Π”ΠΈΠΏΠ»ΠΎΠΌ, курсовая, ΠΊΠΎΠ½Ρ‚Ρ€ΠΎΠ»ΡŒΠ½Π°Ρ Ρ€Π°Π±ΠΎΡ‚Π°
ΠŸΠΎΠΌΠΎΡ‰ΡŒ Π² написании студСнчСских Ρ€Π°Π±ΠΎΡ‚

Π˜Π½Ρ‚Π΅Ρ€Ρ„Π΅Ρ€ΠΈΡ€ΡƒΡŽΡ‰Π°Ρ ΠΈ антипролифСративная активности ΠΏΡ€Π΅ΠΏΠ°Ρ€Π°Ρ‚ΠΎΠ² Π΄Ρ†Π ΠΠš Π² ΠΊΡƒΠ»ΡŒΡ‚ΡƒΡ€Π°Ρ… ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²Ρ‹Ρ… ΠΊΠ»Π΅Ρ‚ΠΎΠΊ Ρ‡Π΅Π»ΠΎΠ²Π΅ΠΊΠ° Ρ€Π°Π·Π»ΠΈΡ‡Π½ΠΎΠ³ΠΎ происхоТдСния

Π”ΠΈΡΡΠ΅Ρ€Ρ‚Π°Ρ†ΠΈΡΠŸΠΎΠΌΠΎΡ‰ΡŒ Π² Π½Π°ΠΏΠΈΡΠ°Π½ΠΈΠΈΠ£Π·Π½Π°Ρ‚ΡŒ ΡΡ‚ΠΎΠΈΠΌΠΎΡΡ‚ΡŒΠΌΠΎΠ΅ΠΉ Ρ€Π°Π±ΠΎΡ‚Ρ‹

Π’ Π½Π°ΡΡ‚оящСС врСмя ΠΎΠ΄Π½ΠΎΠΉ ΠΈΠ· ΠΏΠ΅Ρ€Π²ΠΎΠΎΡ‡Π΅Ρ€Π΅Π΄Π½Ρ‹Ρ… Π·Π°Π΄Π°Ρ‡ ΠΎΠ½ΠΊΠΎΠ»ΠΎΠ³ΠΈΠΈ являСтся ΠΏΠΎΠ²Ρ‹ΡˆΠ΅Π½ΠΈΠ΅ эффСктивности лСчСния ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅ΠΉ, ΠΊΠ°ΠΊ ΠΏΡƒΡ‚Π΅ΠΌ Ρ€Π°Π·Ρ€Π°Π±ΠΎΡ‚ΠΊΠΈ Π½ΠΎΠ²Ρ‹Ρ… ΠΌΠ΅Ρ‚ΠΎΠ΄ΠΎΠ² лСчСния, Ρ‚Π°ΠΊ ΠΈ ΠΏΡƒΡ‚Π΅ΠΌ ΡΠΎΠ²Π΅Ρ€ΡˆΠ΅Π½ΡΡ‚Π²ΠΎΠ²Π°Π½ΠΈΡ Ρ‚Ρ€Π°Π΄ΠΈΡ†ΠΈΠΎΠ½Π½Ρ‹Ρ… тСрапСвтичСских ΠΏΠΎΠ΄Ρ…ΠΎΠ΄ΠΎΠ². Π₯ирургичСскоС Π²ΠΌΠ΅ΡˆΠ°Ρ‚Π΅Π»ΡŒΡΡ‚Π²ΠΎ, Ρ€Π°Π΄ΠΈΠ°Ρ†ΠΈΠΎΠ½Π½ΠΎΠ΅ ΠΎΠ±Π»ΡƒΡ‡Π΅Π½ΠΈΠ΅ ΠΈ Ρ…имиотСрапия ΠΎΡΡ‚Π°ΡŽΡ‚ΡΡ классичСскими ΠΈ Π½Π°ΠΈΠ±ΠΎΠ»Π΅Π΅ распространСнными ΠΌΠ΅Ρ‚ΠΎΠ΄Π°ΠΌΠΈ лСчСния онкологичСских Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ. К ΡΠΎΠΆΠ°Π»Π΅Π½ΠΈΡŽ… Π§ΠΈΡ‚Π°Ρ‚ΡŒ Π΅Ρ‰Ρ‘ >

Π‘ΠΎΠ΄Π΅Ρ€ΠΆΠ°Π½ΠΈΠ΅

  • Бписок сокращСний

Π“Π»Π°Π²Π° 1. ΠšΠΎΡ€Ρ€Π΅ΠΊΡ†ΠΈΡ Π½Π°Ρ€ΡƒΡˆΠ΅Π½ΠΈΠΉ ΠΊΠ»Π΅Ρ‚ΠΎΡ‡Π½ΠΎΠ³ΠΎ Ρ†ΠΈΠΊΠ»Π° с ΠΏΠΎΠΌΠΎΡ‰ΡŒΡŽ siPHK (ΠΎΠ±Π·ΠΎΡ€ Π»ΠΈΡ‚Π΅Ρ€Π°Ρ‚ΡƒΡ€Ρ‹).

1.1. Π’Π²Π΅Π΄Π΅Π½ΠΈΠ΅: РСгуляция ΠΊΠ»Π΅Ρ‚ΠΎΡ‡Π½ΠΎΠ³ΠΎ Ρ†ΠΈΠΊΠ»Π° ΠΈ Π΅Π΅ Π½Π°Ρ€ΡƒΡˆΠ΅Π½ΠΈΡ ΠΊΠ°ΠΊ мишСни для дСйствия ΠΈΠ½Ρ‚Π΅Ρ€Ρ„Π΅Ρ€ΠΈΡ€ΡƒΡŽΡ‰ΠΈΡ… РНК.

1.2. РСгуляция ΠΊΠ»Π΅Ρ‚ΠΎΡ‡Π½ΠΎΠ³ΠΎ Ρ†ΠΈΠΊΠ»Π°.

1.2.1. Π¦ΠΈΠΊΠ»ΠΈΠ½Ρ‹ ΠΈ Ρ†ΠΈΠΊΠ»ΠΈΠ½-зависимыС ΠΊΠΈΠ½Π°Π·Ρ‹.

1.2.2. РСгуляция активности Ρ†ΠΈΠΊΠ»ΠΈΠ½ΠΎΠ² ΠΈ Ρ†ΠΈΠΊΠ»ΠΈΠ½-зависимых ΠΊΠΈΠ½Π°Π·.

1.2.3. «Π’ΠΎΡ‡ΠΊΠΈ ΠΏΡ€ΠΎΠ²Π΅Ρ€ΠΊΠΈ» ΠΊΠ»Π΅Ρ‚ΠΎΡ‡Π½ΠΎΠ³ΠΎ Ρ†ΠΈΠΊΠ»Π°.

1.3. ΠΠ°Ρ€ΡƒΡˆΠ΅Π½ΠΈΡ ΠΊΠ»Π΅Ρ‚ΠΎΡ‡Π½ΠΎΠ³ΠΎ Ρ†ΠΈΠΊΠ»Π° ΠΈ ΠΈΡ… ΠΏΡ€ΠΈΡ‡ΠΈΠ½Ρ‹.

1.3.1. Her2 (c-erb-B2/Neu).

1.3.2. Π¦ΠΈΠΊΠ»ΠΈΠ½ Π’1.

1.3.3. ΠŸΡ€ΠΎΡ‚Π΅ΠΈΠ½ΠΊΠΈΠ½Π°Π·Π° Π‘ (РКБ).

1.4. ΠšΠ»Π΅Ρ‚ΠΎΡ‡Π½Π°Ρ Π΄ΠΈΡ„Ρ„Π΅Ρ€Π΅Π½Ρ†ΠΈΡ€ΠΎΠ²ΠΊΠ°.

1.4.1. ΠŸΡ€ΠΎΡ†Π΅ΡΡΡ‹ ΠΊΠ»Π΅Ρ‚ΠΎΡ‡Π½ΠΎΠΉ Π΄ΠΈΡ„Ρ„Π΅Ρ€Π΅Π½Ρ†ΠΈΡ€ΠΎΠ²ΠΊΠΈ.

1.4.2. Π˜Π½Π΄ΡƒΠΊΡ‚ΠΎΡ€Ρ‹ ΠΊΠ»Π΅Ρ‚ΠΎΡ‡Π½ΠΎΠΉ Π΄ΠΈΡ„Ρ„Π΅Ρ€Π΅Π½Ρ†ΠΈΡ€ΠΎΠ²ΠΊΠΈ.

1.5. Π˜Π½Π³ΠΈΠ±ΠΈΡ€ΠΎΠ²Π°Π½ΠΈΠ΅ экспрСссии Π³Π΅Π½ΠΎΠ² с ΠΏΠΎΠΌΠΎΡ‰ΡŒΡŽ siPHK.

1.5.1. РНК — интСрфСрСнция.

1.5.2. Активация систСмы Π²Ρ€ΠΎΠΆΠ΄Π΅Π½Π½ΠΎΠ³ΠΎ ΠΈΠΌΠΌΡƒΠ½ΠΈΡ‚Π΅Ρ‚Π° ΠΏΠΎΠ΄ дСйствиСм Π΄Ρ†Π ΠΠš.

