MOLMECHSNKTOX · Molecular Mechanisms of Natural Killer cell Cytotoxicity
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2012-10-01 → 2015-11-01
- Финансиране от ЕС
- 181 418 €
- Участници
- 1
- Схема
- MC-IIF
Линиите свързват координатора с партньорите.
Накратко на български
Молекулярните механизми, които регулират работата на NK клетките и техния начин на борба с вирусите, са в центъра на анализа. По-доброто разбиране на тези процеси помага за по-лесна диагностика и търсене на нови терапии при пациенти с имунни дефицити.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Molecular Mechanisms of Natural Killer cell Cytotoxicity
Patients with immunodeficiencies impairing lymphocyte cytotoxicity typically manifest with life-threatening sepsis-like conditions triggered by infection, with viruses in particular, and caused by excessive proliferation of activated immune cells. Treatment includes chemo-immunotherapy and, in the case of familial disease, subsequent hematopoietic stem cell transplantation, after which the survival rate in children has gone up to around 65% in recent years. To date, only a limited number of genes have been identified as causative of such immunodeficiencies, and a majority of clinical cases remain unexplained, creating difficulties for diagnosis. It is therefore critical to expand our understanding of these syndromes and the role of cytotoxic T cells and natural killer (NK) cells in the disease course. A more complete knowledge of these molecular mechanisms may provide opportunities for new therapies, and a full map of the proteins that regulate cytotoxicity will enable further genetic screening in patients with unexplained immunodeficiencies. This project concerns investigations into the molecular mechanisms of cytotoxic lymphocyte function in the context of human immunodeficiencies, in particular the elucidation of presynaptic signaling cascades involving protein families that regulate vesicle trafficking and membrane fusion required for NK cell exocytosis and function. A cross-disciplinary approach was employed for this study, utilizing cutting-edge skills and knowledge in cell biology, immunology and proteomics, as well as insight from other medical fields. During the course of this study, we have understood that the signaling pathways involving effector proteins regulating NK cell exocytosis are indeed quite complex, and therefore further time is required for more conclusive results to be finalized. Hence, several daughter projects stem out of the original protocol, and are ongoing as a result of this program, with very promising preliminary results. The knowledge obtained through this study, and related ongoing work, significantly contributes to the understanding of the complex molecular mechanisms involved in NK cell lytic granule exocytosis, and thus facilitates the diagnosis and treatment of patients suffering from various, as yet uncured, immunodeficiency syndromes. Moreover, advances in this area offer economic benefits to the public and the private sector alike, and the benefits positively impact the whole European Community.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
The study of immunodeficiency syndromes such as familial hemophagocytic lymphohistiocytosis (FHL) and Griscelli Syndrome type 2 (GS2) has revealed a crucial role for Munc13-4, Stx11, Munc18-2 and Rab27a – members of protein families that regulate vesicle trafficking and membrane fusion – in cytotoxic granule exocytosis. Loss-of-function mutations in these proteins result in loss of target cell killing by NK cells and CD8+ T cells, resulting in a life-threatening sepsis-like condition. The precise molecular role of these proteins in granule release remains, however, incompletely understood.The objective of this project is to elucidate presynaptic signaling cascades leading to NK cell exocytosis, and thus obtain a detailed map of the sub-cellular events leading to granule release. The project is divided into three specific aims. Post-translational modifications of the known regulators of exocytosis will be studied. In a second line of investigation, other, as yet unknown, proteins that might be involved in this process, like priming factors, and scaffold and adaptor proteins will be explored. This work will be facilitated by insights from the fields of neuroscience and hormone release; the mechanisms of which also share an exocytic pathway, and for which molecules important for this process have already been discovered. Additionally, to obtain a complete picture of the signaling pathways involved, spatiotemporal patterns of second messenger dynamics during granule release will be assessed. Importantly, primary, human NK cells will be employed throughout this study.In conclusion, this project aims to increase the understanding of the complex molecular mechanisms involved in NK cell cytotoxicity, thus broadening the spectrum of immunodeficiency syndromes and improving the clinical diagnosis and treatment of FHL patients.
Оригинален текст от CORDIS (на английски).
Участници
- KAROLINSKA INSTITUTET · STOCKHOLMКоординаторШвеция
Връзки
Данни: CORDIS, © Европейски съюз