H2020Индивидуална стипендия2019–2020

CL_Exocytosis · “Molecular dissection of cytotoxic lymphocyte exocytosis

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2019-01-01 → 2020-12-31
Финансиране от ЕС: 173 857 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Молекулярните механизми, чрез които цитотоксичните лимфоцити освобождават протеини за унищожаване на ракови или заразени с вируси клетки, са в центъра на анализа. Познанията за този процес помагат за по-добра диагностика и терапия при тежки възпалителни синдроми и рак.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

“Molecular dissection of cytotoxic lymphocyte exocytosis

The Action CL Exocytosis 794830 was carried by the researcher Dr Donatella Galgano under the supervision of Prof. Yenan Bryceson at the Centre Hematology Regenerative Medicine (HERM), Karolinska Institutet, Stockholm, Sweden from January 1st 2019 to December 31st 2020. The project focused on studying the molecular mechanism underlying cytotoxic lymphocyte effector function. These cells are part of the immune system and are responsible for destroying virus-infected or tumor cells. Cytotoxic lymphocytes kill their targets through directed release of cytotoxic proteins which are stored in specialized organelles, termed cytotoxic granules (CGs). The exit of CGs from the cells towards the target is called exocytosis. Defects in CG exocytosis profoundly impair cytotoxic lymphocyte function, resulting in severe, often life-threatening hyperinflammatory syndromes, as well as increased susceptibility to cancer. Clinically, these syndromes are characterized by an uncontrolled growth of immune cells, including cytotoxic lymphocytes and macrophages which infiltrate other tissues, leading directly to necrosis and organ failure. Nowadays, the only curative treatment for these severe conditions is hematopoietic stem cell transplantation, often not without complication. Increasing knowledge about cytotoxic lymphocytes, their activation and molecular mechanisms regulating their effector functions is needed to study such diseases in detail. Using advanced molecular techniques, this research aimed to study how different proteins are required for the effector functions of cytotoxic lymphocytes as well as identify novel regulators that control CG exocytosis. A detailed dissection of lymphocyte cytotoxicity promises to guide new strategies for the diagnosis and therapy of patients suffering of hyperinflammatory syndromes associated with defects in lymphocyte cytotoxicity.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

My PhD experience in the field of immunology focused on deciphering vesicular pathways underlying T cell activation profoundly motivated my move to Dr. Bryceson’s lab, which offers a unique opportunity to explore cytotoxic lymphocyte (CL) exocytosis in the context of human disease. Cytotoxic lymphocyte exocytosis is critical for life, with mutations in genes required for cytotoxicity causative of severe, early-onset hyperinflammatory syndromes. Genetic studies have identified several cytosolic proteins required for CL exocytosis. However, understanding of how these proteins cooperate for exocytosis, their interaction partners and how their activities are regulated is still limited. I propose strategies to gain insight to the molecular regulation of human CL exocytosis. First, prompted by genetic studies, I aim to study the contribution of two distinct Munc13-4 isoforms to lymphocyte cytotoxicity by dissecting their role in cytotoxic granule (CG) exocytosis using advanced live-cell imaging as well as identifying their interaction partners using quantitative mass spectrometry (MS). Second, recycling endosome (RE) have recently been implicated in CG exocytosis, delivering syntaxin-11, an effector molecule required for CG fusion, to the plasma membrane. I plan to use a high-throughput MS approach to identify RE constituents and cargo in order to define new components that may be critical for CG exocytosis. Results will provide novel mechanistic insights to CL exocytosis, which will also be relevant for other exocytic systems. Providing detailed molecular understanding of lymphocyte cytotoxicity in both healthy and pathological conditions, insights promise to guide improved diagnosis and therapy of immune disorders associated with defects in lymphocyte cytotoxicity. Yearning to build a successful academic career, the excellence of the host laboratory will allow me to successfully purse this project and expand technical expertise and my scientific horizon.

Оригинален текст от CORDIS (на английски).

Участници

KAROLINSKA INSTITUTET · STOCKHOLMКоординаторШвеция