Research Stuart Maudsley

Abstract

The aging process is the strongest risk factor for the development of a wide range of diseases including neurodegenerative disorders, cancer, diabetes and cardiovascular disease. The accumulation of damage to our DNA is one of the strongest drivers of the aging process. We aim to understand how we can reduce DNA damage in aging cells. By reducing DNA damage during aging we can protect cells/tissues and reduce the risk of disease development. We will specifically target G protein-coupled receptors (GPCRs), which are proteins found on the surface of every cell in the body. Almost 50% of all medicines act through GPCRs. We have shown that there are multiple ways that medicines can act through GPCRs, eventually leading to either DNA damaging or DNA protecting effects. We will study how GPCR-targeted medicines can be created that enhance the beneficial signaling effects and simultaneously reduce damaging actions. These medicines therefore show a 'bias' for one form of action compared to another. We recently showed that the Relaxin-3 GPCR (RXFP3) plays an important role in modulating DNA damage in aging. We will determine how different signaling mechanisms linked to this receptor can be controlled by new medicines to reduce DNA damage. Put simply, we will use signaling 'bias' to design new and effective medications to reduce DNA damage in aging and therefore reduce the incidence of aging-related disease.

Researcher(s)

• Promoter: Maudsley Stuart

Research team(s)

• Proteinscience, proteomics and epigenetic signaling (PPES)

Project type(s)

• Research Project

Abstract

Arterial stiffening is a hallmark of vascular aging and is associated with a high risk of cardiovascular disease and end-organ failure in kidney and brain (dementia). No effective therapies to combat this life threatening pathology currently exist, which is largely due to the lack of knowledge of the underlying molecular mechanisms. Therefore, this project aims to identify novel druggable targets which opens up new perspectives for discovery and evaluation of inventive therapies for this growing epidemic. Endothelial dysfunction and vascular calcification are two well known pathological processes leading to arterial stiffness. Established mouse models of both will be used to identify the molecular signaling pathways responsible for arterial stiffness by use of quantitative proteomics coupled with bioinformatic analysis. We will also explore the reciprocal relationship between different pathological processes leading to arterial stiffness. As impaired autophagy has been suggested to play a role in vascular aging, this project will also focus on its role in vascular calcification and stiffness. To explore whether autophagy is a candidate target for future intervention studies, complementary in vivo studies will be performed that investigate the effect of both autophagy induction and deficiency on vascular calcification and stiffness. Ultimately, this project aims to prevent or possibly reverse stiffening of large arteries to reduce long-term risk for end-organ damage.

Researcher(s)

• Promoter: Verhulst Anja
• Co-promoter: Fransen Paul
• Co-promoter: Maudsley Stuart

Research team(s)

• Pathophysiology

Project type(s)

• Research Project

Abstract

Psychiatric treatment of patients with depressive illness is characterized by very low remission and recovery rates due to inefficient and inaccurate diagnoses along with a high final non-responsiveness to all psychopharmacological medication (30% to close to 64% in psychotic depression ). With this IOF-SBO project, we aim to optimize treatment strategies for uni- and bipolar depression with or without psychotic symptoms by finding alternative entry points for the development of new antidepressant drugs and through the discovery of peripheral biomarkers for accurate and objective discriminatory diagnostics. In order to establish databases of relevant biomarkers as well as putative targets for future development of psychopharmacological drugs, we will conduct a prospective clinical trial in which patients with uni- or bipolar disorder, with or without psychotic symptoms, will receive electroconvulsive therapy (ECT), the treatment of last resort when other antidepressants have failed. In parallel, post-mortem patient brain tissues will be retrospectively investigated. Samples of both research arms will be analysed by proteomic and metabolomic methodologies using state of the art liquid chromatography-mass spectrometry (LCMS). Final comparative analyses of differentially expressed proteins, protein networks and metabolic pathways will result in the establishment of drug target candidate (DTC) databases for each of the aforementioned disorders and one diagnostic database containing biomarkers objectively discriminating between the 4 depressive subtypes. These databases will likely, in follow-up trajectories, lead to the development of novel antidepressant drugs and diagnostic assays to be implemented in a diagnostic device. Preliminary interviews with potential industrial partners revealed a great interest for collaboration with both pharmaceutical and technology investors.

