Mimi Shirasu-Hiza, PhD
Our laboratory aims to understand how specific circadian-regulated physiological functions contribute to health and disease using Drosophila melanogaster. Circadian rhythm, or the oscillation of biological functions over the 24 hour day, is increasingly recognized as an important factor in human health. Many diseases have a circadian component, particularly inflammatory diseases. For example, you are most likely to have a heart attack at 8 am, flares of rheumatoid arthritis at 6 am, and an asthma attack at 4 am. Moreover, many diseases (bacterial infeciton, Alzheimer's, Parkinson's, Huntington's, bipolar disease, schizophrenia, epilepsy, breast cancer, aging) are associated with loss of circadian regulation. How does loss of circadian regulation accelerate or delay the progression of disease? We found that, in the fly, circadian mutants are immunocompromised against bacterial pathogens and that the immunity of wild-type flies oscillates with circadian rhythm: flies have different survival times depending on the time of day that they are infected. We now have three major foci for our research: innate immune cell function; metabolism; and sleep. Our overarching goal is to use circadian biology as a prism to understand the interaction, coordination, and regulation of complex physiologies in the whole animal that contribute to disease pathology.
“Circadian-regulated physiological functions: how does your circadian clock help you fight disease?"
- BS, Molecular Biophysics and Biochemistry, Yale University
- PhD, Biochemistry and Cell Biology, Univ. of California, San Francisco
- Fellowship: Stanford University School of Medicine
2011 March of Dimes, Basil O'Connor Award
2012 Hirschl Career Award
2016 The Harold and Golden Lamport Award for Excellence in Basic Science Research, CUMC
2011 March of Dimes, Basil O'Connor Award
2012 Hirschl Career Award
2013 NIH R01 GM105775
2013 NIH R01 AG045842
1) Neuroimmunity: How does the brain regulate immunity against infection? 16 neurons in the fly brain are master regulators of circadian rhythm. We are dissecting the molecular pathway from those 16 neurons to peripheral immune cells, working our way from each end by:
a) Defining the neuronal circuits that control circadian immunity
b) Identifying the cell biological mechanisms of immune cells that are circadian-regulated.
2) Novel circadian-regulated immune mechanisms: What non-immune system physiologies significantly affect survival of infection? Why are we more vulnerable to infection when we are tired, depressed, or diabetic? Resistance mechanisms, or mechanisms of the immune system, affect microbial growth. In contrast, tolerance mechanisms affect the organism's ability to tolerate the pathogenic effects of infection. We are identifying tolerance mechanisms associated with:
a) Sleep--why we sleep remains largely mysterious. Does sleep affect immunity against infection and how? We are using new sleep mutants and pharmacological manipulations to probe this relationship.
b) Metabolism--we found that the acute flux of dietary nutrients affects immunity against specific types of infection and are identifying the specific metabolic pathways involved.
3) Neurological disease and immunity: Many neurological disease states, including autism, Alzheimer’s, Parkinson’s, and even aging, lead to both loss of circadian rhythm and misregulation of the immune system. Loss of circadian regulation by genetic or environmental manipulation leads to changes in immunity. Does loss of circadian regulation due to neurological disease also change immunity? And does this immune dysfunction contribute to progression of neurological disease? Drosophila provides an excellent model system for studying many neurological diseases. We are currently focused on three models:
b) Fragile X syndrome (a major cause of autism in humans)
- Meghan Pantalia, graduate student (Genetics)
- Vanessa Hill, graduate student (Integrated Program)
- Melissa Lee, graduate student (Neuroscience)
- Reed O'Connor, graduate student (MSTP)
- Matt Ulgherait, postdoc
- Rebecca Delventhal, postdoc
- Han Kim, technician/lab manager
- Y. Zhuravlev, S. Hirsch, S.N. Jordan, M. Shirasu-Hiza, J. Dumont, and J.C. Canman. 2017. CYK-4 regulates Rac, not Rho, during cytokinesis. Molecular Biology of the Cell (in press).
- O'Connor R.M., Stone E.F., Wayne C.R., Marcinkevicius E.V., Ulgherait M., Delventhal R., Pantalia MM, Hill VM, Zhou CG, McAllister S, Chen A, Ziegenfuss JS, Grueber WB, Canman JC, Shirasu-Hiza MM.A Drosophila model of Fragile X syndrome exhibits defects in phagocytosis by innate immune cells. J Cell Biol 2017 Mar 6;216(3):595-605. doi: 10.1083/jcb.201607093. Epub 2017 Feb 21.
• Highlighted in J Cell Biol: Logan M. Fragile phagocytes: FMRP positively regulates engulfment activity. J CellBiol 2017 Feb 22. doi: 10.1083/jcb.201702034
• Selected as Editors’ Choice in Science Signaling: Mushegian A. Impaired phagocytosis in fragile X. Sci Signal.2017 Apr 4; 10 (473). Doi: 10.1126/scisignal.aan3520
- Sundaramoorthy S, Garcia Badaracco A, Hirsch SM, Park JH, Davies T, Dumont J, Shirasu-Hiza M, Kummel AC, Canman JC.Low efficiency Upconversion Nanoparticles for High-Resolution Coalignment of Near-Infrared and Visible Light Paths on a Light Microscope. . 2017 Feb 21. doi: 10.1021/acsami.6b15322.
