৾୒တཫೖਭೖ૛ધ൉ୗਙ॑ർखथ ‫୒৾ ص‬ध൉ఇ‫ؚ‬অ४ॿ५भઐਡ ‫ص‬স ༌๒叞ূ਎প৾ প৾੹৶৾௺ଢ଼஢ఐ ে੟ఐ৾௧వ1. ࡣࡌࡵ࡟ࢆ➇࠺࡜࠸࠺ࡼࡾࠊᡭἲࢆ㥑౑ࡋ࡚࡝ࡢࡼ࠺࡞᪂つᴫᛕࡇࡢᗘࡣ௧࿴ඖᖺᗘࡢ᪥ᮏ᫬㛫⏕≀Ꮫ఍ࡢᏛ⾡ዡບࢆ⏕ࡳฟࡍ࠿ࢆ㔜せどࡉࢀ࡚࠸ࡿ࡜ᛮࡗࡓࠋࡑࢀ࡞ࡽࡤࠊ㈹ࢆ㡬ࡁࠊ኱ኚ࡟ගᰤ࡟ឤࡌ࡚࠾ࡾࡲࡍࠋ᫬㛫⏕≀Ꮫ఍᪂⯆ศ㔝ࢆ◊✲ࡍࡿ᪉ࡀ⛉Ꮫⓗ࡟㔜せ࡞஦࡟ࡵࡄࡾ࠶

ࡣࠊಟኈ 1 ᖺ࠿ࡽཧຍࡉࡏ࡚㡬࠸࡚࠾ࡾࠊ⚾࡟࡜ࡗ࡚࣍࠺ࢳࣕࣥࢫࡀ኱ࡁ࠸ࡣࡎࠋࡑࡋ࡚ࠊ኱Ꮫ㝔࠿ࡽ㐍Ꮫࡍࡿ࣮࣒ࡢᏛ఍࡛ࡍࠋ⚾ࡣ῝⏣◊✲ᐊ࡟࡚༤ኈྲྀᚓᚋ࡟ 8 ᖺ◊✲ᐊࢆ࠸ࡃࡘࡶゼၥࡋ࡚࠸ࡿ㐣⛬࡛ࠊᮾி኱Ꮫࡢ῝⏣࡯࡝Ꮫ⾡◊✲ࡢ⌧ሙ࠿ࡽ㞳ࢀࠊ〇⸆఍♫ࡢ᥈⣴◊✲ᡤ࣭ྜྷᏕᩍᤵ࡜ฟ఍ࡗࡓࠋ⸆⌮◊✲ᡤ࡛ࡢ๰⸆◊✲ࠊࡑࡋ࡚ᮏ♫࡟࡚⮫ᗋ◊✲ࡸ〇ရᡓ␎ࡢ௻⏬࣭ᐇ⾜ࢆ⾜ࡗ࡚ࡁࡲࡋࡓࠋ᫖ᖺࡼࡾྂᕢ࡟

3. ࢔࣮ࢳࣇ࢓ࢡࢺၥ㢟࠿ࡽࡢ⥲㛗㈹ᡠࡗ࡚Ꮫ⾡◊✲ࢆ෌㛤ࡋࡓ࡜ࡇࢁ࡛ࠊෆᚰࡣ኱Ꮫ࡛෌ࡧ

2004 ᖺᙜ᫬ࠊࣜࢬ࣒◊✲ศ㔝࡛ࡣ᫬ィ㑇ఏᏊ࣏࣮ࣞ

◊✲࡛ࡁࡿࡶࡢ࠿࡜୙Ᏻ࡛ࡋࡓࠋࡑࡢࡓࡵࠊ௒ᅇࡢཷ㈹ࢱ࣮࡟ࡼࡿ⏕⣽⬊࡛ࡢࣜࢬ࣒ゎᯒ⣔ࡀᬑཬࡋࡘࡘ࠶ࡗࡣ႐ࡧࡶࡦ࡜ࡋ࠾࡛࠶ࡾࠊ⢭⚄ⓗ࡟࡜࡚ࡶບࡳ࡟࡞ࡾࡲࡓ≧ἣ࡛࠶ࡾࠊࢱࣥࣃࢡ㉁ࡢ⏕໬Ꮫゎᯒࢆᚓព࡜ࡍࡿ῝ࡍࠋᮏ✏ࡢㄞ⪅ࡣᏛ⏕ࡶከࡃࠊ᫬㛫⏕≀Ꮫࡔࡅ࡛࡞ࡃ༞⏣◊✲ᐊ࡛ࡶࡑࡢᐇ㦂⣔ࢆ❧ࡕୖࡆࡼ࠺࡜ࡋ࡚࠸ࡓࠋࡑᴗᚋࡢ㐍㊰ࡸ࢟ࣕࣜ࢔タィ࡞࡝ࢆ᪥ࠎ⪃࠼ࠊᏛእࡢ᝟ሗࡇ࡛ࠊ῝⏣ඛ⏕࠿ࡽ᭱ึ࡟㡬࠸ࡓࢸ࣮࣐ࡣࠊ᫬ィ㑇ఏᏊࢆ཰㞟ࡋ࡚࠸ࡿ࡜ᛮ࠸ࡲࡍࠋ⚾ࡢࡇࢀࡲ࡛ࡢ⎔ቃ࡛ࡢ⤒ࡢⓎ⌧ࣜࢬ࣒ࢆࣝࢩࣇ࢙࣮ࣛࢮ࣏࣮ࣞࢱ࣮࡟࡚ࣜ࢔ࣝ㦂ࡸࡑࡢ᫬࡟⪃࠼ࡓࡇ࡜ࢆ⤂௓ࡍࡿࡇ࡜࡛ࠊఱ࠿ࡢ࠾ᙺࢱ࢖࣒࡟❧࡚ࢀࡤᖾ࠸࡛ࡍࠋ῝⏣ඛ⏕ࠊᘅ⏣ Ẏඛ⏕㸦⌧ ྡྂᒇ኱Ꮫ ≉௵෸ᩍᤵ㸧ᐃࡍࡿ⣽⬊ᐇ㦂⣔ࢆ❧ࡕୖࡆࡿࡇ࡜࡛࠶ࡗࡓࠋ࡜࡜ࡶ࡟ࠊẖ㐌ࠊ⣽⬊ࣜࢬ࣒ࢹ࣮ࢱࡀฟ࡚ࡁ࡚ࡣ㆟ㄽࡋࠊ
2. ᪂⯆ศ㔝࣭ᴫ᪥᫬ィࡢศᏊ⏕≀Ꮫᐇ㦂ࡢ᮲௳᳨ウἲ࡜࡜ࡶ࡟ࣜࢬ࣒ࡢᇶᮏⓗ࡞ᛶ㉁ࢆᏛ

⚾ࡀ᫬㛫⏕≀Ꮫࡢୡ⏺࡟ධࡗࡓࡁࡗ࠿ࡅࡣࠊ኱Ꮫ㝔࡛ࢇࡔࠋࡑࡢ᳨ウࡢ㝿࡟അ↛ࠊᇵᆅ pH ࢆኚ໬ࡉࡏࡿ࡜ࠊࡢ◊✲ࢸ࣮࣐ࢆ⪃࠼࡚࠸ࡓ༓ⴥ኱Ꮫ⸆Ꮫ㒊ࡢ 4 ᖺ⏕᫬⣽⬊᫬ィࡢ఩┦ࡀࣜࢭࢵࢺࡍࡿࡇ࡜ࢆぢฟࡋࡓࠋ⮬ศࡢ

㸦2003 ᖺ㸧ࠊᴫ᪥᫬ィࡢศᏊ⏕≀Ꮫࡀ㠀ᖖ࡟࣍ࢵࢺ࡞ศ⊂⮬ᛶࢆ᥈ࡋ࡚࠸ࡓ᫬ᮇ࡛࠶ࡗࡓࡓࡵࠊࡑࡢⓎぢࢆ㏣ồ㔝ࡔࡗࡓ࠿ࡽ࡛࠶ࡿࠋ࣡ࢡ࣡ࢡࡍࡿࡇ࡜ࢆồࡵ࡚ẖ᪥ࢆࡉࡏ࡚ḧࡋ࠸࡜῝⏣ඛ⏕࡟࠾㢪࠸ࡋࡓࠋ῝⏣◊✲ᐊࡢ◊㐣ࡈࡋ࡚࠾ࡾࠊ኱Ꮫ 1, 2 ᖺ⏕ࡢ㡭ࡣ㸦Ꮫၥࡼࡾࡶ㸧ࣇࣜ✲ሗ࿌ࢭ࣑ࢼ࣮࡛ࡣࠊ኱Ꮫ㝔⏕ࢆ୰ᚰ࡜ࡍࡿⓎ⾲⪅ࡣ⛉࣮ࢫࢱ࢖࡛ࣝ࢜ࣜࢪࢼࣜࢸ࢕࣮ࢆ㏣ồࡍࡿ࢚ࢡࢫࢺࣜᏛⓗᢈุࢆ⊛Ⅿ࡟ཷࡅ࡚⮬ศࡢဴᏛࢆ☻ࡁୖࡆ࡚࠸ࡃࠋ