Researcher(s)

• Promoter: Morrens Manuel
• Co-promoter: Maudsley Stuart
• Co-promoter: van Nuijs Alexander

Research team(s)

• Collaborative Antwerp Psychiatric Research Institute (CAPRI)

Project type(s)

• Research Project

Abstract

We intend to find out how the most effective, target for drugs can be used in a greater number of ways than thought previously and with fewer side-effects. Our work involves the generation of a greater understanding of how G protein-coupled receptors (GPCRs: the target through which nearly half of all the current drugs in the world work) can control disease in up to three more different ways. These different forms of signaling are often called 'Biased Signals' as the specific drug effects can be channeled into one direction versus another. Our work intends to find out how many ways a drug effect can be biased at these super-important receptors that account for actually 1 in every 100 proteins in the body. It is interesting to note that for nearly all of the world's drugs currently targeting GPCRs were designed with the knowledge of only one of the three potential mechanisms that exist – indeed there may be even more than three different mechanisms! Our work can also pave the way for the discovery of these as of yet unknown mechanisms. In our proposal we focus on a therapeutic GPCR system that we have studied for over 10 years. We are going to investigate how we can identify mechanisms by which we can fine-tune a GPCR called the Relaxin-3 receptor to repair damaged DNA. DNA damage accelerates aging and the onset of nearly all major diseases, e.g. diabetes, cardiovascular disease and dementia. Put simply we will use biased signaling to design better drugs!

Researcher(s)

• Promoter: Maudsley Stuart
• Fellow: Leysen Hanne

Research team(s)

• Proteinscience, proteomics and epigenetic signaling (PPES)

Project type(s)

• Research Project

Abstract

Physical and functional interactions between biomolecules play pivotal roles in all aspects of human health and disease. Gaining a greater understanding of these biomolecular interactions will further expand our understanding of diseases such as cancer, metabolic diseases and neurodegeneration. At UAntwerp, 7 research groups have joined forces to obtain the absolutely necessary equipment to measure these interactions with a Biomolecular Interactions Platform (BIP). This will allow to detect interactions and precisely determine binding affinities between any kind of molecule, from ions and small molecules to high-molecular weight and multi-protein complexes. The BIP will also allow to identify collateral off- targets, crucial in the drug discovery field. Access to a BIP will strongly support ongoing research projects and bring research within the BIP-consortium to a higher level. Since biomolecular interactions are highly influenced by the methodology, it is recommended to measure the interaction by several, independent techniques and continue with the most appropriate one. For this reason, the consortium aims at installing a BIP, consisting of several complementary instruments that each measure biomolecular interactions based on different physical principles. They wish to expand the existing Isothermal Titration Calorimetry with two complementary state-of-the- art techniques: MicroScale Thermophoresis and Grating- Coupled waveguide Interferometry.

Researcher(s)

• Promoter: De Meester Ingrid
• Co-promoter: Delputte Peter
• Co-promoter: De Wael Karolien
• Co-promoter: Dewilde Sylvia
• Co-promoter: De Winter Hans
• Co-promoter: Kooy Frank
• Co-promoter: Lambeir Anne-Marie
• Co-promoter: Maudsley Stuart
• Co-promoter: Van Der Veken Pieter
• Co-promoter: Van Ostade Xaveer

Research team(s)

• Medical Biochemistry

Project type(s)

• Research Project

Abstract

Aging affects the whole body and is linked with metabolic dysfunction, loss of cellular stress resistance and accumulation of cellular damage. Aging is one of the strongest risk factors for the development of both vascular stiffening and neurodegenerative diseases such as Alzheimer's disease (AD). Many of the pathologies linked to aging are now recognized as being highly characteristic of neurodegenerative diseases – suggesting that both vascular stiffening and AD progression may be interconnected via molecular aging pathologies. Protracted, highly complex processes such as aging require the coherent coordination of many different physiological processes. To orchestrate such complex events the body uses proteins termed 'hubs' that can control a multiplicity of physiological processes simultaneously. Our laboratory has already identified multiple 'hubs' within somatic aging networks and in this context we shall specifically investigate, using advanced informatics technologies, how certain key proteins may interconnect these two pathologies. The functional activity of such 'hub' proteins may represent an important target to study for aging, vascular and neurodegenerative research. We propose that the identification of the key age-dependent controlling factors, common between vascular stiffening and AD processes will reveal multiple important targets for future investigation and eventual therapeutic strategy design.