1.5.3. ΠšΠ»ΠΈΠ½ΠΈΡ‡Π΅ΡΠΊΠΈΠ΅ испытания ΠΏΡ€Π΅ΠΏΠ°Ρ€Π°Ρ‚ΠΎΠ² Π½Π° ΠΎΡΠ½ΠΎΠ²Π΅ siPHK.

1.5.4. Π˜Π½Π΄ΡƒΠΊΡ†ΠΈΡ ΠΊΠ»Π΅Ρ‚ΠΎΡ‡Π½ΠΎΠΉ Π΄ΠΈΡ„Ρ„Π΅Ρ€Π΅Π½Ρ†ΠΈΡ€ΠΎΠ²ΠΊΠΈ с ΠΏΠΎΠΌΠΎΡ‰ΡŒΡŽ siPHK.

Π˜Π½Ρ‚Π΅Ρ€Ρ„Π΅Ρ€ΠΈΡ€ΡƒΡŽΡ‰Π°Ρ ΠΈ антипролифСративная активности ΠΏΡ€Π΅ΠΏΠ°Ρ€Π°Ρ‚ΠΎΠ² Π΄Ρ†Π ΠΠš Π² ΠΊΡƒΠ»ΡŒΡ‚ΡƒΡ€Π°Ρ… ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²Ρ‹Ρ… ΠΊΠ»Π΅Ρ‚ΠΎΠΊ Ρ‡Π΅Π»ΠΎΠ²Π΅ΠΊΠ° Ρ€Π°Π·Π»ΠΈΡ‡Π½ΠΎΠ³ΠΎ происхоТдСния (Ρ€Π΅Ρ„Π΅Ρ€Π°Ρ‚, курсовая, Π΄ΠΈΠΏΠ»ΠΎΠΌ, ΠΊΠΎΠ½Ρ‚Ρ€ΠΎΠ»ΡŒΠ½Π°Ρ)

Π’ Π½Π°ΡΡ‚оящСС врСмя ΠΎΠ΄Π½ΠΎΠΉ ΠΈΠ· ΠΏΠ΅Ρ€Π²ΠΎΠΎΡ‡Π΅Ρ€Π΅Π΄Π½Ρ‹Ρ… Π·Π°Π΄Π°Ρ‡ ΠΎΠ½ΠΊΠΎΠ»ΠΎΠ³ΠΈΠΈ являСтся ΠΏΠΎΠ²Ρ‹ΡˆΠ΅Π½ΠΈΠ΅ эффСктивности лСчСния ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅ΠΉ, ΠΊΠ°ΠΊ ΠΏΡƒΡ‚Π΅ΠΌ Ρ€Π°Π·Ρ€Π°Π±ΠΎΡ‚ΠΊΠΈ Π½ΠΎΠ²Ρ‹Ρ… ΠΌΠ΅Ρ‚ΠΎΠ΄ΠΎΠ² лСчСния, Ρ‚Π°ΠΊ ΠΈ ΠΏΡƒΡ‚Π΅ΠΌ ΡΠΎΠ²Π΅Ρ€ΡˆΠ΅Π½ΡΡ‚Π²ΠΎΠ²Π°Π½ΠΈΡ Ρ‚Ρ€Π°Π΄ΠΈΡ†ΠΈΠΎΠ½Π½Ρ‹Ρ… тСрапСвтичСских ΠΏΠΎΠ΄Ρ…ΠΎΠ΄ΠΎΠ². Π₯ирургичСскоС Π²ΠΌΠ΅ΡˆΠ°Ρ‚Π΅Π»ΡŒΡΡ‚Π²ΠΎ, Ρ€Π°Π΄ΠΈΠ°Ρ†ΠΈΠΎΠ½Π½ΠΎΠ΅ ΠΎΠ±Π»ΡƒΡ‡Π΅Π½ΠΈΠ΅ ΠΈ Ρ…имиотСрапия ΠΎΡΡ‚Π°ΡŽΡ‚ΡΡ классичСскими ΠΈ Π½Π°ΠΈΠ±ΠΎΠ»Π΅Π΅ распространСнными ΠΌΠ΅Ρ‚ΠΎΠ΄Π°ΠΌΠΈ лСчСния онкологичСских Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ. К ΡΠΎΠΆΠ°Π»Π΅Π½ΠΈΡŽ, Π΄Π°ΠΆΠ΅ комплСкс соврСмСнных ΠΏΡ€ΠΎΡ‚ΠΈΠ²ΠΎΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²Ρ‹Ρ… мСроприятий, часто Π½Π΅ ΠΏΡ€ΠΈΠ²ΠΎΠ΄ΠΈΡ‚ ΠΊ ΠΏΠΎΠ»Π½ΠΎΠΉ элиминации ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²Ρ‹Ρ… ΠΊΠ»Π΅Ρ‚ΠΎΠΊ. ΠŸΠΎΡΡ‚ΠΎΠΌΡƒ, нСсмотря Π½Π° Π·Π°ΠΌΠ΅Ρ‚Π½Ρ‹Π΅ достиТСния Π² ΠΎΠ±Π»Π°ΡΡ‚ΠΈ Ρ‚Π΅Ρ€Π°ΠΏΠΈΠΈ онкологичСских Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ, ΡƒΠ²Π΅Π»ΠΈΡ‡Π΅Π½ΠΈΠ΅ эффСктивности лСчСния злокачСствСнных ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅ΠΉ ΠΈ ΡΠ½ΠΈΠΆΠ΅Π½ΠΈΠ΅ токсичности Ρ…ΠΈΠΌΠΈΠΎΡ‚Π΅Ρ€Π°ΠΏΠΈΠΈ ΠΏΡƒΡ‚Π΅ΠΌ создания лСкарствСнных срСдств Π³Π΅Π½-Π½Π°ΠΏΡ€Π°Π²Π»Π΅Π½Π½ΠΎΠ³ΠΎ дСйствия ΡΠ²Π»ΡΡŽΡ‚ΡΡ ΠΈΡΠΊΠ»ΡŽΡ‡ΠΈΡ‚Π΅Π»ΡŒΠ½ΠΎ Π°ΠΊΡ‚ΡƒΠ°Π»ΡŒΠ½Ρ‹ΠΌΠΈ.

Π’Π°ΠΆΠ½ΡƒΡŽ Ρ€ΠΎΠ»ΡŒ Π² ΠΏΡ€ΠΎΡ†Π΅ΡΡΠ΅ злокачСствСнной трансформации ΠΊΠ»Π΅Ρ‚ΠΎΠΊ ΠΈΠ³Ρ€Π°ΡŽΡ‚ Π³Π΅Π½Ρ‹, гипСрэкспрСссия ΠΊΠΎΡ‚ΠΎΡ€Ρ‹Ρ… ΠΏΡ€ΠΈΠ²ΠΎΠ΄ΠΈΡ‚ ΠΊ Π½Π΅ΠΊΠΎΠ½Ρ‚Ρ€ΠΎΠ»ΠΈΡ€ΡƒΠ΅ΠΌΠΎΠΉ ΠΏΡ€ΠΎΠ»ΠΈΡ„Π΅Ρ€Π°Ρ†ΠΈΠΈ (Π±Π΅Π»ΠΊΠΈ-рСгуляторы ΠΊΠ»Π΅Ρ‚ΠΎΡ‡Π½ΠΎΠ³ΠΎ Ρ†ΠΈΠΊΠ»Π°) [ 1 ], Π±Π»ΠΎΠΊΠΈΡ€ΠΎΠ²Π°Π½ΠΈΡŽ Π°ΠΏΠΎΠΏΡ‚ΠΎΠ·Π° [ 2 ], Π½Π°Ρ€ΡƒΡˆΠ΅Π½ΠΈΡŽ процСссов Π΄ΠΈΡ„Ρ„Π΅Ρ€Π΅Π½Ρ†ΠΈΡ€ΠΎΠ²ΠΊΠΈ [3], ΠΏΠΎΠ²Ρ‹ΡˆΠ΅Π½ΠΈΡŽ уровня гСнСтичСской Π½Π΅ΡΡ‚Π°Π±ΠΈΠ»ΡŒΠ½ΠΎΡΡ‚ΠΈ [4], Π° Ρ‚Π°ΠΊΠΆΠ΅ ΠΊ ΡƒΡΠΈΠ»Π΅Π½ΠΈΡŽ ΠΈΠ½Π²Π°Π·ΠΈΠ²Π½Ρ‹Ρ… свойств ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²ΠΎΠΉ ΠΊΠ»Π΅Ρ‚ΠΊΠΈ [5−9]. НаиболСС часто, Π² ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²Ρ‹Ρ… ΠΊΠ»Π΅Ρ‚ΠΊΠ°Ρ… Π½Π°Π±Π»ΡŽΠ΄Π°Π΅Ρ‚ΡΡ экспрСссия ΠΌΡƒΡ‚Π°Π½Ρ‚Π½Ρ‹Ρ… Ρ„ΠΎΡ€ΠΌ ΠΈΠ»ΠΈ гипСрэкспрСссия Π½ΠΎΡ€ΠΌΠ°Π»ΡŒΠ½Ρ‹Ρ… ΠΊΠ»Π΅Ρ‚ΠΎΡ‡Π½Ρ‹Ρ… Π³Π΅Π½ΠΎΠ², ΠΊΠΎΠ΄ΠΈΡ€ΡƒΡŽΡ‰ΠΈΡ… Ρ€Π΅Ρ†Π΅ΠΏΡ‚ΠΎΡ€Ρ‹, транскрипционныС Ρ„Π°ΠΊΡ‚ΠΎΡ€Ρ‹, Ρ‚ΠΈΡ€ΠΎΠ·ΠΈΠ½-ΠΊΠΈΠ½Π°Π·Ρ‹ ΠΈ Π΄Ρ€ΡƒΠ³ΠΈΠ΅ рСгуляторныС Π±Π΅Π»ΠΊΠΈ.

