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Design, synthesis and biological evaluation of novel ferroptosis and necroptosis inhibitors. University of Antwerp

Koen Augustyns
Medicinal Chemistry (UAMC)
Different types of cells deaths play a key role in the pathogenesis of many different diseases such as neurodegenerative disorders, multiorgan injury and cancer. In addition to the well-known apoptosis, novel forms of regulated necrosis have been discovered. Particularly, ferroptosis and necroptosis have emerged as new types of non-apoptotic form of cell death of which ferroptosis is involved in reactive oxygen species (ROS) formation. ROS ...

Discovery of necroptosis and ferroptosis inhibitors with potential applications in pathologies associated with regulated necrosis. University of Antwerp

Koen Augustyns
Medicinal Chemistry (UAMC)
The main objective of this research proposal is the discovery of novel chemical tool compounds to investigate the phenotype of necroptosis and ferroptosis at a molecular level in more detail. The use of such tool compounds will result in a better understanding of the different pathways of regulated necrosis, and will also demonstrate where therapeutic targeting is possible, ultimately leading to target identification and validation for novel and ...

Discovery of necroptosis and ferroptosis inhibitors with potential applications in pathologies associated with regulated necrosis. University of Antwerp

Koen Augustyns
Medicinal Chemistry (UAMC)
The main objective of this research proposal is the discovery of novel chemical tool compounds to investigate the phenotype of necroptosis and ferroptosis at a molecular level in more detail. The use of such tool compounds will result in a better understanding of the different pathways of regulated necrosis, and will also demonstrate where therapeutic targeting is possible, ultimately leading to target identification and validation for novel and ...

Necroptosis pathway activation and its role in neuronal cell loss in Alzheimer's disease KU Leuven

Bart De Strooper
Laboratory for the Research of Neurodegenerative Diseases (VIB-KU Leuven)

Accumulation of misfolded, aggregated proteins and the associated neuronal cell loss are considered the most fundamental hallmarks of neurodegenerative diseases, including Alzheimer's disease (AD). Despite the prevalent neuronal cell death in AD, the modality of cell death and molecular events leading to such neuronal cell death mechanisms are seldom investigated. Lack of preclinical models that sufficiently recapitulate AD-relevant neuronal ...

The link between Tau pathology, Granulovacuolar neurodegeneration and Necroptosis in Alzheimer’s Disease. KU Leuven

Dietmar Thal
Laboratory for Neuropathology, Laboratory of Cell Death Research & Therapy (VIB-KU Leuven), Laboratory for the Research of Neurodegenerative Diseases (VIB-KU Leuven)
Neuronal degeneration is the hallmark of Alzheimer's Disease (AD) and the final outcome of complex cellular processes that begin decades before clinical symptoms appear. Although Tau pathology has long been linked to neuronal degeneration and dementia, the molecular mechanisms driving neuronal cell death remain poorly understood. Recent research from my host laboratories has revealed that pathological Tau triggers neuronal necroptosis in AD and ...

Factors that determine RIPK1-dependent necroptosis Ghent University

Peter Vandenabeele
Department of Biomedical molecular biology

When TNF is binding to TNF receptor 1 (TNFR1), the cellular outcomes can be fundamentally different: survival and pro-inflammatory signaling versus cell death signaling to apoptosis or by necroptosis. The former outcomes are initiated by receptor-associated complex I formation, while the latter outcomes are a consequence of a cytosolic complex II. In this project we want to visualize the dynamics of this complexes, especially complex II by ...

Exploiting necroptosis targeting in cancer therapy: High content screening and validation Ghent University

Peter Vandenabeele
Department of Biomedical molecular biology

The balance determines life or death between cell death and cell growth. Cancer occurs when this balance is disturbed. Cancer cells exhibit different levels of resistance to cell death, which cancer cells continue to survive and the tumor can spread. Often, cancer cells also acquire resistance to therapeutic treatment. Recently, it was next to apoptosis (spontaneous cell death) identified a new form of programmed cell death, viz. Necroptosis. ...

MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease KU Leuven

Bart De Strooper
Laboratory for the Research of Neurodegenerative Diseases (VIB-KU Leuven)

Neuronal cell loss is a defining feature of Alzheimer's disease (AD), but the underlying mechanisms remain unclear. We xenografted human or mouse neurons into the brain of a mouse model of AD. Only human neurons displayed tangles, Gallyas silver staining, granulovacuolar neurodegeneration (GVD), phosphorylated tau blood biomarkers, and considerable neuronal cell loss. The long noncoding RNA MEG3 was strongly up-regulated in human ...

DR3 – a Novel Inducer of Necroptosis and Mediator of Intestinal Inflammation and Pathology Ghent University

Peter Vandenabeele
Department of Biomedical molecular biology

Necroptosis is an inflammation-inducing process of induced necrosis. Death receptor 3 (DR3) is much less studied compared to other Death receptors. DR3-antibody inhibition in different mouse models of colitis leads to weakening of disease. This project aim to investigate whether DR3 is involved in Necrotizing enterocolitis (NEC) and whether DR3’s induction of necroptosis is a mechanism in its pathogenesis.

Spatio-temporal aspects and function of MLKL at plasma membrane during necroptosis. Ghent University

Peter Vandenabeele
Department of Biomedical molecular biology

MLKL was recently discovered as crucial executioner in necroptosis. Upon RIPK3-mediated phosphorylation, MLKL relocalizes at the plasma membrane. While MLKL function is still controverted, recent data advocate for a pore-forming capacity of MLKL. In this project, we will visualize the molecular events leading to MLKL plasma membrane relocalization and determine MLKL dynamics and function at the plasma membrane.