Mimi Shirasu-Hiza, PhD

Mimi Shirasu-Hiza, PhD

Research Interest

Neurobiology of Learning and Memory
Behavioral and Systems Neuroscience: Non-human Models
Cellular, Molecular and Developmental Neuroscience
Neurobiology of Disease

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. 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 infection, 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 have three major foci for our research:  circadian-regulated metabolism and immunity; the function of sleep, which remains a mystery; and the use of time-restricted eating to improve circadian regulation and treat disease (i.e., obesity, aging, neurodegenerative disease.  Circadian biology connects the brain and body.  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

 

• Sick and tired of being sick and tired (circadian metabolism and immunity):  There are two broad categories of defense against bacterial infection, resistance and tolerance.  Resistance mechanisms are classic immune responses responsible for killing pathogenic invaders; tolerance mechanisms are much less well understood and increase the host’s ability to withstand the pathogenic effects of infection (Allen et al, Curr Biol 2015).  We found several novel tolerance mechanisms in Drosophila, all driven by metabolism.  Are they connected by circadian rhythms?  Does it matter for survival what time of day the host thinks it is?

• To sleep, perchance to fast (what is the function of sleep?):  One of the most obvious manifestations of circadian rhythms is sleep.  Almost all animals sleep--but how has this idle behavior persisted through evolutionary time?  How has inactivity not been selected against?  How does sleep contribute to fitness?  While the role of sleep in learning and memory is relatively well-established, the role of sleep in health remains lessl understood.  For Drosophila, we found that sleep plays a role in defense against oxidative stress (Hill et al., PLoS Biol 2018).  More recently, we found that sleep also plays a role in lipid metabolism.  Are these functions connected and if so, how?

• You are when you eat (time-restricted eating as a therapeutic intervention):  We live in an era of unprecedented access to food.  We eat too much and we eat at all hours of the day.  Unfortunately, night-eating is associated with many diseases, including obesity, diabetes, cardiovascular disease, depression, and anxiety.  We and others found that time-restricted eating (eating only during specific hours of the day) increases the amplitude of circadian-regulated gene expression and provides multiple health benefits in both Drosophila and mammals (Ulgherait et al, Nature 2021).  For example, time-restricted eating extends lifespan and delays aging of Drosophila.  Many diseases, from obesity to aging to neurodegenerative diseases, are associated with loss of circadian regulation.  Can we use time-restricted eating to rescue circadian rhythms and improve disease outcomes?  And, as we did with aging, can we use this model to identify the mechanisms driving these health benefits?

  • Timothy Chang (graduate student, Biological Sciences)
  • Andres Martinez-Muniz (graduate student, Genetics)
  • Carly Lam (graduate student, Microbiology and Immunology)
  • Jared Gatto (graduate student, Genetics)
  • Samantha Tener (graduate student, Pathology)
  • Chloe Kim (technician)
  • Susan Landau (lab manager)
  • Matt Ulgherait (postdoc)

1)    Pantalia M, Lin Z, Tener SJ, Qiao B, Tang G, Ulgherait M, O'Connor R, Delventhal R, Volpi J, Syed S, Itzhak N, Canman JC, de la Paz Fernández M, Shirasu-Hiza M. Drosophila mutants lacking the glial neurotransmitter-modifying enzyme Ebony exhibit low neurotransmitter levels and altered behavior. Sci Rep. 2023 Jun 27;13(1):10411. doi: 10.1038/s41598-023-36558-7.PMID: 37369755.

2)    Delventhal R, Wooder ER, Basturk M, Sattar M, Lai J, Bolton D, Muthukumar G, Ulgherait M, Shirasu-Hiza MM.  Dietary restriction ameliorates TBI-induced phenotypes in Drosophila melanogaster. Sci Rep. 2022 Jun 9;12(1):9523. doi: 10.1038/s41598-022-13128-x. PMID: 35681073

3)    Ulgherait M, Midoun AM, Park SJ, Gatto J, Tener SJ, Siewert J, Klickstein N, Canman JC, Ja WW, Shirasu-Hiza M.  Circadian Autophagy Drives iTRF-mediated Longevity.  Nature 2021 Oct;598(7880):353-358. doi: 10.1038/s41586-021-03934-0. Epub 2021 Sep 29.PMID: 3458869.

4)    Ulgherait M, Chen A, McAllister SF, Kim HX, Delventhal R, Wayne CR, Garcia CJ, Recinos Y, Oliva M, Canman JC, Picard M, Owusu-Ansah E, Shirasu-Hiza M.  Circadian regulation of mitochondrial uncoupling and lifespan.  Nature Comm 2020 Apr 21;11(1):1927. doi: 10.1038/s41467-020-15617-x.  PMCID:  PMC7174288.

5)    Delventhal R, O’Connor RM, Pantalia M, Ulgherait M, Kim HX, Basturk M, Canman JC, Shirasu-Hiza M.  Dissection of central clock function in Drosophila through cell-specific CRISPR-mediated clock gene disruption.  Elife. 2019 Oct 15;8. pii: e48308. doi: 10.7554/eLife.48308.  PMCID:  PMC6794090.

6)    Lee M, Sitko A, Khalid S, Shirasu-Hiza M, and Mason C.  Spatiotemporal distribution of glia in and around the developing mouse optic tract.  J of Comp Neurol.  2018 May 9. doi: 10.1002/cne.24462.  PMCID: PMC6226340.

7)    Hill VM, O’Connor RM, Sissoko GB, Irobunda IS, Leong S, Canman JC, Shirasu-Hiza M.  A bi-directional relationship between sleep and oxidative stress in Drosophila.  PLoS Biology 2018 Jul 12;16(7):e2005206. doi: 10.1371/journal.pbio.2005206.  PMCID: PMC6042693.

8)    O'Connor RM, Stone EF, Wayne CR, Marcinkevicius EV, 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.  Journal of Cell Biology 2017 Mar 6;216(3):595-605. doi: 10.1083/jcb.201607093. Epub 2017 Feb 21.  PMCID: PMC5350515.

9)    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.  PMCID:  PMC5356364.

10)  Allen VW, O’Connor RM, Ulgherait M, Zhou CG, Stone EF, Hill VM, Murphy KR, Canman JC, Ja WW, Shirasu-Hiza MM. period-regulated feeding behavior and TOR signaling modulate survival of infection. Current Biology 2015 Dec 29. pii: S0960-9822(15)01490-6. PMCID:  PMC4729625.

11)  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 2012 Jan;8(1):e1002445.  PMCID: PMC3257305. 

For a complete list of publications, please visit PubMed.gov

  • Circadian-regulated metabolism 
  • Glial Development and Pathology 
  • Mitochondria Biology and Disease 
  • Neurogenetics 
  • Neural Degeneration and Repair 
  • Sleep 
  • Bystander Intervention Training, January 2024 (Columbia Sexual Violence Response Office)