ΠŸΡƒΡ‚ΠΈ ΠΏΠ΅Ρ€Π΅Π΄Π°Ρ‡ΠΈ сигналов Π² ΠΊΠ»Π΅Ρ‚ΠΊΠ΅ Π²ΠΊΠ»ΡŽΡ‡Π°ΡŽΡ‚ мноТСство Π΄ΡƒΠ±Π»ΠΈΡ€ΡƒΡŽΡ‰ΠΈΡ… Π΄Ρ€ΡƒΠ³ Π΄Ρ€ΡƒΠ³Π° элСмСнтов, поэтому ΠΏΡ€ΠΈ ΠΏΠΎΠ΄Π°Π²Π»Π΅Π½ΠΈΠΈ экспрСссии ΠΎΠ΄Π½ΠΎΠ³ΠΎ ΠΊΠ»Π΅Ρ‚ΠΎΡ‡Π½ΠΎΠ³ΠΎ Ρ„Π°ΠΊΡ‚ΠΎΡ€Π°, ΡƒΡ‡Π°ΡΡ‚Π²ΡƒΡŽΡ‰Π΅Π³ΠΎ Π² ΠΏΠ΅Ρ€Π΅Π΄Π°Ρ‡Π΅ сигнала, Π²ΠΎΠ·ΠΌΠΎΠΆΠ½Π° компСнсация Π΅Π³ΠΎ Ρ„ΡƒΠ½ΠΊΡ†ΠΈΠΈ ΠΏΡƒΡ‚Π΅ΠΌ Π°ΠΊΡ‚ΠΈΠ²Π°Ρ†ΠΈΠΈ Π°Π»ΡŒΡ‚Π΅Ρ€Π½Π°Ρ‚ΠΈΠ²Π½ΠΎΠ³ΠΎ сигнального ΠΏΡƒΡ‚ΠΈ [9]. Π’ ΡΠ²ΡΠ·ΠΈ с ΡΡ‚ΠΈΠΌ, поиск ΠΊΠ»Π΅Ρ‚ΠΎΡ‡Π½Ρ‹Ρ… мишСнСй для Π½Π°ΠΏΡ€Π°Π²Π»Π΅Π½Π½ΠΎΠ³ΠΎ дСйствия тСрапСвтичСских Π°Π³Π΅Π½Ρ‚ΠΎΠ² Ρ€Π°Π·Π»ΠΈΡ‡Π½ΠΎΠΉ ΠΏΡ€ΠΈΡ€ΠΎΠ΄Ρ‹ являСтся Π°ΠΊΡ‚ΡƒΠ°Π»ΡŒΠ½ΠΎΠΉ Π·Π°Π΄Π°Ρ‡Π΅ΠΉ.

РНК-интСрфСрСнция прСдставляСт собой процСсс Π΄Π΅Π³Ρ€Π°Π΄Π°Ρ†ΠΈΠΈ мРНК-мишСни, ΠΊΠΎΡ‚ΠΎΡ€Ρ‹ΠΉ индуцируСтся ΠΏΠΎΠ΄ дСйствиСм Π΄Π²ΡƒΡ†Π΅ΠΏΠΎΡ‡Π΅Ρ‡Π½Ρ‹Ρ… ΠΈΠ½Ρ‚Π΅Ρ€Ρ„Π΅Ρ€ΠΈΡ€ΡƒΡŽΡ‰ΠΈΡ… РНК Π΄Π»ΠΈΠ½ΠΎΠΉ Π½Π΅ ΠΌΠ΅Π½Π΅Π΅ 21−23 звСньСв, Π³ΠΎΠΌΠΎΠ»ΠΎΠ³ΠΈΡ‡Π½Ρ‹Ρ… участку Π΄Π°Π½Π½ΠΎΠΉ мРНК[10]. Π­Ρ‚ΠΎΡ‚ процСсс являСтся эффСктивным способом рСгуляции экспрСссии Π³Π΅Π½ΠΎΠ² Π² ΡΡƒΠΊΠ°Ρ€ΠΈΠΎΡ‚ичСских ΠΊΠ»Π΅Ρ‚ΠΊΠ°Ρ…, появившимся Π² ΠΏΡ€ΠΎΡ†Π΅ΡΡΠ΅ ΡΠ²ΠΎΠ»ΡŽΡ†ΠΈΠΈ.

