Изучение структурных и функциональных особенностей организации хроматина в ядрах сперматозоидов человека методом проточной цитометрии тема диссертации и автореферата по ВАК РФ 03.00.25, кандидат биологических наук Семенова, Елена Вячеславовна

• Семенова, Елена Вячеславовна
• кандидат биологических наук
• 2002

Оглавление диссертации кандидат биологических наук Семенова, Елена Вячеславовна

ВВЕДЕНИЕ.

1. ОБЗОР ЛИТЕРАТУРЫ.

1.1. Динамические изменения структуры хроматина ядер сперматозоидов в процессе созревания и оплодотворения: сперматогенез - образование мужского пронуклеуса.

1.1.1. Сперматогенез.

1.1.2. Характеристика протаминов. Модели взаимодействий ДНК протамины.

1.1.3. Дальнейшая стабилизация структуры хроматина в ядрах спермиев.

1.1.4. Структурная организация суперкомпактного хроматина.

1.1.5. Структуры высших порядков организации хроматина и архитектура ядра сперматозоида.

1.1.6. Оплодотворение. Реорганизация хроматина при образовании мужского пронуклеуса.

1.2. Возмущающие воздействия в сперматогенезе: окислительный стресс и температурный дисбаланс.

1.2.1. Окислительный стресс.

1.2.2. Температурный дисбаланс.

1.3. Техника проточной цитофлуориметрии и её использование для изучения состояния хроматина.

1.3.1. Проточноцитометрические исследования упаковки хроматина.

1.3.2. Изучение состояния хроматина ядер сперматозоидов с помощью техники проточной цитометрии.

1.4. Ядерные протеазы и их роль в структурной организации хроматина.

1.4.1. Ядерные протеазы млекопитающих.

1.4.2. Ядерные протеазы мужских половых клеток.

2. МАТЕРИАЛЫ И МЕТОДЫ.

2.1. Проточные цитометры.

2.2. Приготовление образцов для проточноцитометрического анализа.

2.2.1. Стандартная процедура окрашивания клеток бромистым этидием и обработка гепарином.

2.2.2. Обработка ядер сперматозоидов БН-содержащими реагентами и различными ингибиторами протеаз.

2.3. Процедура лечения бесплодия в программе ЭКО.

2.4. Процедура визуализации эндогенной ядерной протеазы спермиев человека.

2.4.1. Приготовление флуоресцентно меченого ингибитора трипсина соевых бобов.

2.4.2. Обработка сперматозоидов флуоресцентно меченым ингибитором трипсина соевых бобов.

2.5. Статистическая обработка результатов.

3. РЕЗУЛЬТАТЫ ИССЛЕДОВАНИЯ.

3.1. Проточноцитометрический метод оценки состояния хроматина ядер мужских половых клеток и результаты лечения бесплодия в программе ЭКО.

3.1.1. Разработка количественного метода регистрации плотности упаковки хроматина в ядрах сперматозоидов с помощью техники проточной цитометрии.

3.1.2. Проточноцитометрический критерий оценки состояния хроматина ядер сперматозоидов человека - тест на фертильность.

3.1.3. Модифицированная математическая модель обсчета и представления проточноцитометрических данных с использованием асимметрий распределения.

3.1.4. Оценка методом проточной цитометрии эффективности очистки сперматозоидов в программе ЭКО.

3.1.5. Влияние состояния хроматина сперматозоидов на динамику развития эмбрионов человека.

3.2. Обнаружение и исследование эндогенной протеолитической активности в ядрах сперматозоидов человека.

3.2.1. Проточноцитометрический анализ факторов, вызывающих декомпактизацию хроматина мужских половых клеток.

3.2.2. Демонстрация ядерной локализации исследуемой протеолитической активности сперматозоидов человека.

4. ОБСУЖДЕНИЕ РЕЗУЛЬТАТОВ.

4.1. Влияние состояния хроматина сперматозоидов человека на результаты процедуры экстракорпорального оплодотворения.

4.1.1. Существующие методы оценки функционального состояния мужских половых клеток.

4.1.2. Основные причины аномальной организации хроматина ядер мужских половых клеток.

4.1.2. Доказательства взаимосвязи нарушений организации хроматина в ядрах сперматозоидов и мужского бесплодия.

4.1.3. Преимущества и недостатки разработанного нами способа диагностики мужского бесплодия.

4.1.4. Оптимизация процедуры оплодотворения в культуре на основании результатов проточноцитометрического анализа.

4.1.5. Участие отцовского генома в раннем эмбриональном развитии. Негативное влияние аномалий в структурной организации хроматина сперматозоидов на динамику этого процесса.

4.2. Возможное участие эндогенной протеолитической активности спермиев человека в реорганизации хроматина при формировании мужского пронуклеуса.