࣮࣒ࢫ࣏࣮ࢶ㸦BMX ࣇࣛࢵࢺࣛࣥࢻ㸧࡟ࡢࡵࡾ㎸ࢇ࡛᱌ࡢᐃࠊ⚾ࡶࠕ⏕య࣓࣍࢜ࢫࢱࢩࢫࡢ௦⾲౛࡜ࡶゝ࠼ࡿ࠸ࡓࠋ௒ࡢࡼ࠺࡟ SNS ࡣ↓࠿ࡗࡓࡓࡵࠊே࡙࡚࡟⦎⩦pH ࢆ in vitro ࡛ኚ໬ࡉࡏ࡚ほᐹࡉࢀࡓ஦㇟࡟ࠊఱࡢ⏕௰㛫ࢆቑࡸࡋ࡚᝟ሗࢆ㞟ࡵ࡚࠸ࡓࡢࡔࡀࠊᙜ᫬࠿ࡽᯟ⤌⌮ⓗព࿡ࡀ࠶ࡿࡢ࠿ࠖ࡜࠸࠺ᢈุࢆཷࡅࡓࠋ☜࠿࡟ࠊ࢔ࡳࡢ↓࠸୰࡛ࡢヨ⾜㘒ㄗࢆዲࡴᛶ᱁ࡔࡗࡓࠋ኱Ꮫ 3 ᖺ࣮ࢳࣇ࢓ࢡࢺࡢྍ⬟ᛶࡀ࠶ࡿ⌧㇟ࢆ⮬㌟ࡢ༤ኈ◊✲ࢸ⏕࡟࡞ࡗ࡚࠿ࡽࠊᏊ౪ࡢ㡭࠿ࡽ◊✲⪅࡟࡞ࡿࡇ࡜ࢆỴࡵ࣮࣐࡜ࡋ࡚㏣࠺ࡇ࡜࡟୙Ᏻࢆឤࡌࡓࠋࡋ࠿ࡋࠊࡑࡢ᫬ィ࡚࠸ࡓࡢ࡛ࠊ⯆࿡ࡢ࠶ࡿศᏊ⏕≀Ꮫࡸ⸆⌮Ꮫࠊ⚄⤒⛉Ꮫࣜࢭࢵࢺస⏝ࡣ㠀ᖖ࡟ᙉ࠿ࡗࡓࡓࡵࠊࡁࡗ࡜ᴫ᪥᫬ィࡢࢆ୰ᚰ࡟ᡭᙜࡓࡾḟ➨࡟⮬Ꮫࢆ㐍ࡵࡓࠋ4 ᖺ⏕࡟࡞ࡗ࡚㔜せ࡞࣓࢝ࢽࢬ࣒ࡢⓎぢ࡟ࡘ࡞ࡀࡿࡢ࡛ࡣ࡞࠸࠿࡜࠸◊✲ࡢୡ⏺ࢆࡢࡒ࠸ࡓ࡜ࡁ࡟ࠊ⊂⮬ᛶࡀ㈹㈶ࡉࢀࡿୡ⏺

࠺ᮇᚅࡢ᪉ࡀ኱ࡁ࠿ࡗࡓࠋఱࡼࡾࠊࡑࡢࢸ࣮࣐ࡣ⮬ศ⮬࡛࠶ࡿࡇ࡜ࢆ▱ࡗ࡚ᚰࡀ㋀ࡗࡓࠋࡑࡋ࡚ࠊᐇ㦂ⓗ࡞ᡭἲ㌟ࡀ㏣ồࡋ࡞ࡅࢀࡤࠊୡ⏺࡛ㄡࡶ᫂ࡽ࠿࡟ࡍࡿࡇ࡜ࡣ࡛ࡣ◊✲ᐊ࡟ࡼࡗ࡚኱ࡁࡃࡣኚࢃࡽ࡞࠸ࡢ࡟ࠊศ㔝࡟ࡼࡗࡁ࡞࠸ࠋࡑࢀࡣ⣲ᬕࡽࡋ࠸ࢳࣕࣥࢫ࡞ࡢ࡛ࡣ࡜⪃࠼ࡓࠋ࡚⤖ᯝࡢ㔜せᛶࡀ኱ࡁࡃ㐪࠺஦ࢆឤࡌࡓࠋᡭἲࡑࡢࡶࡢ

ᇵᆅ pH ࡟ࡼࡿ᫬ィࣜࢭࢵࢺࡢ㝿࡟Ⓨ⌧ኚືࡍࡿ᫬ィ‫ ݩ‬naohiro.kon@bs.s.u-tokyo.ac.jp
᫬㛫⏕≀Ꮫ
34

Vol. 26, No. 1 (2020)ᮎᲈ᫬ィࡢ᫬้ࣜࢭࢵࢺࢩࢢࢼࣜࣥࢢ࡜ࡋ࡚ᶵ⬟ࡍࡿࡇ࡜ࢆ♧ࡋࡓ 3ࠋ⤖ᯝ࡜ࡋ࡚ࠊᙜึ㐍ࡵࡿ࠿ᝎࢇ࡛࠸ࡓ◊✲ࢸ࣮࣐ࡣࠊᖾ㐠࡞ࡇ࡜࡟༤ኈ༞ᴗ᫬࡟ࡣᮾி኱Ꮫ⥲㛗㈹ࡢཷ㈹ㄽᩥ࡜࡞ࡾࠊಟኈࡢ᫬ࡢỴ᩿ࡀ᭱㧗ࡢᙧ࡛ሗࢃࢀࡓࠋ᭱㏆ࠊ኱Ꮫ㝔⏕࡜ヰࡍ୰࡛ࠊ◊✲⪅࡜ࡋ࡚ࡢ⬟ຊࡸ◊✲ࢸ࣮࣐࡟㛵ࡋ࡚୙Ᏻࢆ⪺ࡃࡇ࡜ࡀ࠶ࡿࠋᐇࡣ⚾ࡢ኱Ꮫ㝔⏕᫬௦ࡶ㸦௒ࡶ㸧୙Ᏻࡔࡽࡅ࡛ࠊ⮬ಙࢆᣢࡗ࡚◊✲ࢆ㐍ࡵ࡚࠸ࡿࢃࡅ࡛ࡣ࡞࠸ࠋࡓࡔࠊ୙Ᏻࢆᣢࡘࡇ࡜ࡣࠊ┠ࡢ๓ࡢㄢ㢟࡟࡝ࢀࡔࡅ┿ᦸ࡟ྲྀࡾ⤌ࡴ࠿ࡢጼໃ࡟
ࡘ࡞ࡀࡿ࡜ᛮ࠺ࠋඛ⾜◊✲ࢆ࡝ࢀࡔࡅ⢭ᰝࡋ࡚⮬ศࡢ⪃࠼᪉ࡢ࣮࣋ࢫ࡟ࡍࡿ࠿ࠊ⮬㌟ࡀ❧࡚ࡿᐇ㦂ィ⏬ࢆ࡝ࢀࡔࡅ⥥ᐦ࡟ࡍࡿ࠿ࠊ୍ࡘࡢᐇ㦂࠿ࡽᚓࡽࢀࡓ⤖ㄽࢆ௚ࡢᐇ㦂⣔࡛ࡶ᳨ドࡋࠊ࡝ࢀ࡯࡝ࡋࡗ࠿ࡾࡋࡓ⛉Ꮫⓗ⤖ㄽࢆᑟࡃ࠿ࠋᙜࡓࡾ๓ࡢࡇ࡜࡞ࡢࡔࡀࠊಙ㢗ᛶࡢ㧗࠸ࢹ࣮ࢱࢆᚓࡿࡇ࡜ࠊࡑࢀࢆከゅⓗ࡟ྫྷ࿡ࡋ࡚㐍ࡵࡿ⛉Ꮫⓗጼໃࡀᅗ 1 ᫬ィࣜࢭࢵࢺࢆᢸ࠺ TGF-ȕ-SMAD-Dec1 ࢩࢢࢼࣜࣥࢢ㑇ఏᏊ⩌ࢆ⥙⨶ⓗ࡟ゎᯒࡋࡓ࡜ࡇࢁࠊbHLH ᆺ㌿෗ᅉᏊࢆࢥ࣮ࢻࡍࡿ Dec1 㑇ఏᏊࡀᛴᛶㄏᑟࡉࢀࡿࡇ࡜ࢆᑡࡋࡎࡘ୙Ᏻࢆྲྀࡾ㝖࠸࡚ࡃࢀࡿࡢ࡛ࡣ࡞࠸ࡔࢁ࠺࠿ࠋ
4. ᶵ⬟ⓗࣛࣥࢲ࣒ࢫࢡ࣮ࣜࢽࣥࢢ-᥈⣴◊✲ࡢ⋤㐨࡜ࡋ࡚-ぢฟࡋࡓࠋDec1 ࡣ໭ᾏ㐨኱Ꮫࡢᮏ㛫 ࡉ࡜ඛ⏕ࡽ᪥ᮏே

Dec1 ◊✲ࢆ㐍ࡵ࡚࠸ࡿ㐣⛬࡛ࠊᇵ㣴⣽⬊ࡢࣜࢬ࣒◊✲⪅ࡀⓎぢࡋࡓ᫬ィ㑇ఏᏊ࡛࠶ࡿࡀ 1ࠊᴫ᪥᫬ィ࡟࠾ᐃ⣔ࡣࠊᮍ▱ᅉᏊࢆᶵ⬟ⓗ࡟ྠᐃࡍࡿࢫࢡ࣮ࣜࢽࣥࢢ⣔࠸࡚࡝ࡢࡼ࠺࡞⏕⌮ⓗᒁ㠃࡛ാ࠸࡚࠸ࡿࡢ࠿ㅦࡀከ࠿࡜ࡋ࡚ᙉຊ࡛࠶ࡿࡇ࡜ࢆឤࡌ࡚࠸ࡓࠋࡑࡇ࡛ࠊ῝⏣◊࡟ࡗࡓࠋࡑࡢࡓࡵࠊDec1 ࡀ᫬ィࣜࢭࢵࢺ࡟ᶵ⬟ⓗ࡟㛵୚࠶ࡗࡓ࢟ࢼ࣮ࢮ㜼ᐖ๣ࢆᡭᙜࡓࡾḟ➨࡟ホ౯ࡋࡓ࡜ࡇࡍࡿࡇ࡜ࢆ♧ࡍࡢࡣ㔜せ࡞ព⩏ࡀ࠶ࡿ࡜ᛮ࠼ࡓࠋDec1ࢁࠊ࿘ᮇࢆ㛗ࡃࡍࡿ໬ྜ≀ࡸ▷ࡃࡍࡿ໬ྜ≀ࢆ࠸ࡃࡘ࠿ㄏᑟࢆᣦᶆ࡟ࢩࢢࢼࣝఏ㐩࡟㛵ࢃࡿ⸆๣ࢆࢫࢡ࣮ࣜࢽぢฟࡋࡓ 4ࠋࡑࡋ࡚⸆๣ࢫࢡ࣮ࣜࢽࣥࢢࡢ୰࡛ࠊ၏୍⣽ࣥࢢࡋࡓ࡜ࡇࢁࠊࢺࣛࣥࢫࣇ࢛࣮࣑ࣥࢢᡂ㛗ᅉᏊ⬊ࣜࢬ࣒ࢆ೵Ṇࡉࡏࡓ໬ྜ≀࡜ࡋ࡚ࠊCa2+/calmodulin-