Π’Π²Π΅Π΄Π΅Π½ΠΈΠ΅

Π² ΠΊΠ»Π΅Ρ‚ΠΊΡƒ Π·1РНК ΠΎΠΏΡ€Π΅Π΄Π΅Π»Π΅Π½Π½ΠΎΠΉ ΠΏΠΎΡΠ»Π΅Π΄ΠΎΠ²Π°Ρ‚Π΅Π»ΡŒΠ½ΠΎΡΡ‚ΠΈ позволяСт эффСктивно ΡΠ½ΠΈΠ·ΠΈΡ‚ΡŒ ΡƒΡ€ΠΎΠ²Π΅Π½ΡŒ экспрСссии Π³Π΅Π½ΠΎΠ², ассоциированных с Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠ΅ΠΌ, Π΄ΠΎ ΡƒΡ€ΠΎΠ²Π½Ρ, ΡΠΎΠΎΡ‚Π²Π΅Ρ‚ΡΡ‚Π²ΡƒΡŽΡ‰Π΅Π³ΠΎ ΡƒΡ€ΠΎΠ²Π½ΡŽ этой мРНК Π² Π½ΠΎΡ€ΠΌΠ°Π»ΡŒΠ½Ρ‹Ρ… ΠΊΠ»Π΅Ρ‚ΠΊΠ°Ρ…. На ΡΠ΅Π³ΠΎΠ΄Π½ΡΡˆΠ½ΠΈΠΉ дСнь ΠΈΠ½Ρ‚Π΅Ρ€Ρ„Π΅Ρ€ΠΈΡ€ΡƒΡŽΡ‰ΠΈΠ΅ РНК Ρ€Π°ΡΡΠΌΠ°Ρ‚Ρ€ΠΈΠ²Π°ΡŽΡ‚ΡΡ Π½Π΅ Ρ‚ΠΎΠ»ΡŒΠΊΠΎ ΠΊΠ°ΠΊ пСрспСктивныС лСкарствСнныС ΠΏΡ€Π΅ΠΏΠ°Ρ€Π°Ρ‚Ρ‹, Π½ΠΎ ΠΈ ΠΊΠ°ΠΊ эффСктивный инструмСнт для поиска молСкулярных мишСнСй для дСйствия лСкарствСнных ΠΏΡ€Π΅ΠΏΠ°Ρ€Π°Ρ‚ΠΎΠ². ИсслСдования ΠΏΠΎΠΊΠ°Π·Ρ‹Π²Π°ΡŽΡ‚, Ρ‡Ρ‚ΠΎ Π² ΠΊΠ°ΠΆΠ΄ΠΎΠΌ ΠΊΠΎΠ½ΠΊΡ€Π΅Ρ‚Π½ΠΎΠΌ случаС онкологичСского заболСвания экспрСссия большого числа Π³Π΅Π½ΠΎΠ², Π°ΠΊΡ‚ΠΈΠ²ΠΈΡ€ΠΎΠ²Π°Π½Π° ΠΈΠ»ΠΈ рСпрСссирована ΠΏΠΎ ΡΡ€Π°Π²Π½Π΅Π½ΠΈΡŽ с Π½ΠΎΡ€ΠΌΠ°Π»ΡŒΠ½Ρ‹ΠΌΠΈ Ρ€ΠΎΠ΄ΠΈΡ‚Π΅Π»ΡŒΡΠΊΠΈΠΌΠΈ ΠΊΠ»Π΅Ρ‚ΠΊΠ°ΠΌΠΈ, ΠΈ, исходя ΠΈΠ· ΡΡ‚ΠΎΠ³ΠΎ, установлСниС Ρ…Ρ€ΠΎΠ½ΠΎΠ»ΠΎΠ³ΠΈΠΈ событий злокачСствСнной трансформации являСтся ΠΏΡ€ΠΎΠ±Π»Π΅ΠΌΠ°Ρ‚ΠΈΡ‡Π½Ρ‹ΠΌ [9]. Π’Π΅ΠΌ Π½Π΅ ΠΌΠ΅Π½Π΅Π΅, ΠΏΠΎΠ΄Π°Π²Π»Π΅Π½ΠΈΠ΅ экспрСссии Π³Π΅Π½ΠΎΠ², ΠΊΠΎΡ‚ΠΎΡ€Ρ‹Π΅ ΠΊΠΎΠ΄ΠΈΡ€ΡƒΡŽΡ‚ Π±Π΅Π»ΠΊΠΈ, Ρ„ΡƒΠ½ΠΊΡ†ΠΈΠΎΠ½Π°Π»ΡŒΠ½ΠΎ располоТСнныС Π½Π° ΠΏΠ΅Ρ€Π΅ΡΠ΅Ρ‡Π΅Π½ΠΈΠΈ рСгуляторных каскадов ΠΈΠ»ΠΈ Π² Π½Π°Ρ‡Π°Π»Π΅ этих каскадов, ΠΌΠΎΠΆΠ΅Ρ‚ привСсти ΠΊ Π²ΠΎΡΡΡ‚Π°Π½ΠΎΠ²Π»Π΅Π½ΠΈΡŽ контроля Π½Π°Π΄ Π΄Π΅Π»Π΅Π½ΠΈΠ΅ΠΌ ΠΊΠ»Π΅Ρ‚ΠΎΠΊ [11]. ВзаимодСйствия Ρ€Π°Π·Π»ΠΈΡ‡Π½Ρ‹Ρ… Π³Π΅Π½ΠΎΠ², ΡƒΡ‡Π°ΡΡ‚Π²ΡƒΡŽΡ‰ΠΈΡ… Π² ΠΏΡ€ΠΎΡ†Π΅ΡΡΠ°Ρ… ΠΊΠ°Π½Ρ†Π΅Ρ€ΠΎΠ³Π΅Π½Π΅Π·Π° интСнсивно ΠΈΡΡΠ»Π΅Π΄ΡƒΡŽΡ‚ΡΡ, Π½ΠΎ Ρ€ΠΎΠ»ΡŒ ΠΊΠ°ΠΆΠ΄ΠΎΠ³ΠΎ Π³Π΅Π½Π° Π² ΡΠ»ΠΎΠΆΠ½ΠΎΠΉ систСмС с Π±ΠΎΠ»Π΅Π΅ Ρ‡Π΅ΠΌ ΠΎΠ΄Π½ΠΈΠΌ гСнСтичСским Π½Π°Ρ€ΡƒΡˆΠ΅Π½ΠΈΠ΅ΠΌ Ρ‚Ρ€Π΅Π±ΡƒΠ΅Ρ‚ ΡƒΠ³Π»ΡƒΠ±Π»Π΅Π½Π½ΠΎΠ³ΠΎ изучСния [12]. ΠΠ°Ρ€ΡƒΡˆΠ΅Π½ΠΈΠ΅ рСгуляции Π³Π΅Π½ΠΎΠ², ΠΊΠΎΠ΄ΠΈΡ€ΡƒΡŽΡ‰ΠΈΡ… ΠΊΠΎΠΌΠΏΠΎΠ½Π΅Π½Ρ‚Ρ‹ ΠΏΠ΅Ρ€Π΅Π΄Π°Ρ‡ΠΈ сигналов ΠΊΠ»Π΅Ρ‚ΠΎΡ‡Π½ΠΎΠ³ΠΎ Ρ†ΠΈΠΊΠ»Π° рассматриваСтся ΠΊΠ°ΠΊ ΠΊΠ»ΡŽΡ‡Π΅Π²ΠΎΠΉ Ρ„Π°ΠΊΡ‚ΠΎΡ€ Π² Ρ€Π°Π·Π²ΠΈΡ‚ΠΈΠΈ Ρ€Π°Π·Π»ΠΈΡ‡Π½Ρ‹Ρ… Ρ‚ΠΈΠΏΠΎΠ² ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅ΠΉ Ρƒ Ρ‡Π΅Π»ΠΎΠ²Π΅ΠΊΠ°[9, И, 12], Ρ‚Π΅ΠΌ Π½Π΅ ΠΌΠ΅Π½Π΅Π΅, тСрапСвтичСская Π·Π½Π°Ρ‡ΠΈΠΌΠΎΡΡ‚ΡŒ ингибирования Ρ‚Π°ΠΊΠΈΡ… Π³Π΅Π½ΠΎΠ² Π² ΠΎΠΏΡƒΡ…олях Ρ€Π°Π·Π»ΠΈΡ‡Π½ΠΎΠ³ΠΎ происхоТдСния ΠΌΠΎΠΆΠ΅Ρ‚ сущСствСнно ΠΎΡ‚Π»ΠΈΡ‡Π°Ρ‚ΡŒΡΡ, поэтому для Π²Ρ‹Π±ΠΎΡ€Π° Π½Π°ΠΈΠ±ΠΎΠ»Π΅Π΅ эффСктивных мишСнСй трСбуСтся сравнСниС Π°Π½Ρ‚ΠΈΠΏΡ€ΠΎΠ»ΠΈΡ„Π΅Ρ€Π°Ρ‚ΠΈΠ²Π½ΠΎΠ³ΠΎ дСйствия ΠΈΠ³ΠΈΠ±ΠΈΡ‚ΠΎΡ€ΠΎΠ² ΠΏΠΎΡ‚Π΅Π½Ρ†ΠΈΠ°Π»ΡŒΠ½Ρ‹Ρ… мишСнСй Π½Π° ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²Ρ‹Ρ… ΠΊΠ»Π΅Ρ‚ΠΊΠ°Ρ… Ρ€Π°Π·Π»ΠΈΡ‡Π½ΠΎΠ³ΠΎ происхоТдСния.

ЦСль ΠΈ Π·Π°Π΄Π°Ρ‡ΠΈ исслСдования

ЦСлью настоящСй Ρ€Π°Π±ΠΎΡ‚Ρ‹ являлось созданиС спСцифичСских ΠΈΠ½Π³ΠΈΠ±ΠΈΡ‚ΠΎΡ€ΠΎΠ² экспрСссии Π³Π΅Π½ΠΎΠ², ΡƒΡ‡Π°ΡΡ‚Π²ΡƒΡŽΡ‰ΠΈΡ… Π² Ρ€Π΅Π³ΡƒΠ»ΡΡ†ΠΈΠΈ ΠΊΠ»Π΅Ρ‚ΠΎΡ‡Π½ΠΎΠ³ΠΎ Ρ†ΠΈΠΊΠ»Π°: НСг2 (с-Π΅Π³Π¬-Π’2, ΠΏΠ΅ΠΉ), ББНВ1 (Ρ†ΠΈΠΊΠ»ΠΈΠ½ Π’1) ΠΈ Π ΠšΠ‘ (ΠΏΡ€ΠΎΡ‚Π΅ΠΈΠ½ΠΊΠΈΠ½Π°Π·Π° Π‘), Π½Π° ΠΎΡΠ½ΠΎΠ²Π΅ Π΄Ρ†Π ΠΠš ΠΈ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΠ΅ влияния этих ΠΈΠ½Π³ΠΈΠ±ΠΈΡ‚ΠΎΡ€ΠΎΠ² Π½Π° ΠΏΡ€ΠΎΠ»ΠΈΡ„Π΅Ρ€Π°Ρ†ΠΈΡŽ ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²Ρ‹Ρ… ΠΊΠ»Π΅Ρ‚ΠΎΠΊ Ρ‡Π΅Π»ΠΎΠ²Π΅ΠΊΠ° Ρ€Π°Π·Π»ΠΈΡ‡Π½ΠΎΠ³ΠΎ происхоТдСния. Π’ Ρ…ΠΎΠ΄Π΅ исслСдования Ρ€Π΅ΡˆΠ°Π»ΠΈΡΡŒ ΡΠ»Π΅Π΄ΡƒΡŽΡ‰ΠΈΠ΅ Π·Π°Π΄Π°Ρ‡ΠΈ:

1. Π˜ΡΡΠ»Π΅Π΄ΠΎΠ²Π°Ρ‚ΡŒ ΡΡ„Ρ„Π΅ΠΊΡ‚ΠΈΠ²Π½ΠΎΡΡ‚ΡŒ ΠΈ Π΄Π»ΠΈΡ‚Π΅Π»ΡŒΠ½ΠΎΡΡ‚ΡŒ ΠΈΠ½Π³ΠΈΠ±ΠΈΡ€ΡƒΡŽΡ‰Π΅Π³ΠΎ дСйствия ΠΌΠ°Π»Ρ‹Ρ… ΠΈΠ½Ρ‚Π΅Ρ€Ρ„Π΅Ρ€ΠΈΡ€ΡƒΡŽΡ‰ΠΈΡ… РНК Ρ„Π ΠΠš), Π½Π°ΠΏΡ€Π°Π²Π»Π΅Π½Π½Ρ‹Ρ… Π½Π° ΠΌΠ ΠΠš Π³Π΅Π½ΠΎΠ² НСг2, Π‘Π‘Π¨1 ΠΈ Π ΠšΠ‘ Π² ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²Ρ‹Ρ… ΠΊΠ»Π΅Ρ‚ΠΊΠ°Ρ… Ρ‡Π΅Π»ΠΎΠ²Π΅ΠΊΠ° Ρ€Π°Π·Π»ΠΈΡ‡Π½ΠΎΠ³ΠΎ происхоТдСния.