Researcher(s)

• Promoter: Maudsley Stuart
• Co-promoter: De Meyer Guido
• Fellow: Hendrickx Jhana

Research team(s)

Project type(s)

• Research Project

Abstract

The elasticity of the arterial wall is a physiologically elegant solution of nature for smoothing the pulsatile flow of blood from the heart to peripheral tissues. The loss of this elasticity during life is a consequence of pathophysiological alterations in the vessels eventually causing arterial stiffening. Emerging evidence demonstrates that arterial stiffness is an important driving force for multiple heart, kidney and brain pathologies (end-organ damage). Nevertheless, it is currently not clear which molecular pathways contribute to arterial stiffness and whether similar mechanisms link diverse end-organ pathologies. Therefore, the present proposal aims to investigate the following research questions in three work packages: Work package 1: Pathophysiological characterization of two mouse models of arterial stiffening and its relationship with end-organ damage. In this part of the project, we will characterize mouse models of two pathophysiological processes leading to arterial stiffness: endothelial dysfunction and extracellular matrix modification/calcification. Two appropriate mouse models, i.e. eNOS knockout mice and warfarin exposed mice will be examined in a longitudinal manner to investigate the time-dependent development of arterial stiffness and its relationship with end-organ damage (heart and kidney damage and brain degeneration). In a next step, a combined mouse model of arterial stiffness and cerebral beta-amyloid accumulation (cross breeding of one of the above models with APP23 transgenic mice) will be applied to explore whether arterial stiffness is able to enhance beta-amyloid accumulation in the brain, thereby promoting the development/progression of Alzheimer's disease. Techniques that will be used to measure arterial stiffness and end-organ damage include high-frequency ultrasound (Vevo2100), tonometry, pressure myography, immunohistochemistry and behavioral assessment of learning and cognition. Work package 2: What are the age-related molecular mechanisms that underlie arterial stiffness leading to end-organ damage? The second part of the project aims to unravel the (common) molecular pathway(s) that underlie the development of arterial stiffness and the end-organ damage by comparing protein expression/post-translational modification status in arteries, hearts, kidneys and brains originating from mice with and without arterial stiffening, using mass spectrometric isobaric mass-tag labeling proteomics (iTRAQ). We aim to investigate the age-dependent generation of potentially convergent pathological signaling processes, across the lifespan of mice, in stiffening arteries, damaged heart and kidney tissue and degenerating brain tissues. The search for potential common molecular pathway(s) ('disease signatures') underlying the development of arterial stiffness may allow the identification of new targets for the prevention or treatment of arterial stiffness and ensuing end-organ damage. Work package 3: How can arterial stiffness and subsequent end-organ damage be prevented or treated? The last work package will evaluate the efficacy of substances that potentially prevent or treat the development of arterial stiffness and the resulting end-organ damage, more in particular heart and kidney failure as well as beta-amyloid accumulation in the brain. Substances that will be tested include molecules that modulate new targets that were identified during the protein expression studies (WP2), affect endothelial dysfunction (NO-donor or guanylate cyclase activator), inhibit calcification (pyrophosphate) or stimulate autophagy (mTOR inhibitor). Taken together, this project aims to unravel the molecular processes involved in arterial stiffness that might lead to prevention and/or treatment of arterial stiffness and hence reduce the risk and severity of age-related heart and kidney damage and brain degeneration.

Researcher(s)

• Promoter: De Meyer Guido
• Co-promoter: D'Haese Patrick
• Co-promoter: Maudsley Stuart

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project website

Project type(s)

• Research Project

Abstract

The application concerns an innovative microscopy platform for visualizing cells, tissue specimen and living small model organisms in three dimensions at unprecedented speed and with excellent resolution and contrast. As a unique feature, the platform is equipped with a light-sheet module, which is based on an orthogonal configuration of laser-generated, micrometer-thin plane illumination and sensitive one-shot detection. Seamless integration with confocal modalities enables imaging the same sample from the micro- to the mesoscale. The device has a broad application radius in the neurosciences domain inter alia for studying neurodegeneration and -regeneration (e.g. whole brain imaging, optogenetics); but it also has direct utility in various other fields such as cardiovascular research (e.g. plaque formation and stability), plant developmental research (e.g. protein localization during plant growth) and ecotoxicology (e.g. teratogenicity and developmental defects in zebrafish). Furthermore, its modular construction will enable adaptation and targeted expansion for future imaging needs.

