Модель крыс с нокаутом гена DAT: дофаминовая дисфункция, эпигенетические механизмы и подходы к генной терапии. Обзор научной литературы

Введение. Модель животных с нокаутом кодирующего гена (DAT-KO) представляет собой ценный экспериментальный инструмент для изучения патофизиологии заболеваний, связанных с нарушением дофаминовой функции, таких как синдром дефицита внимания и гиперактивности, шизофрения, болезнь Паркинсона. Целью обзора является систематизация научных данных о дофаминергической дисфункции, эпигенетических механизмах и подходах к генной терапии на модели крыс с нокаутом гена DAT (DAT-KO).
Материалы и методы. Поиск литературных источников проводился в базах данных PubMed, Scopus, Web of Science и Google Scholar. В обзор включены оригинальные исследования только на английском языке (n=49), опубликованные в период с 1991 по 2025 гг. и посвященные структуре и функциям DAT, моделям нокаута, эпигенетическим механизмам и генной терапии. Результаты представлены в виде блок-схемы PRISMA и рисунков.
Результаты исследования. В моделях нокаута DAT у крыс наблюдается 5–7-кратное повышение внеклеточного уровня дофамина, гиперактивность и структурные изменения в базальных ганглиях, что отражает дофаминовую дисфункцию. Гомозиготные нокаутные животные полностью лишены функционального белка DAT, тогда как гетерозиготы сохраняют около половины его активности и демонстрируют промежуточные фенотипы. Эпигенетическая регуляция экспрессии гена Slc6a3 осуществляется через метилирование ДНК, модификации гистонов (включая ацетилирование H3K9/K14 и метилирование H3K27) и микроРНК, причем в постнатальном онтогенезе крыс промотор DAT остается гипометилированным, что обеспечивает возрастное повышение его экспрессии. Генная терапия с использованием вирусных векторов демонстрирует потенциал восстановления функции DAT.
Обсуждение и заключение. Модель DAT-KO у крыс достоверно воспроизводит ключевые нейрохимические и морфологические особенности дофаминергической дисфункции. Полнота картины, однако, во многом ограничена фрагментарностью данных о динамике эпигенетической регуляции экспрессии дофаминового транспортера в ходе прогрессирования заболеваний и недостаточной доказательной базой по дозозависимым эффектам и долгосрочной безопасности генной терапии. Эпигенетические механизмы открывают новые направления для поиска биомаркеров и персонализированной терапии. Применение генной терапии с использованием аденоассоциированных и лентивирусных векторов демонстрирует потенциал восстановления функции DAT в доклинических моделях, однако требует дальнейшего уточнения дозозависимых эффектов и минимизации иммунного ответа. Перспективными направлениями остаются интеграция эпигенетических маркеров в клинические протоколы, разработка комбинированных стратегий и валидация модели DAT-KO при коморбидных состояниях.

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