2. Π˜ΡΡΠ»Π΅Π΄ΠΎΠ²Π°Ρ‚ΡŒ влияниС Π΄Π»ΠΈΠ½Π½Ρ‹Ρ… Π΄Ρ†Π ΠΠš, Π³ΠΎΠΌΠΎΠ»ΠΎΠ³ΠΈΡ‡Π½Ρ‹Ρ… мРНК Π³Π΅Π½ΠΎΠ² с-ΠœΡƒΡ ΠΈ ΠžΠ Π  Π½Π° ΠΏΡ€ΠΎΠ»ΠΈΡ„Π΅Ρ€Π°Ρ†ΠΈΡŽ ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²Ρ‹Ρ… ΠΊΠ»Π΅Ρ‚ΠΎΠΊ Ρ‡Π΅Π»ΠΎΠ²Π΅ΠΊΠ°.

3. Π˜ΡΡΠ»Π΅Π΄ΠΎΠ²Π°Ρ‚ΡŒ ΠΈΠ·ΠΌΠ΅Π½Π΅Π½ΠΈΠ΅ скорости ΠΏΡ€ΠΎΠ»ΠΈΡ„Π΅Ρ€Π°Ρ†ΠΈΠΈ ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²Ρ‹Ρ… ΠΊΠ»Π΅Ρ‚ΠΎΠΊ Ρ€Π°Π·Π»ΠΈΡ‡Π½ΠΎΠ³ΠΎ происхоТдСния, ΠΏΠΎΠ΄Π²Π΅Ρ€Π³Π½ΡƒΡ‚Ρ‹Ρ… Π΄Π΅ΠΉΡΡ‚Π²ΠΈΡŽ Π·1РНК, Π½Π°ΠΏΡ€Π°Π²Π»Π΅Π½Π½Ρ‹Ρ… Π½Π° ΠΌΠ ΠΠš Π³Π΅Π½ΠΎΠ² НСг2, Π‘Π‘Π«Π’1 ΠΈ Π ΠšΠ‘, послС восстановлСния экспрСссии Π³Π΅Π½ΠΎΠ²-мишСнСй.

4. Π˜ΡΡΠ»Π΅Π΄ΠΎΠ²Π°Ρ‚ΡŒ влияниС ΠΏΠΎΠ»ΡƒΡ‡Π΅Π½Π½Ρ‹Ρ… Π·1РНК Π½Π° ΠΈΠ·ΠΌΠ΅Π½Π΅Π½ΠΈΠ΅ Π³Π΅Π½Π½ΠΎΠΉ экспрСссии Π² ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²Ρ‹Ρ… ΠΊΠ»Π΅Ρ‚ΠΊΠ°Ρ… Ρ‡Π΅Π»ΠΎΠ²Π΅ΠΊΠ° ΠΈ ΠΈΡ… ΠΆΠΈΠ·Π½Π΅ΡΠΏΠΎΡΠΎΠ±Π½ΠΎΡΡ‚ΡŒ.

Π²Ρ‹Π²ΠΎΠ΄Ρ‹.

1. Π Π°Π·Ρ€Π°Π±ΠΎΡ‚Π°Π½Ρ‹ siPHK (siHer, siCyc, siPKC), Π½Π°ΠΏΡ€Π°Π²Π»Π΅Π½Π½Ρ‹Π΅ ΠΊ ΠΌΠ ΠΠš Π³Π΅Π½ΠΎΠ² Her2, CCNB1 ΠΈ Π ΠšΠ‘. Показано, Ρ‡Ρ‚ΠΎ Π΄Π°Π½Π½Ρ‹Π΅ siPHK спСцифично ΠΈΠ½Π³ΠΈΠ±ΠΈΡ€ΡƒΡŽΡ‚ ΡΠΊΡΠΏΡ€Π΅ΡΡΠΈΡŽ Π³Π΅Π½ΠΎΠ²-мишСнСй Π² ΠΊΠ»Π΅Ρ‚ΠΊΠ°Ρ… ΠšΠ’-3−1, SK-N-MC, MCF-7 ΠΈ HL-60: наибольшСС сниТСниС уровня мРНК-мишСнСй (Π΄ΠΎ 10 — 20% ΠΎΡ‚ ΠΊΠΎΠ½Ρ‚роля) достигаСтся Ρ‡Π΅Ρ€Π΅Π· 3 суток послС трансфСкции, Π° ΠΈΡΡ…ΠΎΠ΄Π½Ρ‹ΠΉ ΡƒΡ€ΠΎΠ²Π΅Π½ΡŒ экспрСссии восстанавливаСтся Ρ‡Π΅Ρ€Π΅Π· 7 суток.

2. Показано, Ρ‡Ρ‚ΠΎ ΠΈΠ½Π³ΠΈΠ±ΠΈΡ€ΠΎΠ²Π°Π½ΠΈΠ΅ экспрСссии Π³Π΅Π½ΠΎΠ² Her2, CCNB1 ΠΈ Π ΠšΠ‘ с Ρ€Π°Π·Π½ΠΎΠΉ ΡΡ„Ρ„Π΅ΠΊΡ‚ΠΈΠ²Π½ΠΎΡΡ‚ΡŒΡŽ замСдляСт Π΄Π΅Π»Π΅Π½ΠΈΠ΅ ΠΊΠ»Π΅Ρ‚ΠΎΠΊ ΠšΠ’-3−1, SK-N-MC, MCF-7, ΠΎΠ΄Π½Π°ΠΊΠΎ Π½Π΅ Π²Π»ΠΈΡΠ΅Ρ‚ Π½Π° ΠΏΡ€ΠΎΠ»ΠΈΡ„Π΅Ρ€Π°Ρ†ΠΈΡŽ ΠΊΠ»Π΅Ρ‚ΠΎΠΊ HL-60. ΠžΠ±Π½Π°Ρ€ΡƒΠΆΠ΅Π½ΠΎ, Ρ‡Ρ‚ΠΎ Π½Π°ΠΈΠ±ΠΎΠ»Π΅Π΅ Π²Ρ‹Ρ€Π°ΠΆΠ΅Π½Π½Ρ‹ΠΉ Π°Π½Ρ‚ΠΈΠΏΡ€ΠΎΠ»ΠΈΡ„Π΅Ρ€Π°Ρ‚ΠΈΠ²Π½Ρ‹ΠΉ эффСкт Π½Π°Π±Π»ΡŽΠ΄Π°Π΅Ρ‚ΡΡ Π² ΠΊΠ»Π΅Ρ‚ΠΊΠ°Ρ… нСйробластомы SK-N-MC ΠΏΠΎΠ΄ дСйствиСм siCyc, Π° Ρ€ΠΎΡΡ‚ ΠΊΠ»Π΅Ρ‚ΠΎΠΊ MCF-7 Π½Π°ΠΈΠ±ΠΎΠ»Π΅Π΅ эффСктивно тормозится ΠΏΠΎΠ΄ дСйствиСм siPKC. Π‘Ρ€Π°Π²Π½Π΅Π½ΠΈΠ΅ Π°Π½Ρ‚ΠΈΠΏΡ€ΠΎΠ»ΠΈΡ„Π΅Ρ€Π°Ρ‚ΠΈΠ²Π½ΠΎΠ³ΠΎ дСйствия siPHK, Π½Π°ΠΏΡ€Π°Π²Π»Π΅Π½Π½Ρ‹Ρ… ΠΊ ΠΌΠ ΠΠš Π³Π΅Π½ΠΎΠ² Her2, CCNB1 ΠΈ Π ΠšΠ‘, Π½Π° ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²Ρ‹Π΅ ΠΊΠ»Π΅Ρ‚ΠΊΠΈ Ρ€Π°Π·Π»ΠΈΡ‡Π½ΠΎΠ³ΠΎ происхоТдСния Π²Ρ‹ΠΏΠΎΠ»Π½Π΅Π½ΠΎ Π²ΠΏΠ΅Ρ€Π²Ρ‹Π΅.

