanding of the clinical issues regarding mTOR and
clock/sleep disruptions.

Grant Number: 5R01NS118026-06
NIH Institute/Center: NIH
Principal Investigator: Ruifeng (Ray) Cao