㸦TGF㸧-ǃ ࡢཷᐜయ࢟ࢼ࣮ࢮ㜼ᐖ๣㸦ALK4/5/7 㜼ᐖ๣㸧

dependent protein kinase㸦CaMK㸧II 㜼ᐖ๣࡛࠶ࡿ

SB431542 ࡢᏑᅾୗ࡛ࠊpH ࡟ࡼࡿ Dec1 ㄏᑟ࡜᫬ィࣜ

KN93 ࢆぢฟࡋࡓࠋᙜ᫬ࠊCLOCK ࡸ BMAL1 ࡟ᑐࡋ࡚ࢭࢵࢺࡀ㜼ᐖࡉࢀࡿࡇ࡜ࡀศ࠿ࡗࡓࠋࡉࡽ࡟ゎᯒࢆ㐍ࡵඃࢀࡓᢠయࢆస〇ࡋ࡚࠸ࡓඛ㍮ࡢྜྷ✀ ගࡉࢇ㸦⌧ᮾிࡿ࡜ࠊᇵᆅ pH ኚ໬ࡣ⣽⬊እ࣐ࢺࣜࢵࢡࢫ࡟Ꮡᅾࡍࡿ₯኱Ꮫ ຓᩍ㸧࡟⏕໬Ꮫⓗ࡞࢔ࢻࣂ࢖ࢫࢆࡶࡽ࠸ࠊCaMKIIᅾᆺ㸦୙άᛶᆺ㸧TGF-ǃ ࢆάᛶᆺ࡟ኚ໬ࡉࡏࡿࡇ࡜࡛

ࡣ CLOCK ࢆࣜࣥ㓟໬ࡍࡿࡇ࡜ࡸࠊCLOCK ࡜ BMAl1Dec1 ࢆㄏᑟࡍࡿ࡜࠸࠺ࢩࢢࢼࣝఏ㐩⤒㊰ࡀぢ࠼࡚ࡁࡓࡢ࣊ࢸࣟ஧㔞య໬ࢆಁ㐍ࡍࡿࡇ࡜ࢆぢฟࡋࡓࠋࡑࡋ࡚໭㸦ᅗ 1㸧ࠋTGF-ǃ ࡢάᛶ໬ᵝᘧࡣ࠿࡞ࡾ≉Ṧ࡛ࠊ⣽⬊እᾏ㐨኱Ꮫࡢྜྷᕝ ᭸Ꮚඛ⏕㸦⌧ ㏆␥኱Ꮫ ຓᩍ㸧ࠊᮏ㛫࡟ศἪࡉࢀ࡚ࡶ୙άᛶᆺ࡛ᚅᶵࡋ࡚࠸ࡿࠋpH ࡞࡝ࡢ≀◊୍ඛ⏕ࠊᮏ㛫 ࡉ࡜ඛ⏕࡟యෆ᫬ィ୰ᯡ࡛࠶ࡿど஺ཫ⌮่⃭࡟ᛂࡌ࡚άᛶ໬ࣇ࢛࣮࣒࡟࡞ࡿࡇ࡜ࡣࠊ⒴⣽⬊ศୖ᰾㸦SCN㸧࡟࠾ࡅࡿ CaMKII ࡢゎᯒ࡟㛵ࡋ࡚ඹྠ◊㔝࡛ྂࡃ࠿ࡽ◊✲ࡉࢀ࡚࠸ࡓ 2ࠋࡑࡋ࡚ࠊTGF-ǃ ࡢ௚࡟✲ࢆ࠾㢪࠸ࡋࡓࠋࡑࡢᙜ᫬ࡣ 2009 ᖺ 3 ᭶࡛ࠊ⚾ࡣ༤ኈⓎ⏕࡟㛵୚ࡍࡿᅉᏊ࡛࠶ࡿ࢔ࢡࢳࣅࣥࡶࠊ࢔ࢡࢳࣅࣥཷ

ࢆಟ஢ࡋ࡚ 4 ᭶࠿ࡽࡣ〇⸆఍♫࡟ධ♫ࡍࡿ࡜࠸࠺❧ሙ

ᐜయᵝ࢟ࢼ࣮ࢮ㸦ALK㸧ࢩࢢࢼࣜࣥࢢࢆ௓ࡋ࡚⣽⬊᫬ィ࡛࠶ࡗࡓࡶࡢࡢࠊᮏ㛫◊࡟࡚ SCN ࡢ⬻ࢫࣛ࢖ࢫస〇ἲࢆࣜࢭࢵࢺࡍࡿࡇ࡜ࡀศ࠿ࡗࡓࠋࡇࡢ᫬Ⅼ࡛ࠊᇵᆅ pHࢆ࠶ࡓࡓ࠿ࡃࡈᣦᑟ࠸ࡓࡔ࠸ࡓࠋSCN ࡢࢩࣥࢢࣝࢭࣝ࡜࠸࠺࢔࣮ࢳࣇ࢓ࢡࢺឤࡢ࠶ࡿ◊✲ࡣࠊTGF-ǃ ࡸ࢔ࢡ࡛ࣞ࣋ࣝࡢࣜࢬ࣒࢖࣓࣮ࢪࣥࢢࢆ┠ࡢᙜࡓࡾ࡟ࡋ࡚ࠊ᫬ࢳࣅࣥ࡜࠸ࡗࡓࢩࢢࢼࣝఏ㐩ศ㔝ࡢ㔜㙠࡜᪂ࡋ࠸᫬ィィ୰ᯡࡢືⓗ࡞⨾ࡋࡉ࡟኱ኚ࡟ឤືࡋࡓࡢࢆぬ࠼࡚࠸㑇ఏᏊ Dec1 ࡢᶵ⬟ࢆ㏣ồࡍࡿ◊✲࡟ࢫ࢖ࢵࢳࡋ࡚࠾ࡿࠋࡑࡢゎᯒࡢ⤖ᯝ࡜ࡋ࡚ࠊCaMKII ࡣ⣽⬊ෆࡢ᣺ືไࡾࠊ㛤ጞᙜึᝎࢇ࡛࠸ࡓ࢔࣮ࢳࣇ࢓ࢡࢺၥ㢟ࡶẼ࡟࡞ࡽᚚࡔࡅ࡛࡞ࡃࠊSCN ࡢ⣽⬊㛫࢝ࢵࣉࣜࣥࢢ࡟ࡶ㛵ࢃࡿ࡞ࡃ࡞ࡗ࡚࠸ࡓࠋࡑࡢᚋࠊᗈᓥ኱ᏛࡢἙᮏ ೺ඛ⏕ࠊຍࡇ࡜ࡀศ࠿ࡗࡓࠋࡑࡢᚋࠊCaMKIIǂ ࢟ࢼ࣮ࢮࢹࢵࢻࣀ⸨ ᖾኵඛ⏕ࡼࡾ Dec1 ࣀࢵࢡ࢔࢘ࢺ࣐࢘ࢫࢆඹྠ◊✲ࢵࢡ࢖࣐ࣥ࢘ࢫࢆ⏕⌮Ꮫ◊✲ᡤࡢᒣ⫪ ⴥᏊඛ⏕࡜ࡢඹ࡟࡚ධᡭࡋࠊTGF-ǃ ࢩࢢࢼࣜࣥࢢࡀ⏕యෆ࡟࠾࠸࡚ࡶྠ◊✲࡟ࡼࡾゎᯒࡋࠊᙜヱ࣐࢘ࢫࡣ㍯ᅇࡋ⾜ືࣜࢬ࣒ࡢ᫬㛫⏕≀Ꮫ

Vol. 26, No. 1 (2020)35㛗࿘ᮇ໬ࡸࣜࢬ࣒ᾘኻࢆ♧ࡍࡇ࡜ࢆぢฟࡋࡓ 5ࠋ⯆࿡῝ࢡࣜࣇ࡜࿧ࢇ࡛᪂⸆࣓࣮࣮࢝ࡣᜍࢀ࡚࠸ࡿࠋ᪂⸆࣓࣮࢝࠸ࡇ࡜࡟ࠊCaMKIIǂ ኚ␗࣐࢘ࢫࡣࠊᮅࡢ⾜ື࡜ኪࡢ⾜࣮ࡀ⏕ࡁṧࡿࡓࡵ࡟ࡣࠊ་⒪⤒῭ⓗ࡟ព࿡ࡢ࠶ࡿ᪂⸆ࢆືࡢ⮬⏤⥅⥆࿘ᮇࡀゎ㞳ࡍࡿ࡜࠸࠺⌋ࡋ࠸⾲⌧ᆺࢆ♧ୖᕷࡋ⥆ࡅࡿࡋ࠿࡞࠸ࡢࡔࡀࠊᕷሙ࡟ࡣ᪤࡟ከࡃࡢ⸆ࡀࡋࡓࠋ2 ᣺ືయࣔࢹࣝࡢศᏊ⏕⌮ᇶ┙ࢆ㏣ồࡍࡿᮏ㛫◊Ꮡᅾࡋ࡚࠾ࡾ⡆༢࡛ࡣ࡞࠸ࠋࡑࡇ࡛ࠊ㏆ᖺከࡃࡢࣅࢪࢿ

✲ᐊ࡜ࡢඹྠ◊✲ࡢ୰࡛ࠊ⾜ືࢆไᚚࡍࡿ」ᩘ᣺ືయࡢ

ࢫࢽ࣮ࣗࢫ࡜ࡋ࡚ሗ㐨ࡉࢀ࡚࠸ࡿᵝ࡟ࠊ᪂⸆࣓࣮࣮࢝ࡣ

࢝ࢵࣉࣜࣥࢢ࡟ CaMKII ࡀ㛵ࢃࡿࡇ࡜ࢆぢฟࡏࡓࡢࡣ⫧኱໬ࡋࡓ⤌⧊ࢆ⦰ᑠࡍࡿࡓࡵ࡟ᗘ㔜࡞ࡿேဨ๐ῶࢆ

Ꮀࡋ࠿ࡗࡓࠋࡑࡢᚋࠊ2016 ᖺ࡟ CaMKII ࡣࣘࢫࣜ࢝㸦᪻⾜ࡗ࡚࠸ࡿࠋࡑࡢࡓࡵࠊ◊✲⪅ࡀࡌࡗࡃࡾ࡜๰⸆◊✲࡛⹸㸧ࡢᴫ᪥࣭ᴫ᭶ࣜࢬ࣒ᶵ⬟ 6ࠊ࣐࢘ࢫࡢ╧╀ 7 ࡸ᝟ືࡁࡿ≧ἣ࡛ࡣ࡞ࡃ࡞ࡗ࡚ࡁ࡚࠸ࡿࠋ2016 ᖺࠊ⚾ࡣேဨ