- Davies T, Sundaramoorthy S, Jordan SN, Shirasu-Hiza M, Dumont J, Canman JC.Using fast-acting temperature-sensitive mutants to study cell division on Caenorhabditis elegans..2017;137:283-306. doi: 10.1016/bs.mcb.2016.05.004.
- Ulgherait M, Chen A, Oliva MK, Kim HX, Canman JC, Ja WW, Shirasu-Hiza M. Dietary restriction extends the lifespan of circadian mutants tim and per. Cell Metabolism 2016 Dec 13;24(6):763-764. doi: 10.1016/j.cmet.2016.11.002.
- Jordan SN, Davies T, Dumont J, Shirasu-Hiza M, Canman JC. Cortical PAR polarity proteins promote robust cytokinesis during asymmetric cell division. Journal of Cell Biology 2016 Jan 4;212(1):39-49.
- Allen VW, O’Connor RM, Ulgherait M, Zhou CG, Stone EF, Hill VM, Murphy KR, Canman JC, Ja WW, Shirasu-Hiza MMperiod-regulated feeding behavior and TOR signaling modulate survival of infection. Current Biology 2015 Dec 29. pii: S0960-9822(15)01490-6.
- Amaral FE, Parker D, Randis TM, Kulkarni R, Prince AS, Shirasu-Hiza MM, Ratner AJ. Rheostat Control of S. pneumoniae Virulence by Minimal Manipulation of pneumolysin mRNA Folding Free Energy. PLoS One 2015 Mar 23;10(3):e0119823.
- Davies T, Jordan SN, Chand V, Sees JA, Laband K, Carvalho AX, Shirasu-Hiza M, Kovar DR, Dumont J, Canman JC. High-resolution temporal analysis reveals a functional timeline for the molecular regulation of cytokinesis. Developmental Cell 2014 Jul 28;30(2):209-23.
- Stone EF, Fulton BO, Ayres JS, Pham LN, Ziauddin J, Shirasu-Hiza MM. The circadian clock protein Timeless regulates phagocytosis of bacteria in Drosophila. PLoS Pathogens Jan;8(1):e1002445.
• Highlighted in Nature Rev Microbiol 2012 Feb 13;10(3):162.
- Sait M, Kamneva OK, Fay DS, Kirienko NV, Polek J, Shirasu-Hiza MM, Ward NL. Genomic and experimental evidence suggests that Verrucomicrobium spinosum interacts with eukaryotes. Frontiers in Microbiology. 2011 Oct 18;2:211.
- Shirasu-Hiza MM, Dionne MS, Pham LN, Ayres JS, Schneider DS. Interactions between circadian rhythm and innate immunity in Drosophila melanogaster. Current Biology 2007 May 15;17(10):R353-5.
• Highlighted in Nature 447, Research Highlights, 356-357 (24 May 2007)
- Schneider DS, Ayres JS, Brandt SM, Costa A, Dionne MS, Gordon MD, Mabery EM, Moule MG, Pham LN, Shirasu-Hiza MM. Drosophila eiger mutants are sensitive to extracellular pathogens. PLoS Pathogens 2007 Mar; 3(3): e41.
- Pham LN, Dionne MS, Shirasu-Hiza M, Schneider DS. A specific primed immune response in Drosophila is dependent on phagocytes. PLoS Pathogens, 2007 Mar; 3(3):e2
- Dionne MS, Pham LN, Shirasu-Hiza M, Schneider DS. Akt and FOXO dysregulation contribute to infection-induced wasting in Drosophila. Current Biology
- Mitchison TJ, Maddox P, Gaetz J, Groen A, Shirasu M, Desai A, Salmon ED, Kapoor TM.Roles of polymerization dynamics, opposed motors, and a tensile element in governing the length of Xenopus egg extract spindles. Molecular Biology of the Cell 2005 Jun; 16(6): 3064-76.Epub 2005 Mar 23.
- Shirasu-Hiza M, Perlman ZE, Wittmann T, Karsenti E, Mitchison TJ. Eg5 causes elongation of meiotic spindles when flux-associated microtubule depolymerization is blocked. Current Biology 2004 Nov 9; 14(21): 1941-5.
- Shirasu-Hiza M, Coughlin P, Mitchison TJ. Identification of XMAP215 as a Microtubule Destabilizing Factor in Xenopus Egg Extract by Biochemical Purification. Journal of Cell Biology 2003 Apr 28;161(2):349-58.
For a complete list of publications, please visit PubMed.gov
- Circadian-regulated metabolism
- Glial Development and Pathology
- Mitochondria Biology and Disease
- Neural Degeneration and Repair