3. ΠŸΠΎΠ»ΡƒΡ‡Π΅Π½Ρ‹ Π΄Ρ†Π ΠΠš, Π³ΠΎΠΌΠΎΠ»ΠΎΠ³ΠΈΡ‡Π½Ρ‹Π΅ мРНК Π³Π΅Π½ΠΎΠ² с-ΠœΡƒΡ (dsMyc) ΠΈ GFP (dsEGFP) Π΄Π»ΠΈΠ½ΠΎΠΉ 473 ΠΈ 448 ΠΏ.Π½., соотвСтствСнно. Показано, Ρ‡Ρ‚ΠΎ ΠΏΡ€Π΅ΠΏΠ°Ρ€Π°Ρ‚ dsMyc, Π΄Π΅ΠΉΡΡ‚Π²ΡƒΡŽΡ‰ΠΈΠΉ ΠΊΠ°ΠΊ ΠΏΠΎ ΠΌΠ΅Ρ…Π°Π½ΠΈΠ·ΠΌΡƒ РНК-ΠΈΠ½Ρ‚Π΅Ρ€Ρ„Π΅Ρ€Π΅Π½Ρ†ΠΈΠΈ, Ρ‚Π°ΠΊ ΠΈ Ρ‡Π΅Ρ€Π΅Π· ΠΈΠ½Π΄ΡƒΠΊΡ†ΠΈΡŽ ΠΈΠ½Ρ‚Π΅Ρ€Ρ„Π΅Ρ€ΠΎΠ½ΠΎΠ²ΠΎΠ³ΠΎ ΠΎΡ‚Π²Π΅Ρ‚Π°, сниТаСт ΡƒΡ€ΠΎΠ²Π΅Π½ΡŒ экспрСссии ΠΈΠ½Ρ‚Π΅Ρ€Ρ„Π΅Ρ€ΠΎΠ½-Ρ‡ΡƒΠ²ΡΡ‚Π²ΠΈΡ‚Π΅Π»ΡŒΠ½ΠΎΠ³ΠΎ Π³Π΅Π½Π° с-ΠœΡƒΡ Π±ΠΎΠ»Π΅Π΅ эффСктивно, Ρ‡Π΅ΠΌ ΠΏΡ€Π΅ΠΏΠ°Ρ€Π°Ρ‚ dsEGFP, Π΄Π΅ΠΉΡΡ‚Π²ΡƒΡŽΡ‰ΠΈΠΉ Ρ‚ΠΎΠ»ΡŒΠΊΠΎ ΠΏΠΎ ΠΏΡƒΡ‚ΠΈ ΠΈΠ½Π΄ΡƒΠΊΡ†ΠΈΠΈ ΠΈΠ½Ρ‚Π΅Ρ€Ρ„Π΅Ρ€ΠΎΠ½ΠΎΠ²ΠΎΠ³ΠΎ ΠΎΡ‚Π²Π΅Ρ‚Π°. ΠŸΡ€ΠΈ этом ΠΎΠ±Π° ΠΏΡ€Π΅ΠΏΠ°Ρ€Π°Ρ‚Π° Π΄Ρ†Π ΠΠš со ΡΡ€Π°Π²Π½ΠΈΠΌΠΎΠΉ ΡΡ„Ρ„Π΅ΠΊΡ‚ΠΈΠ²Π½ΠΎΡΡ‚ΡŒΡŽ Π·Π°ΠΌΠ΅Π΄Π»ΡΡŽΡ‚ Π΄Π΅Π»Π΅Π½ΠΈΠ΅ ΠΊΠ»Π΅Ρ‚ΠΎΠΊ ΠšΠ’-3−1 ΠΈ SK-N-MC.

4. Π’ΠΏΠ΅Ρ€Π²Ρ‹Π΅ ΠΈΠ·ΡƒΡ‡Π΅Π½ΠΎ ΠΈΠ·ΠΌΠ΅Π½Π΅Π½ΠΈΠ΅ скорости ΠΏΡ€ΠΎΠ»ΠΈΡ„Π΅Ρ€Π°Ρ†ΠΈΠΈ исслСдованных ΠΊΠ»Π΅Ρ‚ΠΎΡ‡Π½Ρ‹Ρ… Π»ΠΈΠ½ΠΈΠΉ послС восстановлСния экспрСссии Π³Π΅Π½ΠΎΠ² Her2, CCNB1 ΠΈ Π ΠšΠ‘. Показано, Ρ‡Ρ‚ΠΎ ΡΠΊΠΎΡ€ΠΎΡΡ‚ΡŒ дСлСния ΠΊΠ»Π΅Ρ‚ΠΎΠΊ ΠšΠ’-3−1 восстанавливаСтся послС достиТСния исходного уровня экспрСссии Π³Π΅Π½ΠΎΠ²-мишСнСй, Π² Ρ‚ΠΎ Π²Ρ€Π΅ΠΌΡ ΠΊΠ°ΠΊ ΡΠΊΠΎΡ€ΠΎΡΡ‚ΡŒ дСлСния SK-N-MC остаСтся Π² 3 — 10 Ρ€Π°Π· сниТСнной Π΄ΠΎ 12 суток послС воздСйствия siHer, siCyc ΠΈ siPKC, Π° Ρ‚Π°ΠΊΠΆΠ΅ Π΄Π»ΠΈΠ½Π½Ρ‹Ρ… Π΄Ρ†Π ΠΠš.

5. Показано, Ρ‡Ρ‚ΠΎ Π²Π²Π΅Π΄Π΅Π½ΠΈΠ΅ Π² ΠΊΠ»Π΅Ρ‚ΠΊΠΈ siPHK, Π½Π°ΠΏΡ€Π°Π²Π»Π΅Π½Π½Ρ‹Ρ… ΠΊ ΠΌΠ ΠΠš Π³Π΅Π½ΠΎΠ² Her2, CCNB1 ΠΈ Π ΠšΠ‘ Π½Π΅ Π²Ρ‹Π·Ρ‹Π²Π°Π΅Ρ‚ Π³ΠΈΠ±Π΅Π»ΠΈ ΠΊΠ»Π΅Ρ‚ΠΎΠΊ, Π° ΠΏΠΎΠ΄Π°Π²Π»ΡΠ΅Ρ‚ ΠΈΡ… Π΄Π΅Π»Π΅Π½ΠΈΠ΅, Ρ‡Ρ‚ΠΎ подтвСрТдаСтся Π΄Π°Π½Π½Ρ‹ΠΌΠΈ морфологичСского Π°Π½Π°Π»ΠΈΠ·Π°. Напротив, доля ΠΌΠ΅Ρ€Ρ‚Π²Ρ‹Ρ… ΠΊΠ»Π΅Ρ‚ΠΎΠΊ Π² ΠΏΠΎΠΏΡƒΠ»ΡΡ†ΠΈΠΈ, трансфСцированной Π΄Π»ΠΈΠ½Π½ΠΎΠΉ Π΄Ρ†Π ΠΠš Π·Π½Π°Ρ‡ΠΈΡ‚Π΅Π»ΡŒΠ½ΠΎ увСличиваСтся, Ρ‡Ρ‚ΠΎ связано с ΠΈΠ½Π΄ΡƒΠΊΡ†ΠΈΠ΅ΠΉ ΠΈΠ½Ρ‚Π΅Ρ€Ρ„Π΅Ρ€ΠΎΠ½ΠΎΠ²ΠΎΠ³ΠΎ ΠΎΡ‚Π²Π΅Ρ‚Π° ΠΈ Π²Ρ‹Π·Π²Π°Π½Π½ΠΎΠΉ ΠΈΠΌ Π³ΠΈΠ±Π΅Π»ΡŒΡŽ ΠΊΠ»Π΅Ρ‚ΠΎΠΊ.

6. Π‘ ΠΏΠΎΠΌΠΎΡ‰ΡŒΡŽ ΠΏΠΎΠ»Π½ΠΎΠ³Π΅Π½ΠΎΠΌΠ½ΠΎΠ³ΠΎ Π°Π½Π°Π»ΠΈΠ·Π° транскриптома ΠΊΠ»Π΅Ρ‚ΠΎΠΊ SK-N-MC, трансфСцированных siCyc ΠΈ siPKC, ΠΎΠ±Π½Π°Ρ€ΡƒΠΆΠ΅Π½ΠΎ, Ρ‡Ρ‚ΠΎ послС восстановлСния экспрСссии Π³Π΅Π½ΠΎΠ²-мишСнСй, экспрСссия ΠΎΠΏΡ€Π΅Π΄Π΅Π»Π΅Π½Π½Ρ‹Ρ… Π³Π΅Π½ΠΎΠ² (EN02, AK3L1, ALDOC, TXNIP, Π’ NIP, DDIT4 ΠΈ Π΄Ρ€.) остаСтся ΠΈΠ·ΠΌΠ΅Π½Π΅Π½Π½ΠΎΠΉ, Ρ‡Ρ‚ΠΎ ΠΌΠΎΠΆΠ΅Ρ‚ ΠΎΠ±ΡƒΡΠ»Π°Π²Π»ΠΈΠ²Π°Ρ‚ΡŒ Π΄Π»ΠΈΡ‚Π΅Π»ΡŒΠ½ΠΎΠ΅ Π°Π½Ρ‚ΠΈΠΏΡ€ΠΎΠ»ΠΈΡ„Π΅Ρ€Π°Ρ‚ΠΈΠ²Π½ΠΎΠ΅ дСйствиС исслСдуСмых siPHK Π² ΡΡ‚ΠΎΠΉ ΠΊΠ»Π΅Ρ‚ΠΎΡ‡Π½ΠΎΠΉ Π»ΠΈΠ½ΠΈΠΈ.

3.10.