8 ࡜ࡢ㛵㐃ࡶሗ࿌ࡉࢀࠊࣜࢬ࣒㛵㐃࢟ࢼ࣮ࢮ࡜ࡋ࡚ࡢ㔜๐ῶࡀ㐍ࡴ◊✲ᡤ࠿ࡽᮏ♫ࡢ᪂タ㒊⨫ࡢ❧ࡕୖࡆ࣓ࣥ

せᛶࡀ⊂❧ࡋࡓ◊✲ᐊ࡟ࡼࡗ࡚☜❧ࡋࡓࠋᴫ᪥᫬ィ࡟㛵ࣂ࣮࡜ࡋ࡚࿧ࡤࢀࡿࡇ࡜࡟࡞ࡗࡓࠋ⏕࿨⛉Ꮫࡸ⸆⌮ࡢ▱ࢃࡿ㑇ఏᏊࣁࣥࢸ࢕ࣥࢢࡣࠊ㔜せ࡞ศᏊࡢ࡯࡜ࢇ࡝ࡣ㡰㆑ࡋ࠿ᣢࡕྜࢃࡏ࡚࠸࡞࠿ࡗࡓࡓࡵࠊ࠶ࢃ࡚࡚ኪ㛫࡟᪩㑇ఏᏛ࡟ࡼࡗ࡚Ⓨぢࡉࢀ࡚࠸ࡿࠋCaMKII ࡢሙྜࠊ᏶඲✄⏣኱Ꮫࣅࢪࢿࢫࢫࢡ࣮ࣝ࡟㏻࠸ࠊ⤒Ⴀ࡟㛵ࢃࡿయ⣔ⓗḞᦆࡣࢩࣙ࢘ࢪࣙ࢘ࣂ࢚ࡸ࣐࢘ࢫ࡛ࡣ⮴Ṛ࡛࠶ࡿ࡜⪃࡞▱㆑ࢆᏛࢇࡔࠋᮏ♫࡛ࡣ᪂⸆⮫ᗋ◊✲࡜〇ရᡓ␎࡟ᦠ࠼ࡽࢀ࡚࠸ࡿࡓࡵࠊ㡰㑇ఏᏛ࡛ࡣྲྀࡾ࡙ࡽ࠸㑇ఏᏊ࡞ࡢࢃࡾࠊ㦵἞⒪㡿ᇦ࡟࠾ࡅࡿ⮫ᗋ⸆⌮◊✲ࢆぢࡼ࠺ぢࡲࡡ࠿ࡶࡋࢀ࡞࠸ࠋࡇࡢⅬࠊ⣽⬊࡛ࡢ⸆⌮ࢫࢡ࣮ࣜࢽࣥࢢࡣࠊ࡛㐍ࡵࡓ 12ࠋ⣽⬊ࡉ࠼⏕Ꮡࡋ࡚࠸ࢀࡤࠊಶయ࡛ࣞ࣋ࣝࡢ⮴Ṛၥ㢟ࢆᅇ఍♫࡛ࡣ๰⸆࠿ࡽ⮫ᗋ◊✲ࠊࣅࢪࢿࢫࡲ࡛ᦠࢃࡗࡓࡀࠊ㑊࡛ࡁࡿࠋ࠸ࡎࢀ࡟ࡏࡼࠊᶵ⬟ࢆᣦᶆ࡜ࡋࡓࣛࣥࢲ࣒ࢫධ♫๓࡟ᢪ࠸࡚࠸ࡓ␲ၥ ࠕ࡞ࡐᇶ♏⛉Ꮫࡀࡇࢀ࡯࡝ࡢࢡ࣮ࣜࢽࣥࢢࡣ᪂つศᏊࣁࣥࢸ࢕ࣥࢢࡢ⋤㐨࡛࠶ࡿࡇࢫࣆ࣮ࢻ࡛Ⓨᒎࡋ࡚࠸ࡿࡢ࡟ࠊ᪂⸆㛤Ⓨࡣᅔ㞴࡟࡞ࡗ࡚࡜ࢆ㌟ࢆࡶࡗ࡚Ꮫࢇࡔ⤒㦂࡜࡞ࡗࡓࠋࡁ࡚࠸ࡿࡢ࠿㸽ࠖ࡜࠸࠺␲ၥࡣࠊ࠸ࡃࡘ࠿⌮⏤ࡀぢ࠼ࡓẼࡀࡍࡿࠋᇶ♏⛉Ꮫศ㔝࡟㛵ࢃࡿ஦࡜ࡋ࡚ࡣࠊࢺࢵࣉࢪ

5. 〇⸆௻ᴗ࡬

࣮ࣕࢼࣝ࡟ᥖ㍕ࡉࢀࡿ་Ꮫᡂᯝࡢከࡃࡣࠊ〇⸆఍♫࡟࡚኱Ꮫ㝔࡛ࡢ᫬㛫⏕≀Ꮫ◊✲࡟ࡇࡢୖ࡞࠸ᴦࡋࡳࢆឤ෌⌧ᛶࡀྲྀࢀ࡞࠸࡜࠸࠺ၥ㢟ࡀ࠶ࡿ 13ࠋࡘࡲࡾࠊᏛ⾡◊ࡌ࡚࠸ࡓࡓࡵࠊࡑࡢࡲࡲᏛ⾡ᶵ㛵࡛◊✲ࢆ⥆ࡅࡓ࠸Ẽᣢ✲ࡢⓎぢࡢ࡯࡜ࢇ࡝ࡀ๰⸆ࢩ࣮ࢬࡢᇶ┙࡟࡞ࡗ࡚࠸࡞ࡕࡶ࠶ࡗࡓࠋ୍᪉࡛ࠊ኱Ꮫ㝔ࡢ 5 ᖺ㛫ࡢ⮬ศࡢດຊࡀࠊ࠸࡝ࡇࢁ࠿ࠊ⏘ᴗ࡟࠾ࡅࡿᶆⓗࣂࣜࢹ࣮ࢩࣙࣥࡢ↓㥏ᢞ♫఍࡟ᑐࡍࡿ㈉⊩࡜ࡋ࡚ࡣㄽᩥࠊᩥᏐ㏻ࡾ paper ࡟ࡋ㈨ࡢཎᅉ࡜࡞ࡗ࡚࠸ࡿࠋࡇࡢၥ㢟ࡣࠊᏛ⾡άື࡜་⸆ရ࠿࡞ࡽ࡞࠸ࡇ࡜࡟ᑡࡋ≀㊊ࡾ࡞ࡉࢆឤࡌࡓࠋᐇ㉁ⓗ࡞ព㛤Ⓨ࡜ࡣᮏ㉁ⓗ࡟┠ⓗࡀ␗࡞ࡿࡇ࡜࡟㉳ᅉࡋ࡚࠸ࡿ࡜࿡࡛♫఍࡟ᙺ❧ࡘ◊✲࡜ࡣఱ࠿ࢆᝎࡴ୰࡛ࠊᛮ⪃ࡢᇶ┙ᛮ࠺ࠋᏛ⾡άືࡣࠊ᪂つᛶࡸヰ㢟ᛶࡀ㧗࠸ࡇ࡜ࡀ㔜せ࡛࡟་⸆ရ◊✲ࡢ⪃࠼᪉ࢆᣢࡕࡓ࠸࡜ᛮ࠺ࡼ࠺࡟࡞ࡗࡓࠋ࠶ࡾࠊ㧗࢖ࣥࣃࢡࢺ㞧ㄅ࡬ࡢᥖ㍕ࡸㄽᩥࡢබ⾲ᩘࡀホ౯ࡑࡋ࡚ࠊࢫࢱࢳࣥ࡜࠸࠺᪥ᮏⓎࡢ⏬ᮇⓗ࡞ᢠࢥࣞࢫࢸࣟᇶ‽࡜࡞ࡗ࡚࠸ࡿࡇ࡜ࡀከ࠸ࠋ୍᪉࡛ࠊ་⸆ရ㛤Ⓨࡣࣄ࣮ࣝ⸆ࢆୡ⏺࡟ඛ㥑ࡅ࡚㛤Ⓨ࣭ၟᴗ໬ࡋࡓᐇ⦼ࡀ࠶ࡿ➨ࢺ࡛ࡢ⸆ຠࢆᢸಖࡍࡿᬑ㐢ⓗ࡛ᙉ࠸ᶆⓗࡢⓎ᥀ࡸ㧗࠸୍୕ඹ࡜࠸࠺〇⸆఍♫࡟⯆࿡ࢆᣢࡗࡓࠋ┿⳦ࡢᇵ㣴ᾮ࠿෌⌧ᛶࡢࢹ࣮ࢱࢆồࡵ࡚࠾ࡾࠊ⣧⣔⤫࣐࢘ࢫ࡛ࡋ࠿☜ㄆࡽࡢࢫࢡ࣮ࣜࢽࣥࢢ࡟ࡼࡗ࡚ぢฟࡉࢀࡓࢫࢱࢳࣥࡀࠊື

