Motomu Shimaoka is a Principal Investigator who leads a
NIH-funded laboratory at the CBR Institute. His
research is focused on understanding the conformational
regulation of integrins in inflammation and developing
novel integrin-targted therapeutics towards autoimmune
and inflammatory diseaes. He received an
ASH-Stratton-Jaffé Fund Scholar Award from the American
Society of Hematology in 2004. Prior to joining the CBR
institute & Harvard Medical, he served as a staff
physician at an ICU in Osaka University Hospital.
Contact:
Phone: 617-278-3272
E-mail: shimaoka@cbrinstitute.org
Assistant Professor
Department Anesthesia, Harvard Medical School
CBR Institute for Biomedical Research
Education :
1989 M.D. Osaka University Medical School
1997 Ph.D. Osaka University Graduate School
2000 Postdoc Harvard Medical School
Positions and Employment
1989-1992 Clinical Fellow, Anesthesa, Osaka Prefecture
Hospital
1992-1993 Clinical Fellow, ICU, Osaka Univ. Hospital
1993-1995 Research Fellow, Anesthesa, Osaka Univ. Med.
School
1995-1998 Instructor, ICU, Osaka Univ. Hospital
1998-2000 Research Fellow, CBR & Dept Pathology,
Harvard
2000-2003 Instructor of Anesthesia, Harvard Medical
School
2003- Assistant Professor of Anesthesia, Harvard
Medical School
Professional Memberships
2007
Ad hoc member, NIH MOSS Study Section
2005 Ad hoc member, NIH MOSS Study Section
Honors
2004
ASH Junior Faculty Scholar Award
Original
articles (selected)
52. Peer, D., Park, E.J., Morishita, Y., Carman,
C.V., Shimaoka, M. 2008 Systemic leukocyte-directed
sirNA delivery revealing cyclin D1 as an
anti-inflammatory target. Science. 2008. 319: 627-630.
51. Park, E.J., Mora, J.R., Carman,
C.V., Chen, JF., Sasaki, Y., Cheng, G., von Andrian,
U.H., Shimaoka, M. Aberrant activation of integrin
alpha4beta7 suppresses lymphocyte migration to the gut.
J. Clin. Invest. 2007. 117:
2526-2538.
50.
Peer, D., Zhu, P., Carman CV., Lieberman, J., Shimaoka,
M. Selective gene silencing in activated leukocytes by
targeting siRNAs to the Integrin lymphocyte
function-associated antigen-1. Proc Natl Acad Sci U. S.
A. 2007. 104: 4095-100.
49. Astrof, N.S., Salas, A., Shimaoka, M., Chen, JF.,
Springer, T.A. The importance of force linkage in
mechanochemistry of adhesion receptors. Biochemistry
2006. 45: 15020-8.
48. Yang, W., Carman, C.V., Kim, M., Salas, A.,
Shimaoka, M., Springer, T.A. A small molecule agonist
of an integrin aLb2. J Biol Chem. 2006. 281: 37904-12.
47. Nishida, N., Xie, C., Shimaoka, M., Cheng, Y.,
Walz, T., Springer, TA. Activation of Leukocyte beta(2)
Integrins by Conversion from Bent to Extended
Conformations. Immunity 2006. 25:583-94.
46. Shimaoka, M., Kim, M., Cohen, E., Yang, W., Astrof,
N., Peer, D., Salas, A., Ferrand, A., Springer, TA.
AL-57, a novel ligand-mimetic antibody to integrin
LFA-1, reveals chemokine-induced affinity upregulation
in lymphocytes. Proc Natl Acad Sci U. S. A. 2006.
38:13991-6
45. Huang, L., Shimaoka, M., Rondon, I., Roy, I.,
Chang, Q., Po, M., Dransfield, D. T., Ladner, R. C.,
Edge, A. S., Salas, A Wood, C. R., Springer, T. A.,
Cohen, E. H. Identification and characterization of a
human monoclonal antagonistic antibody AL-57 specific
for the high affinity form of lymphocyte
function-associated antigen-1. J. Leukoc. Biol. 2006.
80:905-14.
44.
Jin, M., Song, G., Kim, Y.-S., Astrof, N., Shimaoka,
M., Wittrup, D., and Springer, T. A. Directed evolution
to probe protein allestery: integrin I domains of
unprecedented affinity. Proc Natl Acad Sci U. S. A.
2006. 113: 5758-63.
43. Salas, A., Shimaoka, M., Phan, U., Kim, M.,
Springer, T.A. Transition from rolling to firm adhesion
can be mimicked by extension of integrin alpha L beta 2
in an intermediate-affinity state. J Biol Chem. 2006.
281: 10876-82.