ВЫВОДЫ.

Введение диссертации (часть автореферата) на тему «Изучение структурных и функциональных особенностей организации хроматина в ядрах сперматозоидов человека методом проточной цитометрии»

Одним из важнейших этапов подготовки мужских половых клеток к процессу оплодотворения является радикальная реорганизация структуры ядра в ходе сперматогенеза. Хроматин зрелых сперматозоидов человека отличается от хроматина других типов клеток не только по составу, но и по значительно более высокой степени компактизации: обычные гистоны почти на 85% замещаются специфическими основными белками протаминами, что приводит к практически полному отсутствию нуклеосомной организации ДНК; кроме того, дополнительная стабилизация достигается за счет формирования дисульфидных мостиков между молекулами протаминов, в результате чего образуется исключительно плотная, почти кристаллическая структура (W. Ward and D. Coffey, 1991; J. Kramer and S. Krawetz, 1996). Такое конденсированное состояние хроматина на заключительных стадиях дифференцировки крайне важно для дальнейшего функционирования сперматозоида, с одной стороны, защищая мужской геном от вредных воздействий, с другой стороны, являясь необходимой предпосылкой обратной реорганизации при формировании мужского пронуклеуса. После слияния половых клеток происходит деконденсация плотноупакованного хроматина сперматозоидов, сопровождающаяся заменой протаминов гистонами. В результате генетический материал мужских гамет вновь приобретает характерную для соматических клеток нуклеОсомную организацию, что делает возможным его объединение в одном ядре с женским пронуклеусом и последующую адекватную экспрессию генетической информации (J. Newport, 1987; J. Kleinchmidt and H. Steinbeisser, 1991; G. Almouzni and A. Wolffe, 1993). Очевидно, что нарушение запрограммированной структурной перестройки хроматина сперматозоида может привести к образованию дефектного мужского пронуклеуса и негативно повлиять на ранние стадии эмбриогенеза.

К сожалению, механизмы, обуславливающие такую радикальную переупаковку хроматина, остаются во многом неясными. Поэтому разработка методов тестирования состояния организованного в хроматин генетического материала мужских половых клеток и исследование молекулярно-клеточных факторов, обеспечивающих эффективность процессов реорганизации хроматина в сперматогенезе и после слияния с яйцеклеткой представляют, несомненно, важную медико-биологическую проблему. В связи с развитием новых вспомогательных репродуктивных технологий эта проблема приобрела особую актуальность, поскольку все больше данных свидетельствует о взаимосвязи аномалий упаковки хроматина мужских половых клеток с их оплодотворяющим потенциалом (P. Bianchi et al., 1996; R. Golan et al., 1996; K. Hoshi et al., 1996; B. Sailer et al., 1996; J. Sun et al., 1997; S. Lopes et al., 1998; D. Sakkas et al., 1998; D. Evenson et al., 1994; 1998; D. Irvine et al., 2000; J. Erenpreiss et al., 2001). Кроме того, исследования в этом направлении могут быть полезны для понимания такого фундаментального биологического процесса, как процесс оплодотворения.

Целью настоящей работы является изучение с помощью техники проточной цитометрии структурно-функциональных особенностей организации хроматина ядер сперматозоидов человека и молекулярных механизмов, лежащих в основе коренной переупаковки генетического материала мужских половых клеток в различные периоды жизнедеятельности.

1. ОБЗОР ЛИТЕРАТУРЫ

Заключение диссертации по теме «Гистология, цитология, клеточная биология», Семенова, Елена Вячеславовна

ВЫВОДЫ

1. Разработан метод оценки состояния хроматина в ядрах сперматозоидов человека с помощью техники проточной цитофлуориметрии и на его основе сформулирован критерий, позволяющий классифицировать семенной материал в соответствии с его оплодотворяющей способностью. Данный подход может быть использован для диагностики мужской стерильности и в качестве прогностического теста для оптимизации программ по вспомогательной репродукции.

2. Частота оплодотворения в культуре и частота наступления беременности у пациентов с недостаточной степенью конденсации хроматина ядер сперматозоидов существенно снижены.

3. Аномалии упаковки хроматина в ядрах мужских половых клеток негативно влияют на ранние стадии развития эмбрионов человека, приводя к замедлению темпов дробления в культуре.

4. В ядрах зрелых сперматозоидов человека существует эндогенная протеолитическая активность. Определены условия ее активации и высказана гипотеза о возможной роли данной протеазы в процессе радикальной реорганизации хроматина мужских половых клеток после слияния с яйцеклеткой.

5. Области преимущественной локализации исследуемой протеазны/протеаз в ядрах сперматозоидов человека продемонстрированы с помощью флуоресцентно меченого ингибитора протеаз.

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