࡛ࡁ࡞࠸▱ぢࡸࠊ␗࡞ࡿ◊✲⎔ቃ࡛ࡢ෌⌧࡟ࢥࢶࢆせࡍ≀ヨ㦂ࡸ⮫ᗋヨ㦂࡛ᅔ㞴࡟఍࠸࡞ࡀࡽୡ࡟ฟ࡚ࠊᚠ⎔ჾࡿࡼ࠺࡞ࢹ࣮ࢱࡣࠊ๰⸆ⓗ࡟౯್ࡀప࠸ࠋ᪥ᮏࡣ་⸆ရศ㔝ࡢ⏬ᮇⓗⓎ᫂࡟ࡘ࡞ࡀࡗࡓ๰⸆≀ㄒ 9 ࢆㄞࢇ࡛ឤࢆ㛤Ⓨ࡛ࡁࡿᩘᑡ࡞࠸ᅜ࡛࠶ࡾࠊᏛ⾡࡜⏘ᴗࡢ㐃ᖏ࡟ࡼ㖭ࢆཷࡅࡓࠋධ♫ᚋࡣᚠ⎔㡿ᇦ࡟࠾ࡅࡿ◊✲ᡤ࡟࡚ࠊ⹫

ࡿ་⒪ࣅࢪࢿࢫࡢάᛶ໬ࡣ㠀ᖖ࡟㔜せ࡞ၥ㢟࡞ࡢࡔࡀࠊ⾑෌℺ὶ㞀ᐖࡢಖㆤࢆ┠ⓗ࡜ࡋࡓ໬ྜ≀ࢺࢥࣥࢻࣜ࢔

10 ࡸ᪂つࡢ࣑Ca2+ࢳࣕࢿࣝ㸦Mitochondrial Calcium

๓㏙ࡢࡼ࠺࡞౯್ほࡢ㐪࠸ࢆ࡝࠺࡟࠿ࡍࡾྜࡏ࡛ࡁ࡞
࠸ࡶࡢ࠿࡜⪃࠼࡚࠸ࡿࠋ

Uniporter㸧ࡢపศᏊ㜼ᐖ๣ 11 ࢆྠᐃࡋࡓࠋ〇⸆఍♫ࡢ◊✲⎔ቃࡣࠊタഛࡸ㈝⏝ࠊேᮦࡢ㇏ᐩࡉ࡛㠀ᖖ࡟ࣁ࢖࡛ࣞ࣋ࣝ࠶ࡿ஦࡟㦫࠸ࡓ୍᪉࡛ࠊ࡯࡜ࢇ࡝ࡢ๰⸆◊✲άື

6. ኱Ꮫ࡟ᡠࡗ࡚ఱࢆ◊✲ࡍࡿ࡭ࡁ࠿㸽-♫఍࡟ࡘ࡞ࡀࡿ᫬㛫⏕≀Ꮫࢆ┠ᣦࡋ࡚-ࡣ⤖ᐇࡋ࡞࠸ࡇ࡜ࡸࠊ๰⸆ࣅࢪࢿࢫ⮬యࡀᛴ⃭࡞⾶㏥ᮇ኱ࡁ࡞⤌⧊࡟ᒓࡍࡿே㛫ࡣㄡࡋࡶᝎࡴࡇ࡜ࡔࡀࠊ⤌⧊࡟࠶ࡿࡇ࡜࡟វ↛࡜ࡋࡓࠋ་⸆ရࣅࢪࢿࢫ࡛ࡣ᪂⸆ࡣ≉࠿ࡽᮇᚅࡉࢀࡿࡇ࡜࡜ࠊ⮬ศࡢᕼᮃ࡜ࡢᢡࡾྜ࠸ࢆࡘࡅチ㸦ࣃࢸࣥࢺ㸧࡟ࡼࡗ࡚⊂༨ⓗ࡞㈍኎ᮇ㛫ࡀἲⓗ࡟ㄆࡵ࡞ࡅࢀࡤ࠸ࡅ࡞࠸ࠋᮏ♫ࡢ௙஦ࡣ⮬ศࡀᮃࢇࡔ㐨࡛ࡣ࡞ࡽࢀࡿࡢࡔࡀࠊ≉チࡀษࢀࡓ㏵➃࡟Ᏻ౯࡞ࢪ࢙ࢿࣜࢵࢡ࠿ࡗࡓࡓࡵࠊ㠀ᖖ࡟ᝎࢇࡔࡀࠊࡑࡢࡲࡲ㐍ࡴࡇ࡜ࡣ࡛ࡁ

་⸆ရ࡟ᕷሙࢆዣࢃࢀࡿࠋࡇࢀ࡟ࡼࡾࠊ≉チᮇ㛫ࡢ⤊஢࡞࠿ࡗࡓࠋᐙᗞ࡛ࡣ஧ே┠ࡢᏊ౪ࡀ⏕ࡲࢀࡓ࡜ࡇࢁ࡛ࠊ࡜࡜ࡶ࡟〇ရ኎ୖࡀᓴࡢࡼ࠺࡟ῶᑡࡍࡿࡓࡵࠊࣃࢸࣥࢺ〇⸆఍♫ࢆ㎡ࡵࡿࡇ࡜ࡣỴ᩿ࢆせࡋࡓࡀࠊࡸࡾࡓ࠸஦࡟᫬㛫⏕≀Ꮫ
36

Vol. 26, No. 1 (2020)ᅗ 2 ࢝ࣝࣇ࢛ࣝࢽ࢔࣐࢘ࢫ Freerunner ኚ␗యᕥ㸧࢝ࣝࣇ࢛ࣝࢽ࢔࣐࢘ࢫࡣࠊ୍ኵ୍ጔࡸ∗ぶࡢ⫱ඣ࡞࡝ࡢ≉ᚩࡀ࠶ࡿྑ㸧Free runner ኚ␗యࡢ࢔ࢡࢺࢢ࣒ࣛ㸦ᬯᮇࢆ⅊Ⰽ⾲♧㸧㸧ᣮᡓࡋ࡞࠸ே⏕ࢆṌࡴࡇ࡜ࡣ↓ព࿡࡜⪃࠼ࡓࠋ῝⏣ඛ⏕࡟ࡼࡿ⾜ື㔞ࡢᢚไ㸧࡞࡝௚ࡢ㠀どぬගཷᐜࡶ㞀ᐖࡉࢀ࡟┦ㄯࡋࡓ࡜ࡇࢁࠊ୍㐣ⓗ࡞࣏ࢪࢩࣙࣥࢆ⏝ពࡋ࡚㡬ࡅ࡚࠸ࡓࠋࡋ࠿ࡋࠊ࢝ࢼࢲࡢࢲࣝࣁ࢘ࢪ࣮኱Ꮫࡢࡿ࡜ࡢ࠶ࡓࡓ࠿࠸ゝⴥࢆ㡬࠸ࡓࠋ࠿ࡃࡋ࡚ࠊ2018 ᖺࡼBenjamin Rusak ࣛ࣎࠿ࡽฟ࡚࠸ࡓㄽᩥࢆぢ࡚┠ࢆ␲ࡾྂᕢࡢ◊✲ᐊ࡟ᡠࡗ࡚ࡃࡿࡇ࡜ࡀ࡛ࡁࡓࠋࡑࡋ࡚ࠊ⏕ࡗࡓࠋ୍ኵ୍ጔ࡜ゝ࠺≉Ṧ࡞⦾Ṫᵝᘧࢆ♧ࡍࢩࣟ࢔ࢩࢿ࿨⛉Ꮫ⏘ᴗࡢᐇ᝟ࢆᏛࢇࡔୖ࡛ࠊ⮬ศࡣ᫬㛫⏕≀Ꮫࡢᇶࢬ࣑ᒓࡢ࢝ࣜࣇ࢛ࣝࢽ࢔࣐࢘ࢫ࡟࠾࠸࡚ࠊCM558 ࡜࠸♏࡟ᡠࡾఱࢆ⾜࠺࡭ࡁ࠿࡜⪃࠼ࡓࠋ2017 ᖺ࡟యෆ᫬ィ࠺⮬↛Ⓨ⏕ኚ␗ࡣࠊග࣐ࢫ࢟ࣥࢢࡣ࠶ࡲࡾᙳ㡪ࢆཷࡅ࡞ศ㔝ࡀࣀ࣮࣋ࣝ㈹ࡢᑐ㇟࡜࡞ࡾࠊ᫬㛫⏕≀Ꮫࡢ♫఍ࡢㄆ࠸ࡀࠊ᫂ᬯࢧ࢖ࢡࣝ࡬ࡢྠㄪࡀ◚⥢ࡍࡿࡇ࡜ࡀሗ࿌ࡉࢀ▱ᗘࡣ㧗ࡲࡗࡓࡀࠊࡑࡢᡂᯝࡀᛂ⏝ࡉࢀ࡚⤒῭ⓗ࡞άᛶ࡚࠸ࡓ 15ࠋ῝⏣ඛ⏕࡜┦ㄯࡋࠊRusak ඛ⏕࡟ࢥࣥࢱࢡ

໬࡟኱ࡁࡃ㈉⊩ࡋ࡚࠸ࡿ≧ἣ࡜ࡣゝ࠸㞴࠸ࠋయෆ᫬ィࡀࢺࡋࡓ࡜ࡇࢁࠊᙜヱㄽᩥࡢ➹㢌ⴭ⪅࡛࠶ࡿ Marleen de᭱ࡶ┤᥋ⓗ࡟⚾ࡓࡕࡢ⏕ά࡜㛵ࢃࡿࡢࡣࠊࡲࡂࢀࡶ࡞ࡃ

Groot ༤ ኈ ࡣ ࠊ ࡑ ࡢ ኚ ␗ ࣐ ࢘ ࢫ ࡜ ࡜ ࡶ ࡟ Joseph╧╀ࡢไᚚ࡛࠶ࡿࠋࡋ࠿ࡋࠊ╧╀㞀ᐖࡢ୰࡛ࡶ࡜ࡾࢃࡅ

Takahashi ࣛ࣎࡟⛣ࡾࠊཎᅉ㑇ఏᏊࡢゎᯒࢆ⾜࡞ࡗ࡚యෆ᫬ィ࡜ࡢᅉᯝ㛵ಀࡀ᫂░࡞ᴫ᪥ࣜࢬ࣒ᛶ╧╀㞀ᐖ࠸ࡿࡇ࡜ࢆ▱ࡗࡓࠋࡑࡋ࡚ de Groot ༤ኈ࡟⪺࠸ࡓ࡜ࡇ