42. Song, G., Lazar, GA., Kortemme, T., Shimaoka, M.,
Desjarlais, JR., Baker, D., Springer, TA. Rational
design of ICAM-1 variants for antagonizing integrin
LFA-1-dependent adhesion. J. Biol. Chem. 2006. 281:
5042-9.
41. Zhang, M., Alicot, EM., Chiu, I., Li, J., Verna,
N., Vorup-Jensen, T., Kessler, B., Shimaoka, M., Chan,
R., Friend, D., Mahmood, U., Weissleder, R., Moore,
FD., Carroll, MC. Identification of the target
self-antigens in reperfusion injury. J. Exp. Med. 2006.
203: 141-52.
40. Song, G., Yang, Y., Liu, J-h., Casasnovas, J.M.,
Shimaoka, M., Springer, T.A., Wang, J-h. Structural
basis of ICAM recognition revealed in a complex between
the binding domains of ICAM-3 and integrin
aLb2
at 1.65 Å. Proc. Natl. Acad. Sci. U.S.A. 102: 3366-71,
2005.
39. Vorup-Jensen, T., Carman, C.V., Shimaoka, M.,
Schuck, P., Svitel, J., Springer, T.A. Exposure of
acidic residues as a danger signal for recognition of
fibrinogen and other macromolecules by integrin
aXb2.
Proc. Natl. Acad. Sci. U.S.A. 2005. 102:1614-9.
38. Xie, C., Shimaoka, M., Xiao, T., Schwab, P.,
Klickstein, L.B., Springer, T.A., The integrin a
subunit leg extends at a Ca2+-dependent epitope in the
thigh/genu interface upon activation. Proc. Natl. Acad.
Sci. U.S.A. 101: 15422-7. 2004.
37. Lu, C., Shimaoka,
M., Sales, A., Springer, TA. The mechanism of action
and binding sites for competitive, antagonistic,
allosteric and agonistic antibodies to the I domain of
integrin LFA-1. J Immunol. 173: 3972-8. 2004.
36. Salas A, Shimaoka M, Kogan AN, Harwood C, von
Andrian UH, Springer TA. 2004. Rolling adhesion through
an extended conformation of integrin aLb2 and relation
to aI and b I-like domain interaction. Immunity 2004.
20: 393-406.
35. Yang, W., Shimaoka, M., Salas, A., Takagi, J.,
Springer, TA. Intersubunit signal transmission in
integrins by a receptor-like interaction with a pull
spring. Proc. Natl. Acad. Sci. U.S.A. 2004. 101:
2906-2911.
34. Yang, W., Shimaoka, M., Chen JF., Springer, TA.
Activation of integrin b subunit I-like domains by
one-turn C-terminal a-helix deletions. Proc. Natl.
Acad. Sci. U.S.A. 2004. 101: 2333-2338.
33. Sedeek, K.A., Takeuchi, M., Suchodolski, K.,
Vargas, S.O., Shimaoka, M., Schnitzer, J.J., Kacmarek,
R.M. Open-lung protective ventilation with pressure
control ventilation, high-frequency oscillation, and
intratracheal pulmonary ventilation results in similar
gas exchange, hemodynamics, and lung mechanics.
Anesthesiology 2003. 99: 1102-1111.
32. Shimaoka, M., Salas, A., Yang, W., Weitz-Schmitdt,
G., Springer, TA. Small molecule integrin antagonists
that bind to the b2 subunit I-like domain and activate
signals in one direction and block them in the other.
Immunity 2003 19:391-402.
31. Vorup-Jensen, T., Ostermeier, C., Shimaoka, M.,
Hommel, U., Springer, T.A. Structure and allosteric
regulation of the aXb2 integrin I domain. Proc. Natl.
Acad. Sci. U.S.A. 2003 100: 1873-1878.
30. Shimaoka, M., Xiao,T., Liu,JH, Yang Y., Dong,Y.,
Jun,CD., McCormack, A., Zhang,R., Joachimiak,A.,
Takagi,J., Wang,JH., Springer, TA. Structures of the aL
I domain and its complex with ICAM-1 reveal a
shape-shifting pathway for integrin regulation. Cell.
2003. 112: 99-111.
29. Shimaoka, M., Lu, C., Salas, A., Xiao, T., Takagi,
J., Springer T.A. Stabilizing the aM inserted domain in
alternative conformations with a range of engineered
disulfide bonds. Proc. Natl. Acad. Sci. U.S.A. 2002.
99: 16737-16741.
28. Salas, A., Shimaoka. M., Carman, C.V., Chen S.,
Springer T.A. Transition from rolling to firm adhesion
is regulated by the conformation of the I domain of the
integrin LFA-1. J. Biol Chem 2002. 277: 50255-50262.
