• Sujata Rao, PhD

    Assistant Staff, Opthalmic Research, The Cleveland Clinic

    Research: “Circadian Regulation of Eye Development”

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    Research

    Environmental light is the most pervasive biological stimulus of the visual system and yet the contribution of light towards development of the visual system is poorly understood. My previous research has demonstrated that in mice light is required for the correct formation of the retinal vasculature as well as development of the neurons. Surprisingly, it is the fetus that is light responsive and not the mother and requires the photopigment, melanopsin in the fetus for this pathway to be active. This finding revealed a novel role for environmental light in regulating eye development besides being the stimulus for its function.

    Based on this analysis we now are investigating the following questions which will help us to understand how light can affect eye development and ultimately the function of the eye.

    1. Does light regulate a local circadian clock in the retina.
      At the cellular level, circadian clock is a biological oscillation that has a period of approximately 24hrs. This oscillation is generated through a transcriptional translational feedback loop of a few core genes and their products and the output of clock results in regulation of metabolic and physiological processes. Not much is known about circadian clocks and their function at this stage of eye development so we are investigating the role of some of the known genes which are important for generation and maintenance of circadian clock.
    2. Identify the downstream effectors of light mediated changes
      To fully understand how environmental light might impact eye development it is important to identify the effector/s that are activated by the light and melanopsin signaling. We are using genomic analysis to determine if there are changes that are occurring in retina from animals that were maintained in constant darkness versus animals kept in regular lighting conditions.

      Together the data that we generate from this analysis will help us to identify the molecular pathways that are activated by light during development and how perturbation of these leads to eye diseases. Once we have that information then we can begin to design novel therapeutic targets for these diseases.

    Publications

    1. Length of Day During Early Gestation as an Independent Predictor of Risk for Seever Retinopathy of Prematurity. Ophthalmology, 2013. Yang MB, Rao S, Copenhagen DR, Lang RL
    2. A direct and melanopsin-dependent fetal light response regulates mouse eye development.
    3. Rao S , Chun C, Fan J, Kofron JM, Yang MB, Hegde RS, Ferrara N, Copenhagen DR, Lang RA. Nature. 2013 Feb 14;494(7436):243-6. nature11823. Epub 2013 Jan 16.
    4. Stefater JA 3rd, Rao S, Bezold K, Aplin AC, Nicosia RF, Pollard J, Ferrara N, Lang RA. Macrophage Wnt-Calcineurin-Flt1 signaling regulates mouse wound angiogenesis and repair. Blood. 2013 Jan 9.
    5. Zhong Z, Zylstra-Diegel CR, Schumacher CA, Baker JJ, Carpenter AC, Rao S, Yao W, Guan M, Helms JA, Lane NE, Lang RA, Williams BO. Wntless functions in mature osteoblasts to regulate bone mass PNAS 2012 Aug 14;109(33)197-204.
    6. Stefater JA 3rd, Lewkowich I, Rao S, Mariggi G, Carpenter AC, Burr AR, Fan J, Ajima R, Molkentin JD, Williams BO, Wills-Karp M, Pollard JW, Yamaguchi T, Ferrara N, Gerhardt H, Lang RA. Regulation of angiogenesis by a non-canonical Wnt-Flt1 pathway in myeloid cells. Nature. 2011 May 29;474(7352):511-5
    7. Gordon EJ, Rao S, Pollard JW, Nutt SL, Lang RA, Harvey NL Macrophages define dermal lymphatic vessel calibre during development by regulating lymphatic endothelial cell proliferation. Development. 2010 Nov;137(22):3899-910.
    8. Carpenter AC, Rao S, Wells JM, Campbell K, Lang RA. Generation of mice with a conditional null allele for Wntless. Genesis. 2010 Sep;48(9):554-8.
    9. Lin SL, Li B, Rao S, Yeo EJ, Hudson TE, Nowlin BT, Pei H, Chen L, Zheng JJ, Carroll TJ, Pollard JW, McMahon AP, Lang RA, Duffield JS. Macrophage Wnt7b is critical for kidney repair and regeneration. PNAS. 2010 Mar 2;107(9):4194-9. Epub Feb16
    10. Grandy D, Shan J, Zhang X, Rao S, Akunuru S, Li H, Zhang Y, Alpatov I, Zhang XA, Lang RA, Shi DL, Zheng JJ. Discovery and characterization of a small molecule inhibitor of the PDZ domain of disheveled. Journal of Biological Chemistry, 2009 Jun 12;284 (24):16256-63
    11. Nrarp coordinates endothelial Notch and Wnt signaling to control vessel density in angiogenesis. Phng LK, Potente M, Leslie JD, Babbage J, Nyqvist D, Lobov I, Ondr JK, Rao S, Lang RA, Thurston G, Gerhardt H, Developmental Cell, 2009 Jan; 16(1); 70-82
    12. Rao S, Lobov IB, Vallance JE, Tsujikawa K, Shiojima I, Akunuru S, Walsh K,Benjamin L, Lang RA. Obligatory participation of macrophages in an angiopoietin 2-mediated cell death switch. Development, 2007 Dec;134(24):4449-58. (Cover)
    13. Rao S*, Lobov IB*, Carroll TJ, Vallance JE, Ito M, Ondr JK, Kurup S, Glass DA, Patel MS, Shu W, Morrisey EE, McMahon AP, Karsenty G, Lang RA. WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature.
    14. Nature , 2005 Sep 15;437(7057):417-21. * Authors contributed equally
    15. Green D, Liu L, Lam YC, Mukai L, Rao S, Ramagiri S, Krishnan KS, Engel JE, Lin JJ, Wu CF.Unique biochemical and behavioral alterations in Drosophila shibire(ts1) mutants imply a conformational state affecting dynamin subcellular distribution and synaptic vesicle cycling. Journal of Neurobiology, 2002 Nov 15;53(3):319-29
    16. Rao S, Stewart BA, Rivlin PK, Vilinsky I, Watson BO, Lang C, Boulianne GL, Salpeter MM, Deitcher DL. Two distinct effects on neurotransmission in a temperature-senstive SNAP-25 mutant. EMBO, 2001
    17. Rao S, Lang C, Levitan ES, Deitcher DL. Visualization of neuropeptide expression, transport and exocytosis in Drosophila melanogaster. Journal of Neurobiology,2001
    18. Krishnan KS, Rikhy R, Rao S, Shivalkar M, Mosko M, Narayan R, Etter P, Estes PS, Ramaswami M. Nuecleoside diphosphate kinase, a source of GTP, is required for dynamin dependent synaptic vesicle recycling. Neuron, 2001 Apr;30(1):197-210
    19. Stimson DT, Estes PS, Rao S, Krishnan KS, Kelly LE, Ramaswami M. Drosophila stoned proteins regulate the rate and fidelity of synaptic vesicle internalization. Journal of Neuroscience, 2001 May 1;2 (9):3034-44
    20. Krishnan KS, Chakravarty S, Rao S, Raghuram V, Ramaswami M. Alleviation of the temperature-sensitive paralytic phenotype of shibire (ts) mutants in drosophila by sub-anesthetic concentration of carbon dioxide. Journal of Neurogenetics, 1996 Sept;10(4):221-38
    21. Ramaswami, Rao S, van der Bliek A, Kelly RB, Krishnan KS. Genetic studies on dynamin function in drosophila. Journal of Neurogenetics, 1993 Dec;9(2):73-87

Copyright ©2011 E. Matilda Ziegler Foundation for the Blind