Π—Π°ΠΊΠ»ΡŽΡ‡Π΅Π½ΠΈΠ΅

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ΠΠ°Ρ€ΡƒΡˆΠ΅Π½ΠΈΡ рСгуляции ΠΊΠ»Π΅Ρ‚ΠΎΡ‡Π½ΠΎΠ³ΠΎ Ρ†ΠΈΠΊΠ»Π°, ΡΠ²Π»ΡΡŽΡ‰ΠΈΠ΅ΡΡ ΠΏΡ€ΠΈΡ‡ΠΈΠ½ΠΎΠΉ развития ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²Ρ‹Ρ… Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ, ΠΌΠΎΠ³ΡƒΡ‚ Π±Ρ‹Ρ‚ΡŒ Π²Ρ‹Π·Π²Π°Π½Ρ‹ гипСрэкспрСссиСй ΠΈΠ»ΠΈ экспрСссиСй Ρ…ΠΈΠΌΠ΅Ρ€Π½Ρ‹Ρ… ΠΈΠ»ΠΈ ΠΌΡƒΡ‚Π°Π½Ρ‚Π½Ρ‹Ρ… Π²Π°Ρ€ΠΈΠ°Π½Ρ‚ΠΎΠ² рСгуляторных Ρ„Π°ΠΊΡ‚ΠΎΡ€ΠΎΠ², ΠΊΠΎΡ‚ΠΎΡ€Ρ‹Π΅ относятся ΠΊ Ρ€Π°Π·Π»ΠΈΡ‡Π½Ρ‹ΠΌ классам Π±Π΅Π»ΠΊΠΎΠ². ΠŸΠΎΡΡ‚ΠΎΠΌΡƒ ΡƒΠ½ΠΈΠ²Π΅Ρ€ΡΠ°Π»ΡŒΠ½Ρ‹ΠΌ ΠΏΠΎΠ΄Ρ…ΠΎΠ΄ΠΎΠΌ для подавлСния ΠΈΡ… ΡΠΊΡΠΏΡ€Π΅ΡΡΠΈΠΈ являСтся использованиС ΠΈΠ½Ρ‚Π΅Ρ€Ρ„Π΅Ρ€ΠΈΡ€ΡƒΡŽΡ‰ΠΈΡ… РНК, Π²Ρ‹Π·Ρ‹Π²Π°ΡŽΡ‰ΠΈΡ… Π΄Π΅Π³Ρ€Π°Π΄Π°Ρ†ΠΈΡŽ мРНК-мишСни ΠΏΠΎ ΠΌΠ΅Ρ…Π°Π½ΠΈΠ·ΠΌΡƒ РНК-ΠΈΠ½Ρ‚Π΅Ρ€Ρ„Π΅Ρ€Π΅Π½Ρ†ΠΈΠΈ. Π’Π°ΠΊΠΈΠ΅ ΠΈΠ½Ρ‚Π΅Ρ€Ρ„Π΅Ρ€ΠΈΡ€ΡƒΡŽΡ‰ΠΈΠ΅ РНК ΠΌΠΎΠ³ΡƒΡ‚ Π½Π΅ Ρ‚ΠΎΠ»ΡŒΠΊΠΎ Ρ€Π°ΡΡΠΌΠ°Ρ‚Ρ€ΠΈΠ²Π°Ρ‚ΡŒΡΡ, ΠΊΠ°ΠΊ ΠΏΡ€ΠΎΡ‚ΠΎΠΏΠΈΡ‚Ρ‹ лСкарствСнных ΠΏΡ€Π΅ΠΏΠ°Ρ€Π°Ρ‚ΠΎΠ² Π½ΠΎΠ²ΠΎΠ³ΠΎ поколСния, Π½ΠΎ ΠΈ ΠΈΡΠΏΠΎΠ»ΡŒΠ·ΠΎΠ²Π°Ρ‚ΡŒΡΡ для поиска Π½ΠΎΠ²Ρ‹Ρ… молСкулярных мишСнСй для ΠΏΡ€Π΅ΠΏΠ°Ρ€Π°Ρ‚ΠΎΠ² Π΄Ρ€ΡƒΠ³ΠΎΠ³ΠΎ Ρ‚ΠΈΠΏΠ° дСйствия. Ряд ΠΏΡ€Π΅ΠΏΠ°Ρ€Π°Ρ‚ΠΎΠ² Π½Π° ΠΎΡΠ½ΠΎΠ²Π΅ Π·1РНК ΡƒΠΆΠ΅ ΠΏΡ€ΠΎΡ…ΠΎΠ΄ΠΈΡ‚ клиничСскиС испытания, ΠΊΠΎΡ‚ΠΎΡ€Ρ‹Π΅ позволят Π²Ρ‹ΡΠ²ΠΈΡ‚ΡŒ ΠΊΠ°ΠΊ тСрапСвтичСский ΠΏΠΎΡ‚Π΅Π½Ρ†ΠΈΠ°Π», Ρ‚Π°ΠΊ ΠΈ ΠΈΡ… Π²ΠΎΠ·ΠΌΠΎΠΆΠ½Ρ‹Π΅ ΠΏΠΎΠ±ΠΎΡ‡Π½Ρ‹Π΅ эффСкты. ΠŸΠΎΡΠΊΠΎΠ»ΡŒΠΊΡƒ Ρ†Π΅ΠΏΡŒ ΠΏΠ΅Ρ€Π΅Π΄Π°Ρ‡ΠΈ рСгуляторных сигналов Π² ΠΊΠ»Π΅Ρ‚ΠΊΠ΅ носит каскадный Ρ…Π°Ρ€Π°ΠΊΡ‚Π΅Ρ€ ΠΈ ΡΠΎΡΡ‚ΠΎΠΈΡ‚ ΠΈΠ· ΠΌΠ½ΠΎΠΆΠ΅ΡΡ‚Π²Π° Π΄ΡƒΠ±Π»ΠΈΡ€ΡƒΡŽΡ‰ΠΈΡ… Π΄Ρ€ΡƒΠ³ Π΄Ρ€ΡƒΠ³Π° ΠΏΡƒΡ‚Π΅ΠΉ, Ρ‚ΠΎ Π²Π°ΠΆΠ½ΠΎΠΉ Π·Π°Π΄Π°Ρ‡Π΅ΠΉ являСтся поиск Ρ‚Π°ΠΊΠΈΡ… молСкулярных мишСнСй, ΠΏΠΎΠ΄Π°Π²Π»Π΅Π½ΠΈΠ΅ экспрСссии ΠΊΠΎΡ‚ΠΎΡ€Ρ‹Ρ… ΠΏΡ€ΠΈΠ²ΠΎΠ΄ΠΈΠ»ΠΎ Π±Ρ‹ ΠΊ Π½Π΅ΠΎΠ±Ρ€Π°Ρ‚ΠΈΠΌΡ‹ΠΌ ΠΈ Π½Π΅ΠΊΠΎΠΌΠΏΠ΅Π½ΡΠΈΡ€ΡƒΠ΅ΠΌΡ‹ΠΌ послСдствиям для ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²ΠΎΠΉ ΠΊΠ»Π΅Ρ‚ΠΊΠΈ, ΠΊ ΠΎΡΡ‚Π°Π½ΠΎΠ²ΠΊΠ΅ Π΅Π΅ Π΄Π΅Π»Π΅Π½ΠΈΡ.