Researcher(s)

• Promoter: Timmermans Jean-Pierre
• Co-promoter: Adriaensen Dirk
• Co-promoter: De Meyer Guido
• Co-promoter: De Vos Winnok
• Co-promoter: D'Haese Patrick
• Co-promoter: Giugliano Michele
• Co-promoter: Jordanova Albena
• Co-promoter: Keliris Georgios A.
• Co-promoter: Knapen Dries
• Co-promoter: Maudsley Stuart
• Co-promoter: Ponsaerts Peter
• Co-promoter: Timmerman Vincent
• Co-promoter: Vissenberg Kris

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

Abstract

The instrument acquired in this project is a matrix assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometer capable of mass spectrometry imaging (MSI). This technique is especially developed for the identification of biomolecules in a manner that retains cytological and histological patterning. This novel technical process, abbreviated to MALDI-MSI represents an interesting and extremely productive intersection between mass spectrometric and imaging platforms. Therefore, this grant is bridging 3 University of Antwerp CORE facilities (Center for Proteomics, Bio-Imaging lab and the Biomedical Microscopic Imaging Core). Using this MALDI-MSI platform, multiple research groups, brought together by a common interest in investigating molecular damage associated with aberrant aging mechanisms, will be able to identify a diverse range of small molecules (peptides and metabolites) as well as larger proteins directly on tissue slides, preserving the topological, histological and cytological data. This is not possible with routine proteomics and metabolomics technologies nor with advanced imaging techniques.

Researcher(s)

• Promoter: Maudsley Stuart
• Co-promoter: Baggerman Geert
• Co-promoter: Blust Ronny
• Co-promoter: Bogers John-Paul
• Co-promoter: Dewilde Sylvia
• Co-promoter: Husson Steven
• Co-promoter: Laukens Kris
• Co-promoter: Lemière Filip
• Co-promoter: Mertens Inge
• Co-promoter: Sobott Frank
• Co-promoter: Valkenborg Dirk
• Co-promoter: Van Der Linden Annemie
• Co-promoter: Van Ostade Xaveer

Research team(s)

Project type(s)

• Research Project

Abstract

In the framework of this project, a method will be established for automated and standardized microscopic evaluation of large numbers of biological samples. Protocols will be tailored for histological tissue preparations and for cell cultures. To this end, a combination of optics, robotics and bio-image informatics will be used.

Researcher(s)

• Promoter: De Vos Winnok
• Co-promoter: Bogers John-Paul
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Maudsley Stuart
• Co-promoter: Timmerman Vincent
• Co-promoter: Van Der Linden Annemie

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand the Flemish Public Service. UA provides the Flemish Public Service research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Maudsley Stuart

Research team(s)

Project type(s)

• Research Project

Abstract

Using advanced molecular biological techniques, the promotor intends to develop an in-depth appreciation of how dementias and neurodegeneration occur and in doing, reveal the best mechanisms to combat these diseases with new drug therapies.

Researcher(s)

• Promoter: Maudsley Stuart
• Fellow: Maudsley Stuart

Research team(s)

• Proteinscience, proteomics and epigenetic signaling (PPES)

Project type(s)

• Research Project

Abstract

The primary aim of the proposed research program is to develop an understanding of the quantitative and qualitative post-genomic sequelae of CNS disorders, whose genomic origins have been extensively characterized at the Department of Molecular Genetics and at other Institutions in the VIB, these include: familial Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), frontal temporal lobar degeneration (FTLD), mild cognitive impairment (MCI) and early-onset dementia (EOD).

Researcher(s)

• Promoter: Maudsley Stuart
• Co-promoter: Van Broeckhoven Christine

Research team(s)

Project type(s)

• Research Project

Abstract

Using advanced molecular biological techniques, the promotor intends to develop an in-depth appreciation of how dementias and neurodegeneration occur and in doing, reveal the best mechanisms to combat these diseases with new

Researcher(s)

• Promoter: Maudsley Stuart

Research team(s)

Project type(s)

• Research Project