㸦CRSD, Circadian Rhythm Sleep Disorder㸧࡛ࡉ࠼ࠊࢁࠊᙼዪࡣㄽᩥබ⾲ᚋ 15 ᖺ௨ୖ࡟ࢃࡓࡗ࡚ CM558 ࡢ᫬ィ㑇ఏᏊࡢኚ␗࡟㉳ᅉࡍࡿ࡜ᛮࢃࢀࡿࡢࡣ୍㒊ࡢᝈኚ␗㑇ఏᏊࡢ᥈⣴ࢆ⥆ࡅ࡚ࡁࡓࡀࠊཎᅉࢆᮍࡔྠᐃ࡛ࡁ⪅࡛࠶ࡿࠋࣄࢺࡢࣜࢬ࣒ྠㄪࢆไᚚࡍࡿ་⸆ရࢆ⪃࠼ࡿ࡚࠸࡞࠸ࡇ࡜ࢆᩍ࠼࡚ࡃࢀࡓࠋኚ␗ࡣ᪤▱ࡢ᫬ィ㑇ఏᏊୖ࡛ࠊ≉␗ⓗ࠿ࡘᬑ㐢ⓗ࡞࣓࢝ࢽࢬ࣒ࡣࡲࡔぢࡘ࠿ࡗ࡚ࡢ୰࡟ࡣᏑᅾࡋ࡞࠸ࡇ࡜࠿ࡽࠊ⌧≧ࡢ᫬㛫⏕≀ᏛࡢศᏊ࠸࡞࠸࡜ឤࡌࡓࠋࡑࡇ࡛ࠊCRSD ࡢ୰࡛ࡶ࡜ࡾࢃࡅ㝿❧ⓗ⌮ゎ࡛ࡣ CM558 ࡢ⾲⌧ᆺࡣㄝ᫂୙ྍ⬟࡜ࡢࡇ࡜ࡔࡗࡓ⑕≧ࢆ♧ࡍ㠀 24 ᫬㛫╧╀ぬ㓰⑕ೃ⩌㸦non-24㸧࡟ࡗࡓࠋ⚾㐩ࡣࡑࡢ㑇ఏᏊࣁࣥࢸ࢕ࣥࢢ࡟㛵ࡋ࡚ඹྠ◊✲╔┠ࡋࡓࠋᮏ⑌ᝈࡣ╧╀࣭ぬ㓰ࣜࢬ࣒ࡀẖ᪥ 0.5 - 1 ᫬ࢆ⏦ࡋฟࡓࡀࠊࡑࢀ࡟ᑐࡋ࡚ࠊᙜヱ࣐࢘ࢫ࡜㛵㐃ࡍࡿ඲㛫ࡎࡘ㐜ࢀ࡚࠸ࡃ࡜࠸࠺㔜⠜࡞ࣜࢬ࣒ྠㄪ୙඲ࢆ♧ࡍ࡚ࡢ᝟ሗ࣭ᐇ㦂ᮦᩱ࡜࡜ࡶ࡟◊✲ࢆࣂࢺࣥࢱࢵࢳࡋ࡚ࡃ

14ࠋnon-24 ᝈ⪅ࡢከࡃࡣ┣┠࡛࠶ࡾࠊࡑࡢཎᅉࡣᴫ᪥ග

ࢀࡿ࡜࠸࠺᭱㧗ࡢᙧ࡛ᛂ࠼࡚ࡃࢀࡓࠋ᪥ᮏ࡟ࡑࡢኚ␗࣐

ཷᐜࡢ㞀ᐖ࡛ㄝ᫂ࡀࡘࡃࡢࡔࡀࠊどぬࡀṇᖖ࡞ே࡟࠾࠸

࢘ࢫࢆ㍺ධࡋࠊ⾜ືࣜࢬ࣒ࢆゎᯒࡋࡓ⤖ᯝࠊග࣐ࢫ࡚࢟ࣥࡶ⛥࡟Ⓨ⑕ࡍࡿࠋࡇࡢどぬṇᖖ non-24 ࡟㛵ࢃࡿศᏊࢢࡣṇᖖ࡛࠶ࡿࡶࡢࡢࠊ᫂ᬯࢧ࢖ࢡࣝࢆ↓どࡋࡓ㍯ᅇࡋࢆྠᐃࡍࢀࡤࠊࣄࢺࡢᴫ᪥᫬ィࡢྠㄪ࣓࢝ࢽࢬ࣒ࡢ⌮ゎ⾜ືࣜࢬ࣒ࡢ⮬⏤⥅⥆ࢆ☜ㄆ࡛ࡁࡓ㸦ᅗ 2㸧ࠋ᫂ᬯୗ࡛࡟ࡘ࡞ࡀࡿࠋ╧╀⸆ࡣྂࡃ࠿ࡽ GABA ཷᐜయ࡟స⏝ࡍࡶ⾜ືࣜࢬ࣒ࡀࣇ࣮ࣜࣛࣥ㸦⮬⏤⥅⥆㸧ࡍࡿࡇ࡜࠿ࡽࠊࡿ⸆๣ࡀࡼࡃ౑⏝ࡉࢀ࡚ࡁࡓࡀࠊ㏆ᖺⓎ኎ࡉࢀࡓ࣓ࣛࢺ⚾ࡓࡕࡣࡑࡢཎᅉ࡜࡞ࡿ㑇ఏᏊኚ␗ࢆ Free runner ࡜ࢽࣥ࢔ࢦࢽࢫࢺࡸ࢜ࣞ࢟ࢩࣥ࢔ࣥࢱࢦࢽࢫࢺ࡞࡝ࣜࢬ࿧ࢇ࡛࠸ࡿࠋ࢝ࣜࣇ࢛ࣝࢽ࢔࣐࢘ࢫࡣࢡ࣮ࣟࢬࢻࢥࣟࢽ࣒ᶵ⬟࡟┤᥋స⏝ࡍࡿ⸆๣ࡣᏳ඲ᛶࡀ㧗࠸࡜࠸࠺࣓࣮ࣜ⥔ᣢࡢࡓࡵ㑇ఏⓗ⫼ᬒࡀከᵝࡔࡀࠊࡑࡢከᵝ࡞୰࡛ࡶࢵࢺ࡛ᕷሙཧධ࡛ࡁ࡚࠸ࡿࠋࡑࡇ࡛ࠊࣜࢬ࣒ྠㄪ࡟㛵ࢃ

Free runner ࡢ⾲⌧ᆺࡣ᫂☜࡞ᖖᰁⰍయຎᛶ㑇ఏࢆ♧ࡿ≉␗ⓗ࡞⤒㊰ࢆྠᐃࡍࢀࡤࠊ᪂つࡢ་⒪ᢏ⾡ࡢ㛤Ⓨ࡟ࡍࠋࡲࡓࠊ୍㒊ࡢ࣐࢘ࢫ࡛ࡣ non-24 ᵝ⑕≧࡟ຍ࠼ࠊ࠶ࡶࡘ࡞ࡀࡿࡢ࡛ࡣ࡜ᮇᚅࡋ࡚࠸ࡿࠋᐇ㦂ື≀࡟࠾ࡅࡿග

ࡿ᮲௳ୗ࡟࠾࠸࡚╧╀┦ᚋ㏥⑕ೃ⩌㸦DSPS㸧ᵝ⑕≧ࡀྠㄪࡢ㞀ᐖ౛ࢆㄪ࡭┤ࡋࡓ࡜ࡇࢁࠊ࡯࡜ࢇ࡝ࡣ⥙⭷ࡢᴫほᐹࡉࢀࡿࡇ࡜ࡀศ࠿ࡗࡓࠋどぬṇᖖ non-24 ᝈ⪅ࡢ᪥ ග ཷ ᐜ ⣽ ⬊ ࡛ ࠶ ࡿ ipRGC 㸦 intrinsically

26%ࡣ non-24 Ⓨ⑕๓࡟ DSPS ࢆ♧ࡍࡇ࡜ࡀ▱ࡽࢀ࡚࠾photosensitive retinal ganglion cells㸧ࡢᶵ⬟㞀ᐖ࡛࠶ࡾ 14ࠊࡇࡢⅬ࡟࠾࠸࡚ࡶ Free runner ኚ␗࡜ࣄࢺどぬࡾࠊගྠㄪ࡜࡜ࡶ࡟࣐ࢫ࢟ࣥࢢ㸦ኪ⾜ᛶື≀࡟࠾ࡅࡿගṇᖖ non-24 ࡣ⑕≧ࡀఝ࡚࠸ࡿࠋᖾ㐠࡞ࡇ࡜࡟ࠊ᪥ᮏࡣ᫬㛫⏕≀Ꮫ

Vol. 26, No. 1 (2020)37

どぬṇᖖ non-24 ࡢ⮫ᗋ◊✲࡛ୡ⏺ࢆ࣮ࣜࢻࡋ࡚࠸ࡿࠋTTFL ࢆᵓᡂࡍࡿ᫬ィ㑇ఏᏊࡢከࡃࡀ᫂ࡽ࠿࡜࡞ࡗࡓ࢝ࣜࣇ࢛ࣝࢽ࢔࣐࢘ࢫ Free runner ࡜ࠊࣄࢺ non-24 ࡢ⌧≧࡛ࡉ࠼ࠊ┿᰾⏕≀ࡢᴫ᪥᫬ィࡢ୕኱ᛶ㉁ࡣศᏊࡢゝẚ㍑ゎᯒ࡟ࡼࡗ࡚ࠊ᪥ᮏⓎࡢࢺࣛࣥࢫ࣮ࣞࢩࣙࢼࣝ᫬㛫ⴥ࡛᏶඲࡟ࡣㄝ࡛᫂ࡁ࡚࠸࡞࠸ࠋࡑࡋ࡚ࠊື≀ࠊ┿⳦ࠊ⏕≀ᏛࢆⓎಙ࡛ࡁࢀࡤ᭷ព⩏࡜⪃࠼࡚࠸ࡿࠋ᳜≀ࠊࢩ࢔ࣀࣂࢡࢸࣜ࢔ࡢ㛫࡛᫬ィ㑇ఏᏊࡢ┦ྠᛶࡣ㝈ᐃⓗ࡛࠶ࡿ࡜࠸࠺஦ᐇࡣఱࢆ♧၀ࡋ࡚࠸ࡿࡢࡔࢁ࠺