27. Takeuchi, M., Goddon, S., Dolhnikoff, M., Shimaoka,
M., Hess, D., Amato M.B.P., Kacmarek, R.M. Set positive
end-expiratory pressure during protective ventilation
affects lung injury. Anesthesiology 2002. 97: 682-92.
26. Ma, Q., Shimaoka, M., Lu, C., Jing, H., Carman,
C.V., Springer, T.A. Activation induced conformational
changes in the I-domain region of LFA-1. J Biol Chem
2002. 277: 10638-10641.
25. Jun, C.D., Carman, C.V., Redick, S.D., Shimaoka,
M., Erickson, H.P., Springer, T.A. Ultrastructure and
function of dimeric, soluble intercellular adhesion
molecule-1 (ICAM-1). J. Biol. Chem. 2001.
276:29019-29027.
24. Sakaue, G., Shimaoka, M., Fukuoka, T., Hiroi, T.,
Inoue, T., Hashimoto, N., Sakaguchi, T., Sawa, Y.,
Morishita, R., Kiyono, H., Noguchi, K., Mashimo, T.
NF-kB decoy suppresses cytokine expression and thermal
hyperalgesia in a rat neuropathic pain model.
Neuroreport. 2001. 12:2079-2084.
23. Jun, C.D., Shimaoka, M., Carman C.V., Takagi, J.,
Springer T.A. Dimerization and the effectiveness of
ICAM-1 in mediating LFA-1-dependent adhesion. Proc.
Natl. Acad. Sci. U.S.A. 2001 98: 6830-6835.
22. Shimaoka, M., Lu, C., Palframan, R., von Andrian,
U., Takagi, J., Springer, T.A. Reversibly locking a
protein fold in an active conformation with a disulfide
bond: integrin aL I-domains with high affinity and
antagonist activity in vivo. Proc. Natl. Acad. Sci.
U.S.A. 2001 98:6009-6014.
21. Lu, C., Shimaoka, M., Zhang, Q., Takagi, J.,
Springer, T.A. Locking in alternative conformations of
the integrin aLb2 I domain with disulfide bonds reveals
functional relationships among integrin domains. Proc.
Natl. Acad. Sci. U.S.A. 2001 98:2393-2398
20. Lu, C., Shimaoka, M., Ferzly, M., Oxvig, C.,
Takagi, J., Springer, T.A. An isolated,
surface-expressed I domain of the integrin aLb2 is
sufficient for strong adhesive function when locked in
the open conformation with a disulfide bond. Proc.
Natl. Acad. Sci. U.S.A. 2001 98:2387-2392
19. Imanaka, H., Shimaoka, M., Matsuura, N., Nishimura,
M., Ohta, N., Taenaka, N., Kiyono, H.
Ventilator-induced lung injury is associated with
neutrophil infiltration, macrophage activation and
TGF-b mRNA upregulation in rat lung. Anesth. Analg.
2001. 92: 428-436.
18. Shimaoka, M., Shifman, J.M., Jing, H., Takagi, J.,
Mayo, S.L., Springer, T.A. Computational design of an
integrin I domain stabilized in the open high affinity
conformation. Nature Struct. Biol. 2000. 7: 674-678.
17. Shimazu, T., Shimaoka, M., Sugimoto, H., Taenaka,
N., Hasegawa, T., & the Osaka HUS Critical Care
Study Group. Does blood type B protect against
haemolytic uraemic syndrome? an analysis of the 1996
Sakai outbreak of Escherichia coli O157:H7 (VTEC O157)
infection. J Infect 2000 41: 45-49.
16. Sugimoto, M., Shimaoka, M., Taenaka, N., Kiyono,
H., and Yoshiya, I. Satellate ganglion block attenuates
lymphocyte activation. Reg Anesth Pain Med 1999 24:
30-35.
15. Shimaoka, M., Hosotsubo, K., Sugimoto, M., Sakaue,
G., Taenaka, N., Yoshiya, I., Kiyono, H. Influence of
surgucal stress on T cells: enhancement of early phase
of lymphocytes activation. Anesth Analg 1998 87:
1431-1435.
14. Iijima, H., Takahashi, I., Hiroi, T., Shimaoka, M.,
Kawano S., Nagano, K., Hori, M., Kiyono, H. Orally
administered cholera toxin prevents murine intestinal T
cell from staphylococcal enterotoxin B-induced anergy.
Gastoenterology 1998, 115: 1197-1204.
13. Nishimura, S., Fujino, Y., Shimaoka, M., Hagihira,
S., Taenaka, N., Yoshiya, I. Circadian secretion
pattern of melatonin after major surgery. J. Pineal.
Res 1998 25: 73-77.
