The synchronous communication among different cell types within a tissue or organism to achieve normal function is poorly understood. A variety of secreted extracellular signals that are generated in discrete tissues often have the potential to impact homeostasis throughout the entire organism. Occasionally, these signals can be destructive: in numerous age-onset neurodegenerative diseases, for example, dysfunction arises in a defined subset of neurons and subsequently initiates a degenerative cascade in peripheral tissues. Yet, signals from one tissue to another can also be constructive and end in the coordinate protection of the organism. Dr. Douglas has identified a transduction signaling component that originates in the nervous system and can confer protection against stress in distally associated tissues. Preliminary studies show that expression of a constitutively-activated Heat Shock transcription Factor, HSF-1, exclusively in the nervous system of the nematode C. elegans: (1) protects against heat stress; (2) slows aging; and (3) detoxifies model-disease proteins in distal tissues. Heat-protection conferred by secreted HSF-1 signals requires a functional thermo- sensory neural circuit and RNA transporters, suggesting that a putative RNA signal is required for its propagation. In contrast, long-lifespan and proteo-detoxification phenotypes require a distinct signaling pathway for their propagation involving the insulin/IGF-1 transcription factor DAF-16. Thus the site and nature of HSF-1 activation in the nervous system specifies its mode of protection against different stressors. In this study, Dr. Douglas will characterize the generation, propagation and ultimate receipt of these extracellular signaling events in a living, intact organism.
In Aim 1, he will identify key neurons which are capable of secreting protective HSF-1 signals and define the participating machinery within those select neurons.
In Aim 2, the identity of each divergent signal will be uncovered.
In Aim 3, cellular factors will be identified within recipient tissues which are required to recognize the different HSF-1 signals and initiate protective programs. Training in the mentored phase will prepare Dr. Douglas to direct an independent lab using the well developed and tractable genetics, neurobiology, and biochemistry of C. elegans to address new questions of biological importance. Training under this award will include: learning to utilize the C. elegans nervous system to study neural-born extracellular signaling events in the intact animal; mass spectrometry techniques in quantitative proteomics which are necessary to identify pertinent signaling molecules and associated machinery; bioinformatic techniques necessary for small RNA profiling and tissue-specific ribosomal profiling; new investigational methods in the fields of protein homeostasis and aging; and mentorship skills such as teaching and grant writing. These will greatly facilitate Dr. Douglas' transition and success as an independent investigator.
The identification of a secreted signal that detoxifies model-disease proteins in distally associated tissues may provide new methods to treat age-onset neurodegenerative diseases caused by genetic mutation or environmental stress. Furthermore, the basic premise that the same signal transduction event occurring in distinct neurons can confer different phenotypic advantages throughout the entire animal opens new avenues of research to explore whether similar signaling mechanisms arise in more highly evolved species.
|Wang, Chensu; Niederstrasser, Hanspeter; Douglas, Peter M et al. (2017) Small-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan. Nat Commun 8:2270|
|Das, Ritika; Melo, Justine A; Thondamal, Manjunatha et al. (2017) The homeodomain-interacting protein kinase HPK-1 preserves protein homeostasis and longevity through master regulatory control of the HSF-1 chaperone network and TORC1-restricted autophagy in Caenorhabditis elegans. PLoS Genet 13:e1007038|
|Arneaud, Sonja L B; Douglas, Peter M (2016) The stress response paradox: fighting degeneration at the cost of cancer. FEBS J 283:4047-4055|
|Douglas, Peter M; Baird, Nathan A; Simic, Milos S et al. (2015) Heterotypic Signals from Neural HSF-1 Separate Thermotolerance from Longevity. Cell Rep 12:1196-1204|
|Baird, Nathan A; Douglas, Peter M; Simic, Milos S et al. (2014) HSF-1-mediated cytoskeletal integrity determines thermotolerance and life span. Science 346:360-3|
|Douglas, Peter M; Dillin, Andrew (2014) The disposable soma theory of aging in reverse. Cell Res 24:7-8|