7. ᣺ືయࡣ࡝ࡇ࡟㸽 -⾲ᒙࡢࣜࢬ࣒࡜῝ᒙࡢ᣺ືయ-࠿㸽ࣜࢬ࣒ኚ␗యࡢ㡰㑇ఏᏛࡢᡂຌせᅉࡣࠊ᫬ィ㑇ఏᏊᇶ♏⛉Ꮫ࡜ࡋ࡚ࡢ᫬㛫⏕≀Ꮫࡢ┠ᶆ࡟❧ࡕ㏉ࡗ࡚ࡳࡢከࡃࡀᶵ⬟Ḟᦆ࡛⮴Ṛ࡛ࡣ࡞ࡃࠊಶయࡀ࣊ࣝࢩ࣮࡞≧ࡿࠋࡑࡶࡑࡶᴫ᪥᫬ィࡢ᣺ື࣓࢝ࢽࢬ࣒ࡣ࡝ࡇࡲ࡛ゎࡅែ࡛ overt rhythm ࡢホ౯ࡀ࡛ࡁࡓࡇ࡜࡛࠶ࡗࡓ࡜ᛮ࠺ࠋࡓࡢࡔࢁ࠺࠿㸽1984 ᖺ࡟ࢩࣙ࢘ࢪࣙ࢘ࣂ࢚ࡢ Per 㑇ఏࡇࢀ࡟ᑐࡋ࡚ࠊ࠸ࡃࡘ࠿ࡢ⣔⤫ࡢ┿᰾⏕≀ࡢ᫬ィᶵ⬟࡟Ꮚࡀሗ࿌ࡉࢀ࡚௨᮶㺂┿⳦ࠊ့ங㢮ࠊࢩ࢔ࣀࣂࢡࢸࣜ࢔ࠊ

ඹ㏻ࡋ࡚ാࡃᅉᏊ࡛࠶ࡿ CK1 ࡸ CK2ࠊGSK3 ࡞࡝ࡢศ᳜≀࡟࠾࠸࡚᫬ィ㑇ఏᏊࡀ⥆ࠎ࡜ྠᐃࡉࢀࠊ௒ࡸ㌿෗࣭Ꮚࡣࠊ᏶඲Ḟᦆࡢಶయࡣ࣊ࣝࢩ࣮࡞≧ែࢆಖ࡚࡞࠸ࠋࡘ⩻ヂࣇ࢕࣮ࢻࣂࢵࢡ࣮ࣝࣉ㸦TTFL㸧ࡀ⾲ฟࡉࢀࡿࣜࢬࡲࡾࠊ┿᰾⏕≀ࡢ⣔⤫㛫ඹ㏻ࡢ᪤▱᫬ィᅉᏊࡣࠊࣜࢬ࣒

࣒㸦overt rhythm㸧๰ฟࡢᇶᮏ㦵᱁࡛࠶ࡿࡇ࡜ࡣ␲࠺వ࡟ᶵ⬟≉໬ࡋࡓศᏊ࡛ࡣ࡞ࡃࠊᮏ᮶ࡢᶵ⬟ࡣ⣽⬊ࡢࣁ࢘ᆅࡶ࡞࠸ࠋ⚾⮬㌟ࡀ᫬㛫⏕≀Ꮫࢆጞࡵࡓࢱ࢖࣑ࣥࢢࡣ࢖ࢫ࣮࢟ࣆࣥࢢ࡛࠶ࡿࠋࡇࡇ࠿ࡽࠊ᣺ືయࡢ㐍໬ⓗ㉳※ࡣࣥࢱ࣮ࣟࢵࢡࣇ࢕࣮ࢻࣂࢵࢡ࣮ࣝࣉࣔࢹࣝࡢ඲┒ᮇ࡜⣽⬊ࡢᇶᮏᶵ⬟ࡢ᣺ື࡛࠶ࡗࡓ࡜⪃࠼ࡿࡢࡀ⮬↛࡛࠶࠶ࡗ࡚ࠊື≀ࡢ᣺ືయࡢᇶᮏ㦵᱁ࡣ TTFL ࡜⪃࠼ࡿࡇࡿ࡜ᛮ࠺ࠋࡇࡢࡼ࠺࡟㏻ㄝࢆ␲࠺ጼໃ࡛⪃࠼┤ࡋ࡚ぢࡿ࡜࡟␲ၥࢆᣢࡗ࡚࠸࡞࠿ࡗࡓࠋࡋ࠿ࡋ⪃࠼┤ࡋ࡚ࡳࡿ࡜ࠊ࡜ࠊ⌧⾜ࡢ᫬ィⓎ᣺ࣔࢹࣝ࡟ࡣ୙ᛮ㆟࡞Ⅼࡶከࡃ࠶ࡾࠊ

overt rhythm ࡟ᚲ㡲࡛࠶ࡿᅉᏊࡣ᣺ືయࡢᵓᡂせ⣲ᴫ᪥᣺ືయࡢᏑᅾࡍࡿ῝ᒙ࡟ே㛫ࡣᮍࡔ㊊ࢆ㋃ࡳධࢀ࡛࠶ࡿ࡜ࡣ㝈ࡽࡎࠊࣜࢬ࣒ฟຊᅉᏊࡢྍ⬟ᛶࡶ⪃࠼ࡽࢀ࡚࠸࡞࠸ࡢ࡛ࡣ࡞࠸ࡢ࠿࡜ᛮ࠼࡚ࡃࡿࠋᮍ▱ࡢ㒊ศࡀ࠶ࡿࠋ᫬㛫⏕≀Ꮫ࡟ᡠࡗ࡚ࡁ୍࡚㐃ࡢሗ࿌ࢆ෌ࡧຮᙉࡋ࡚ࡿࡇ࡜ࡇࡑࡀࠊᇶ♏◊✲⪅࡟࡜ࡗ࡚ࡣࡇࡢ࠺࠼࡞࠸㠃ⓑẼ࡟࡞ࡗ࡚࠸ࡿࡇ࡜ࡣࠊTTFL ࡀᶵ⬟ࡋ࡞࠸⣽⬊࡟࠾ࡅࡉ࡛࠶ࡾࠊ௒ᚋࡢࢿ࢜ࢡࣟࣀࣂ࢖࢜ࣟࢪ࣮ࡢⓎᒎ࡟ᑡࡋࡿᴫ᪥ࣜࢬ࣒ࡀ」ᩘࡢ◊✲ᐊ࠿ࡽሗ࿌ࡉࢀ࡚࠸ࡿⅬ࡛࡛ࡶ㈉⊩ࡋ࡚࠸ࡁࡓ࠸࡜⪃࠼࡚࠸ࡿࠋ࠶ࡿࠋࡑࡢࡓࡵࠊTTFL ࢆ၏୍ࡢ᣺ື࣓࢝ࢽࢬ࣒࡜ࡋ࡚◊✲ࢆ㐍ࡵࡿࡢࡣ㞴ࡋ࠸≧ἣ࡜ឤࡌ࡚࠸ࡿࠋ᣺ືయ࡜ࡣ

8. ࠾ࢃࡾ࡟ఱ࠿ࢆ⪃࠼ࡿ᫬࡟ࡣࠊᴫ᪥᫬ィࡢᐃ⩏࡜ࡶ࠸࠼ࡿ୕኱ᛶࡇࡢᗘࡢᐤ✏࡟㝿ࡋ࡚ࠊࡇࢀࡲ࡛⮬ศࡀ࠸࠿࡟ከࡃࡢ㉁ࡀࡼࡾ࡝ࡇࢁ࡟࡞ࡿࠋࡍ࡞ࢃࡕࠊ⮬ᚊ᣺ືᛶࠊྠㄪᛶࠊ᪉ࠎ࠿ࡽᡭཌ࠸ࡈᨭ᥼ࢆ㡬࠸࡚ࡁࡓ࠿ࢆឤࡌࡲࡋࡓࠋ῝ᗘ⿵ൾᛶࡀ࡝ࡇࡲ࡛ㄝ࡛᫂ࡁࡿ࠿࡟ࡼࡗ࡚ࠊ⌧≧࡛ศ⏣ඛ⏕ࠊᘅ⏣ඛ⏕ࢆࡣࡌࡵࠊ⮬ศࢆ◊✲⪅࡜ࡋ࡚⫱࡚࡚࠿ࡗ࡚࠸࡞࠸࣏࢖ࣥࢺࡀぢ࠼࡚ࡃࡿࠋ⮬ᚊ᣺ືᛶ࡟㛵ࡋࡃࢀࡓ᫬㛫⏕≀Ꮫࡢඛ⏕᪉࡟ᚰࡼࡾឤㅰࡋ࡚࠾ࡾࡲࡍࠋ࡚ࡣࠊࡑࡢ㛢ࡌࡓ࣮ࣝࣉᵓ㐀ࡺ࠼ࠊTTFL ࣔࢹࣝࡀ᣺ືࡲࡓࠊ➨୍୕ඹᰴᘧ఍♫࡟࠾࠸࡚ࡶከࡃࡢ᪉ࠎࡢ࠾ୡヰᵓ㐀࡜ࡋ࡚ཷࡅධࢀࡸࡍ࠸᱁ዲ࡟࡞ࡗ࡚࠸ࡿࠋࡋ࠿ࡋࠊ࡟࡞ࡾࠊ๰⸆࣭⫱⸆◊✲ࡸ་⸆ရࣅࢪࢿࢫࢆ㏻ࡌࡓ㈗㔜