12. Izumi, R,. Shimaoka, M., Nagaoka, C., Komaki, M.,
Mizutani, A., Yoh, M., Honda, T., Taenaka, N., Yoshiya,
I. Effectiveness of hand-disinfection by a flow water
system using electrolytic products of sodium chloride,
compared with a conventional method using alcoholic
solution in a intensive care unit (letter). Critical
Care (Lond) 1998 2: 79-80.
11. Egawa, T., Shimaoka, M., Shimizu, N., Hagihira, S.,
Fujino, Y., Nishimura, S., Taenaka, N., Yoshimime, T.,
Yoshiya, I. A case of multiple aneurysms of the vein of
Galen with heart failure due to persistent fetal
circulation. J. Anesthesia 1998 12: 100-102.
10. Sugimoto, M., Shimaoka, M., Hosotsubo, K.,
Tanigami, H., Taenaka, N., Kiyono, H., and Yoshiya, I.
Upregulation of Fas ligand mRNA expression in
peripheral blood mononuclear cells after major surgery.
Clin Exp Immunol 1998. 112: 120-125.
9. Shimaoka, M., Fujino, Y., Taenaka, N., Hiroi, T.,
Kiyono, H., and Yoshiya, I. High frequency oscillatory
ventilation attenuates the activation of alveolar
macrophage and neutrophil in lung injury. Critical Care
(Lond) 1998. 2: 35-39.
8. Yamada, K., Shimaoka, M., Nagayama, K., Hiroi, T.,
Kiyono, H., and Honda, T. Bacterial invasion induced
interleukin-7 receptor expression in colonic epithelial
cell line, T84. Eur. J. Immunol 1997. 27: 3456-3460.
7. Sugimoto, M., Shimaoka, M., Hagihira, S., Fujino,
Y., Nishimura, S., Kamata, S., Taenaka, N., and
Yoshiya, I. Tension pneumopericardium following
tracheoplasty for congenital tracheal stenosis.
Anaesth. Intens. Care 1997. 25: 539-541.
6. Shimaoka, M., Ikeda, M., Iida, T., Taenaka, N.,
Yoshiya, I., and Honda, T. Fucoidin, a potent inhibitor
of leukocyte rolling, prevents neutrophil influx into
phorbol-ester-induced inflammatory sites in rabbit
lungs. Am. J. Respir. Crit. Care Med. 1996. 153:
307-311.
5. Okuda, Y., Sakoda, S., Shimaoka, M., and Yanagihara,
T. Nitric oxide induces apoptosis in mouse splenic T
lymphocytes. Immunol. Lett. 1996. 52: 135-138.
4. Shimaoka, M., Iida, T., Ohara, A., Taenaka, N.,
Mashimo, T., Honda ,T., and Yoshiya, I. Ketamine
inhibits nitric oxide production in activated
macrophages. Br. J. Anesthesia 1996. 77: 238-242.
3. Shimaoka, M., Yoh, M., Takarada, Y., Yamamoto, K.,
and Honda, T. Detection of the gene for toxic shock
syndrome toxin 1 in Staphylococcus aureus using
enzyme-labeled oligonucleotide probes. J. Med.
Microbiol. 1996. 44: 215-218.
2. Shimaoka, M., Iida, T., Ohara, A., Taenaka, N.,
Mashimo, T., Honda, T., and Yoshiya, I. NOC, a
nitric-oxide-releasing compound, induces dose dependent
apoptosis in macrophages. Biochem. Biophys. Res.
Commun. 1995. 209: 519-526.
1. Shimaoka, M., Yoh, M., Segawa, A., Takarada, Y.,
Yamamoto, K., and Honda, T. Development of
enzyme-labeled oligonucleotide probe for detection of
mecA gene in methicillin-resistant Staphylococcus
aureus. J. Clin. Microbiol. 1994. 32: 1866-1869.
Review articles
4.
Astrof, N.S., Peer, D., Shimaoka, M. Development &
Application of Conformation-Selective Integrin
Antibodies In: Leventhal, M., Gad, S.C., editors.
Development of therapeutic agent, John Wiley &
Sons; 2008 (in press)
3.
Shimaoka, M., Springer, T.A. Therapeutic antagonists
and the conformational regulation of b2 integrin. Curr
Topic Med Chem 2004. 4: 1485-1495.
2. Shimaoka, M., Springer, T.A. Therapeutic antagonists
and the conformational regulation of integrin structure
and function. Nature Rev Drug Discover 2003. 2:
703-716.
1. Shimaoka, M., Takagi, J., Springer, T.A.
Conformational regulation of integrin structure and
function. Annu. Rev. Biophys. Biomol. Struct. 2002. 31:
485-516.