Π’ Π½Π°ΡΡ‚оящСй Ρ€Π°Π±ΠΎΡ‚Π΅ Π½Π°ΠΌΠΈ Π±Ρ‹Π»Π° ΠΏΡ€Π΅Π΄Π»ΠΎΠΆΠ΅Π½ΠΈΠ° ΠΈ ΠΎΠΏΡ€ΠΎΠ±ΠΈΡ€ΠΎΠ²Π°Π½Π° схСма исслСдования влияния ΠΈΠ½Ρ‚Π΅Ρ€Ρ„Π΅Ρ€ΠΈΡ€ΡƒΡŽΡ‰ΠΈΡ… РНК Π½Π° ΠΏΡ€ΠΎΠ»ΠΈΡ„Π΅Ρ€Π°Ρ†ΠΈΡŽ ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²Ρ‹Ρ… ΠΊΠ»Π΅Ρ‚ΠΎΠΊ Π½Π° ΠΏΡ€ΠΈΠΌΠ΅Ρ€Π΅ вгРНК, Π³ΠΎΠΌΠΎΠ»ΠΎΠ³ΠΈΡ‡Π½Ρ‹Ρ… мРНК Π³Π΅Π½ΠΎΠ² НСг2, Π‘Π‘Π«Π’1 ΠΈ Π ΠšΠ‘, Π° Ρ‚Π°ΠΊΠΆΠ΅ Π΄Π»ΠΈΠ½Π½Ρ‹Ρ… Π΄Ρ†Π ΠΠš Π³ΠΎΠΌΠΎΠ»ΠΎΠ³ΠΈΡ‡Π½Ρ‹Ρ… мРНК Π³Π΅Π½ΠΎΠ² с-ΠœΡƒΡ ΠΈ ΠžΠ Π . ΠžΠ±Π½Π°Ρ€ΡƒΠΆΠ΅Π½ΠΎ, Ρ‡Ρ‚ΠΎ Π΄Π°Π½Π½Ρ‹Π΅ ΠΈΠ½Ρ‚Π΅Ρ€Ρ„Π΅Ρ€ΠΈΡ€ΡƒΡŽΡ‰ΠΈΠ΅ РНК с Ρ€Π°Π·Π½ΠΎΠΉ ΡΡ„Ρ„Π΅ΠΊΡ‚ΠΈΠ²Π½ΠΎΡΡ‚ΡŒΡŽ Π·Π°ΠΌΠ΅Π΄Π»ΡΡŽΡ‚ Π΄Π΅Π»Π΅Π½ΠΈΠ΅ ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²Ρ‹Ρ… ΠΊΠ»Π΅Ρ‚ΠΎΠΊ Ρ€Π°Π·Π»ΠΈΡ‡Π½ΠΎΠ³ΠΎ происхоТдСния, Ρ‡Ρ‚ΠΎ ΡƒΠΊΠ°Π·Ρ‹Π²Π°Π΅Ρ‚ Π½Π° Π½Π΅ΠΎΠ±Ρ…ΠΎΠ΄ΠΈΠΌΠΎΡΡ‚ΡŒ ΠΈΠ΄Π΅Π½Ρ‚ΠΈΡ„ΠΈΠΊΠ°Ρ†ΠΈΠΈ ΠΈΠ½Π΄ΠΈΠ²ΠΈΠ΄ΡƒΠ°Π»ΡŒΠ½Ρ‹Ρ… молСкулярных мишСнСй для Ρ‚Π΅Ρ€Π°ΠΏΠΈΠΈ ΠΊΠ°ΠΆΠ΄ΠΎΠ³ΠΎ Ρ‚ΠΈΠΏΠ° ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²ΠΎΠ³ΠΎ заболСвания. Π’Ρ€Π°Π΄ΠΈΡ†ΠΈΠΎΠ½Π½ΠΎΠΉ мишСнью для Π³Π΅Π½-Π½Π°ΠΏΡ€Π°Π²Π»Π΅Π½Π½Ρ‹Ρ… ΠΏΡ€Π΅ΠΏΠ°Ρ€Π°Ρ‚ΠΎΠ², ΠΏΡ€Π΅Π΄Π½Π°Π·Π½Π°Ρ‡Π΅Π½Π½Ρ‹Ρ… для лСчСния ΠΎΠΏΡƒΡ…ΠΎΠ»ΠΈ ΠΌΠΎΠ»ΠΎΡ‡Π½ΠΎΠΉ ΠΆΠ΅Π»Π΅Π·Ρ‹ являСтся Π³Π΅Π½ НСг2, ΠΎΠ΄Π½Π°ΠΊΠΎ Π½Π°ΠΌΠΈ ΠΎΠ±Π½Π°Ρ€ΡƒΠΆΠ΅Π½ΠΎ, Ρ‡Ρ‚ΠΎ Π·Π½Π°Ρ‡ΠΈΡ‚Π΅Π»ΡŒΠ½ΠΎ Π±ΠΎΠ»Π΅Π΅ эффСктивной мишСнью для блокирования ΠΏΡ€ΠΎΠ»ΠΈΡ„Π΅Ρ€Π°Ρ†ΠΈΠΈ ΠΊΠ»Π΅Ρ‚ΠΎΠΊ ΠΎΠΏΡƒΡ…ΠΎΠ»ΠΈ ΠΌΠΎΠ»ΠΎΡ‡Π½ΠΎΠΉ ΠΆΠ΅Π»Π΅Π·Ρ‹ МБР-7 являСтся Π³Π΅Π½ РКБ. НаиболСС эффСктивными мишСнями для подавлСния роста нСйробластомы Π‘Πš-М-МБ ΡΠ²Π»ΡΡŽΡ‚ΡΡ Π³Π΅Π½Ρ‹ Π‘Π‘ΠœΠ’1 ΠΈ Π ΠšΠ‘, ΠΈΠ½Π³ΠΈΠ±ΠΈΡ€ΠΎΠ²Π°Π½ΠΈΠ΅ экспрСссии этих Π³Π΅Π½ΠΎΠ² Π²Ρ‹Π·Ρ‹Π²Π°Π΅Ρ‚ Π΄Π»ΠΈΡ‚Π΅Π»ΡŒΠ½ΠΎΠ΅ сниТСниС скорости ΠΏΡ€ΠΎΠ»ΠΈΡ„Π΅Ρ€Π°Ρ†ΠΈΠΈ, ΠΊΠΎΡ‚ΠΎΡ€ΠΎΠ΅ сохраняСтся Π΄Π°ΠΆΠ΅ послС восстановлСния исходного уровня экспрСссии Π³Π΅Π½ΠΎΠ²-мишСнСй. Π”Π°Π½Π½Ρ‹Π΅ Π³Π΅Π½Ρ‹ ΠΌΠΎΠ³ΡƒΡ‚ Ρ€Π°ΡΡΠΌΠ°Ρ‚Ρ€ΠΈΠ²Π°Ρ‚ΡŒΡΡ ΠΊΠ°ΠΊ пСрспСктивныС мишСни для Ρ‚Π΅Ρ€Π°ΠΏΠΈΠΈ нСйробластом ΠΈ Ρ€Π°ΠΊΠ° ΠΌΠ°Π»ΠΎΡ‡Π½ΠΎΠΉ ΠΆΠ΅Π»Π΅Π·Ρ‹.

ΠŸΠΎΠ»ΡƒΡ‡Π΅Π½Π½Ρ‹Π΅ Π½Π°ΠΌΠΈ ΠΈΠ½Π³ΠΈΠ±ΠΈΡ‚ΠΎΡ€Ρ‹ экспрСссии Π³Π΅Π½ΠΎΠ² НСг2, Π‘Π‘Π«Π’1 ΠΈ Π ΠšΠ‘ ΠΌΠΎΠ³ΡƒΡ‚ Ρ€Π°ΡΡΠΌΠ°Ρ‚Ρ€ΠΈΠ²Π°Ρ‚ΡŒΡΡ ΠΊΠ°ΠΊ ΠΏΡ€ΠΎΡ‚ΠΎΡ‚ΠΈΠΏΡ‹ лСкарствСнных срСдств, для сдСрТивания роста ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²Ρ‹Ρ… ΠΊΠ»Π΅Ρ‚ΠΎΠΊ, ΠΏΠ΅Ρ€Π΅ΠΆΠΈΠ²ΡˆΠΈΡ… Ρ…ΠΈΠΌΠΈΠΎΡ‚Π΅Ρ€Π°ΠΏΠΈΡŽ, ΠΈ, Ρ‚Π°ΠΊΠΈΠΌ ΠΎΠ±Ρ€Π°Π·ΠΎΠΌ, ΠΌΠΎΠ³ΡƒΡ‚ ΡΡ‚Π°Ρ‚ΡŒ ΠΎΠ΄Π½ΠΈΠΌ ΠΈΠ· ΠΊΠΎΠΌΠΏΠΎΠ½Π΅Π½Ρ‚ΠΎΠ² комплСксной Ρ‚Π΅Ρ€Π°ΠΏΠΈΠΈ ΠΏΡ€ΠΈ ΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²Ρ‹Ρ… заболСваниях ΠΈ Π½Π΅ΠΉΡ€ΠΎΠ±Π»Π°ΡΡ‚ΠΎΠΌΠ°Ρ…, Π² Ρ‡Π°ΡΡ‚ности. Π˜Π΄Π΅Π½Ρ‚ΠΈΡ„ΠΈΡ†ΠΈΡ€ΠΎΠ²Π°Π½Π½Ρ‹Π΅ молСкулярныС мишСни ΠΌΠΎΠ³ΡƒΡ‚ Π±Ρ‹Ρ‚ΡŒ ΠΈΡΠΏΠΎΠ»ΡŒΠ·ΠΎΠ²Π°Π½Ρ‹ Ρ‚Π°ΠΊΠΆΠ΅ для поиска низкомолСкулярных ΠΈΠ½Π³ΠΈΠ±ΠΈΡ‚ΠΎΡ€ΠΎΠ² Ρ„ΡƒΠ½ΠΊΡ†ΠΈΠΉ этих Π±Π΅Π»ΠΊΠΎΠ², для получСния лСкарствСнных срСдств Π½ΠΎΠ²ΠΎΠ³ΠΎ поколСния. ΠžΠΏΡ€ΠΎΠ±ΠΈΡ€ΠΎΠ²Π°Π½Π½Π°Ρ Π½Π°ΠΌΠΈ тСхнологичСская ΠΏΠ»Π°Ρ‚Ρ„ΠΎΡ€ΠΌΠ° ΠΌΠΎΠΆΠ΅Ρ‚ ΠΈΡΠΏΠΎΠ»ΡŒΠ·ΠΎΠ²Π°Ρ‚ΡŒΡΡ ΠΏΡ€ΠΈ скринингС молСкулярных мишСнСй для ΠΏΡ€ΠΎΡ‚ΠΈΠ²ΠΎΠΎΠΏΡƒΡ…ΠΎΠ»Π΅Π²Ρ‹Ρ… ΠΏΡ€Π΅ΠΏΠ°Ρ€Π°Ρ‚ΠΎΠ² ΠΈ ΠΌΠΎΠΆΠ΅Ρ‚ Π±Ρ‹Ρ‚ΡŒ использована для Ρ€Π°ΡΡˆΠΈΡ€Π΅Π½Π½Ρ‹Ρ… исслСдований Ρ€Π°Π·Π»ΠΈΡ‡Π½ΠΎΠΉ Ρ†Π΅Π»Π΅Π²ΠΎΠΉ направлСнности.

ΠŸΠΎΠΊΠ°Π·Π°Ρ‚ΡŒ вСсь тСкст

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