TTFL ࡀ᣺ືᮏయ࡞ࡽࡤࠊ᫬ィ㑇ఏᏊࡢⓎ⌧ࣞ࣋ࣝ⮬య࡞⤒㦂ࢆࡉࡏ࡚㡬ࡁࡲࡋࡓࠋ኱Ꮫ࡟ᡠࡗ࡚࠿ࡽࡣࠊගྠ

ࡀ state variable ࡜ࡋ࡚ᶵ⬟ࡍࡿࡣࡎ࡛࠶ࡿࡀࠊື≀ࡢㄪ࣓࢝ࢽࢬ࣒ࡸ᣺ືཎ⌮ࡢ㏣ồࡢࡓࡵࠊྡྂᒇᕷ❧኱Ꮫࢥ࢔᫬ィ㑇ఏᏊࡢⓎ⌧ࣜࢬ࣒ࡣ overt rhythm ⏕ᡂ࡟ᚲࡢ⢆ ࿴ᙪඛ⏕ࠊ෠⏣ ῟ඛ⏕ࠊຍ⸨ ၿ❶ࡉࢇࠊ᪩✄⏣㡲࡛ࡣ࡞࠸࡜ࡍࡿሗ࿌ࡀከ࠸ 16-18ࠋྠㄪᛶ࡟㛵ࡋ࡚ࡣࠊ኱Ꮫࡢᒾᓮ ⚽㞝ඛ⏕ࠊἙᮏ ᑦ኱ࡉࢇࠊᕝᓮ ὯྖࡉࢇࠊPeriod ࡸ Dec ࡞࡝ࠊࣜࢬ࣒ࡢ఩┦ࢩࣇࢺ࡟࠾ࡅࡿ᫬ィᯈᮌ ኱▱ࡉࢇࠊዉⰋඛ➃኱Ꮫࡢ㐲⸨ ồඛ⏕ࠊୖᮏ ᜤ㑇ఏᏊࡢᙺ๭ࡣ♧ࡉࢀ࡚࠸ࡿࡶࡢࡢࠊ᫬ィ㑇ఏᏊኚ␗యᖹࡉࢇࠊ⏕⌮Ꮫ◊✲ᡤࡢᴮᮌ ு௓ඛ⏕ࠊ⌮໬Ꮫ◊✲ᡤ࡟࠾࠸࡚ࠊ㸦Free runner ኚ␗యࡢᵝ࡟㸧᫂ᬯ࡬ࡢྠㄪࡢ㯮⃝ ඖඛ⏕ࠊ൤ಖ ఙ࿃ඛ⏕ࠊ㤶ᕝ኱Ꮫࡢᮡᒣ ᗣ᠇ࡀ᏶඲࡟◚⥢ࡍࡿࡼ࠺࡞౛ࡣ↓࠸ᵝ࡟ᛮ࠼ࡿࠋ㣗㣵࡟ࡼඛ⏕ࠊ୰᰿ 㐩ேࡉࢇࠊ஑ᕞ኱Ꮫࡢఀ⸨ ᾈྐඛ⏕ࠊ㛵 ඖࡿࣜࢬ࣒ྠㄪ࡟㛵ࡋ࡚ࡣࠊ㣗㣵ண▱⾜ືࢆไᚚࡍࡿᴫ᪥⚽ඛ⏕࡟ࡣከࡃࡢࡈᑾຊ࣭ࡈຓゝࢆ㡬ࡁࠊᚰ࠿ࡽឤㅰࡋ

᣺ືయࡣ SCN እ࡟Ꮡᅾࡋࠊ᪤▱ࡢ᫬ィ㑇ఏᏊ࡛ࡣㄝ࡚᫂࠾ࡾࡲࡍࠋࡲࡓࠊ῝⏣◊✲ᐊࡢࢫࢱࢵࣇࠊᑠᓥ ኱㍜࡛ࡁ࡞࠸㒊ศࡀከ࠸ 22ࠋࡲࡓࠊᗘ⿵ൾᛶ࡟⮳ࡗ࡚ࡣࠊඛ⏕ࠊΎỈ ㈗⨾Ꮚඛ⏕ࠊྜྷ✀ ගඛ⏕ࠊᮌ⫤ ┤つඛ⏕

TTFL ࢆᵓᡂࡍࡿ㌿෗ࠊ⩻ヂࠊmRNA/ࢱࣥࣃࢡ㉁ศゎࠊ࡟ࡣ࠸ࡘࡶ᭷⏝࡞࢔ࢻࣂ࢖ࢫࢆ㡬࠸࡚࠾ࡾࡲࡍࠋ◊✲ࢆ

ࢱࣥࣃࢡ㉁ࡢ᰾⛣⾜࡞࡝ࡢ཯ᛂࡣ୍⥴࡟㐍ࡵ࡚ࡁࡓᆤ⏣ ໷ྐࡉࢇࠊཎ ༓ᑜࡉࢇࠊ⋤ ᖾᗘឤཷᛶ࡛࠶ࡿࡀࠊ

TTFL ࡢᴫ᪥ࣜࢬ࣒࿘ᮇࡣ⿵ൾࡉࢀ࡚࠸ࡿࠋከࡃࡢᗘឿࡉࢇࠊᱵ⏣ ⨾ᕹࡉࢇࠊᑠᓥ భ௓ࡉࢇࠊቑ⏣ 㞝୍ᮁឤཷᛶ཯ᛂࡢ㏿ᗘኚ໬ࢆ⿵ൾࡋࠊ᣺ືయ࡛ࣞ࣋ࣝ࿘ᮇࢆ

ࡉࢇࡣࢳ࣮࣒ࢆ┒ࡾୖࡆ࡚ࡃࢀ࡚ឤㅰࡋ࡚࠸ࡲࡍࠋ᭱ᚋ

୍ᐃ࡟ಖࡘ࣓࢝ࢽࢬ࣒ࡀᚲせ࡜ᛮࢃࢀࡿࠋࡍ࡞ࢃࡕࠊ࡟ࠊ⚾ࡀࡸࡾࡓ࠸஦࡟ᣮᡓࡍࡿࡇ࡜ࢆࠊ࠸ࡘࡶᛂ᥼ࡋぢ᫬㛫⏕≀Ꮫ
38Vol. 26, No. 1 (2020)Ᏺࡗ࡚ࡃࢀ࡚࠸ࡿᐙ᪘࡟ឤㅰࡋ࡚࠸ࡲࡍࠋ≉࡟ࠊ⚾ࡀᐙ

permeability transition. Sci. Rep., 7, 3864 (2017).

ࢆ୙ᅾ࡟ࡍࡿࡇ࡜ࡀከ࠸୰ࠊ⮬㌟ࡶാࡁ࡞ࡀࡽᗂ࠸Ꮚ౪

*correspondence㐩࡜ᐙᗞࢆᏲࡗ࡚࠸ࡿጔ࡟᭱኱㝈ࡢឤㅰࡢẼᣢࡕࢆ⾲ࡋࡓ࠸࡜ᛮ࠸ࡲࡍࠋ

11. Kon, N.* et al. DS16570511 is a small-molecule
inhibitor of the mitochondrial calcium uniporter.

Cell

Death

Discov.,

3,17045(2017).

*correspondenceཧ⪃ᩥ⊩
1. Honma, S. et al. Dec1 and Dec2 are regulators of

12. Sone, T.#, Kon, N.#*, Gaither, K.W.# et al. Effects

the mammalian molecular clock. Nature 419, 841-of 3-year denosumab on hip geometry in Japanese

844 (2002).

postmenopausal

2. Miyazono, K., Katsuno, Y., Koinuma, D., Ehata, S.,& Morikawa, M. Intracellular and extracellular
TGF-ǃ VLJQDOLQJ LQ FDQFHU VRPH UHFHQW WRSLFV

Front. Med. 12, 387-411 (2018).
3. Kon, N. et al. Activation of TGF-ǃ/activin

osteoporosis.

women

BoneRep.

andmenwith

7,164(2017).

*correspondence, #equally contribution.
13. Bespalov, A., Barnett, A.G., & Begley, C.G.
Industry is more alarmed about reproducibility
than academia. Nature. 563, 626 (2018).

signalling resets the circadian clock through rapid

14. Hayakawa, T. et al. Clinical analyses of sightedinduction of Dec1 transcripts. Nat. Cell Biol., 10,

patients with non-24-hour sleep-ZDNH V\QGURPH

1463-1469 (2008).

a study of 57 consecutively diagnosed cases. Sleep

4. Kon, N., Sugiyama, Y., Yoshitane, H., Kameshita,

28, 945-952 (2005).

I., & Fukada, Y. Cell-based inhibitor screening

15. de Groot, M.H., & Rusak, B. Entrainment

identifies multiple protein kinases important for

LPSDLUHG PDVNLQJ VSDUHG DQ DSSDUHQW JHQHWLF

circadian clock oscillations. Commun. Integr. Biol.

abnormality that prevents circadian rhythm

8, e982405 (2015).

entrainment to 24-h lighting cycles in California

5. Kon, N. et al. CaMKII is essential for the cellularmice. Neurosci. Lett. 327, 203-207 (2002).

clock and coupling between morning and evening

16. Lakin-Thomas, P.L. Transcriptional feedback

behavioral rhythms. Genes Dev., 28, 1101–1110

RVFLOODWRUV maybe, maybe not. J. Biol. Rhythms.

(2014).

21, 83-92 (2006).

6. Kaiser, T.S. et al., The genomic basis of circadian

17. McDearmon, E.L. et al. Dissecting the functions ofand circalunar timing adaptations in a midge.

the mammalian clock protein BMAL1 by tissue-Nature 540, 69-73 (2016).

specific rescue in mice. Science 314, 1304-1308

7. Tatsuki, F. et al. Involvement of Ca2+-dependent
hyperpolarization in sleep duration in mammals.

Neuron 90, 70-85 (2016).

(2006).
18. Fan, Y., Hida, A., Anderson, D.A., Izumo, M., &Johnson, C.H. Cycling of CRYPTOCHROME

8. Hagihara, H., et al. Circadian gene circuitry

proteins is not necessary for circadian-clock

predicts hyperactive behavior in a mood disorderfunction in mammalian fibroblasts. Curr. Biol. 17,

mouse model. Cell Rep. 14, 2784-2796 (2016).

1091-1100 (2007).

9. ᒣෆ ႐⨾Ꮚࠊୡ⏺୍࡛␒኎ࢀ࡚࠸ࡿ⸆ (ᑠᏛ㤋,2006)

19. ᾏ⪁ཎ ྐᶞᩥࠊྜྷᮧ ᓫ (⦅) ᫬㛫⏕≀Ꮫ (໬Ꮫྠே,2012)

10. Kon, N.*, Satoh, A., Miyoshi, N. A small-molecule
DS44170716 inhibits Ca2+-induced mitochondrial᫬㛫⏕≀Ꮫ

Vol. 26, No. 1 (2020)39