ENIGMA · Histone Deacetylase protein complex controls cardiac hypertrophy
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2012-07-01 → 2016-06-30
- Финансиране от ЕС
- 100 000 €
- Участници
- 1
- Схема
- MC-CIG
Линиите свързват координатора с партньорите.
Накратко на български
Протеините HDAC4 и ENIGMA влияят върху превръщането на гладките мускулни клетки в кръвоносните съдове в костна тъкан. Разбирането на този механизъм помага при търсенето на начини за ограничаване на калцификацията на сърдечните клапи и артериите.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Enigma – Histone Deacetylase protein complex controls cardiac hypertrophy
Arterial calcification and valvular calcifications are associated with significant morbidity and mortality. Studies have now conclusively showed that an osteochondrogenic differentiation of vascular smooth muscle cells (VSMC) is a key mechanism in the development of vascular calcification, opening a direction for therapeutic interventions. We used VSMCs, ex-vivo mouse aortic rings and human calcified aortic valves to show that HDAC4 is upregulated in vascular and valve calcification. Despite being exclusively cytoplasmic in VSMCs we show using both gain- and loss- of function approaches that HDAC4 is a positive regulator of the process. In the cytoplasm HDAC4 binds to the LIM domains of the adaptor protein ENIGMA (Pdlim7) to promote vascular ossification of VSMCs. We identified a new role and a new mechanistic paradigm for HDAC4.We provide multiple lines of evidence that the cytoplasmic activity of HDAC4 promotes vascular calcification, and identify HDAC4, and ENIGMA as mediators of this pathological process.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
A variety of cardiovascular disorders provoke the heart to enlarge through hypertrophic growth of cardiomyocytes, resulting in heart failure and sudden death. Based on in vivo and in vitro models of cardiac hypertrophy, it is apparent that histone-modifying enzymes act as key regulators of cardiac growth. Although their upstream regulation has been studied, the mechanism whereby class IIa Histone deacetylases (HDACs) repress transcription has not been elucidated.In preliminary studies, we performed an association screen with the Class IIa HDAC4 and a heart cDNA library, and identified the protein ENIGMA as an HDAC4 binding partner. Further studies showed that other PDZ and LIM proteins do not bind class IIa HDACs, and that ENIGMA can bind class I HDACs with its PDZ domain and class IIa HDACs with its 3LIM domain. These novel preliminary results give rise to our main hypothesis that Enigma is a protein scaffold anchoring class I HDACs to class IIa HDACs to create a complex with high deacetylase activity that represses cardiac hypertrophy.A combination of detailed studies will be conducted to gain an understanding of the composition of this protein complex and its biological role. Specifically, I propose to (1) map the interactions between class IIa HDACs and ENIGMA in detail; (2) determine the endogenous class I HDACs-ENIGMA-Class IIa HDACs' ternary complex; and (3) determine the role of the ENIGMA complex in suppressing hypertrophy in vivo.Multidisciplinary approaches will be used to examine this hypothesis. Biochemical and molecular biology methods, as well as yeast assays, will be used to assess the interaction between ENIGMA and the HDACs. Further cell biology studies will examine the biological role of the ENIGMA ternary complex in cardiomyocytes in primary cultures, using a novel tissue engineered cardiac construct, and using a gene targeted mouse model. These studies will provide important insights into the mechanisms of cardiac hypertrophy.
Оригинален текст от CORDIS (на английски).
Участници
- THE HEALTH CORPORATION - RAMBAM · HaifaКоординаторИзраел
Връзки
Данни: CORDIS, © Европейски съюз