Mulder Lab, Vascular Medicine

Cardiovascular disease

We aim to clarify disturbances in lipoprotein, lipid and sterol metabolism that contribute to cardiometabolic diseases, with a focus on familial hypercholesterolemia and type 2 diabetes mellitus. We perform basic and translational research to develop specific diagnostic tools and to identify novel targets for improved personalized therapeutic approaches. We perform high throughput lipid and sterol measurements for large cohort studies such as Parelsnoer and Generation R.

Our diagnostic analyses are detailed analyses of lipoprotein profiles of patients with idiopathic dyslipidemias to support optimization of personalized treatments for the individual patient.

Vascular ageing

Non-atherosclerotic vascular ageing underlies dysfunction of multiple organs and is therefore a point-of-convergence for the treatment of age-related diseases such as cardiovascular disease and dementia. Lipids and lipoproteins not only play a role in the development of atherosclerosis, they also modulate vascular function. We apply in vivo and ex vivo models of vascular function to improve our understanding of the role of various sterol- and lipid species in vascular ageing and to identify novel targets for prevention and treatment.

Age-related macular degeneration

Patients with age-related macular degeneration (AMD) typically have elevated plasma levels of large HDL. AMD is one of the leading causes for blindness in the elderly in the Western world and is characterized by lipid-rich extracellular deposits (drusen) between the basal lamina of the retinal pigment epithelium and the Bruch’s membrane. We aim to provide a functional explanation for the association of high large-HDL levels with AMD, also in relation with peripheral blood mononuclear cells, and to investigate the potential of HDL as a therapeutic target.

Alzheimer’s disease

Liver X receptors (LXR) modulate cholesterol homeostasis and inflammation and are involved in cardiometabolic diseases and in various neurodegenerative diseases including Alzheimer’s disease. Activation of LXR appears to be  a promising target in preventing and delaying the progression of AD, but can also cause detrimental fat accumulation in the liver and in the circulation. These adverse effects are not induced by LXR-activating seaweed-derived oxyphytosterols. We aim to provide seaweed-derived compounds with activity against Alzheimer’s disease, thereby contributing to further development of affordable sustainable nutraceuticals to be used in Alzheimer’s disease prevention or in delaying disease progression.

• Seaweed-based products to defeat Alzheimer’s disease. We investigate the potential of lipid extracts derived from Asian and European brown seaweeds and of specific oxyphytosterols in the prevention of disease development using Alzheimer mouse models. In addition, we assess if modulation of the endogenous LXR-agonist desmosterol can be a therapeutic approach for Alzheimer’s disease.
• HDL and peripheral blood mononuclear cells: partners in crime in age-related macular degeneration (AMD). This project aims to unravel the role of HDL and peripheral blood mononuclear cells in the development and progression of AMD.
• Role of lipids and sterols and modulation thereof in the progression of vascular aging. The project addresses age-related imbalances in lipid and sterol homeostasis in a mouse model for accelerated aging. Moreover, we explore brown seaweed as a source of LXR-activating molecules that modulate lipid and/or sterol metabolism to protect against age-related dysfunction of blood vessels.

• Activation of Liver X Receptors and Peroxisome Proliferator-Activated Receptors by Lipid Extracts of Brown Seaweeds: A Potential Application in Alzheimer's Disease? Martens N, Zhan N, Gardi Voortman 1, Frank P J Leijten 1, Connor van Rheenen 1, Suzanne van Leerdam 1, Xicheng Geng 3, Michiel Huybrechts 4, Hongbing Liu 3, Johan W Jonker 5, Folkert Kuipers 5 6, Dieter Lütjohann 7, Tim Vanmierlo 1 2 8, Monique T Mulder. Nutrients. 2023 Jun 30;15(13):3004.
• Identification of Side Chain Oxidized Sterols as Novel Liver X Receptor Agonists with Therapeutic Potential in the Treatment of Cardiovascular and Neurodegenerative Diseases. Zhan N, Boyang Wang, Nikita Martens, Yankai Liu, Shangge Zhao, Gardi Voortman, Jeroen van Rooij, Frank Leijten, Tim Vanmierlo, Folkert Kuipers, Johan W Jonker, Vincent W Bloks, Dieter Lütjohann, Marcella Palumbo, Francesca Zimetti, Maria Pia Adorni, Hongbing Liu, Monique T Mulder. Int J Mol Sci. 2023 Jan 9;24(2):1290.
• Maternal lipid levels in early pregnancy as a predictor of childhood lipid levels: a prospective cohort study. Adank MC, Johansen AK, Benschop L, Van Streun SP, Smak Gregoor AM, Øyri LKL, Mulder MT, Steegers EAP, Holven KB, Roeters van Lennep JE. BMC Pregnancy Childbirth. 2022 Jul 23;22(1):588
• 24(S)-Saringosterol Prevents Cognitive Decline in a Mouse Model for Alzheimer's Disease. Martens N, Schepers M, Zhan N, Leijten F, Voortman G, Tiane A, Rombaut B, Poisquet J, Sande NV, Kerksiek A, Kuipers F, Jonker JW, Liu H, Lütjohann D, Vanmierlo T, Mulder MT. Mar Drugs. 2021 Mar 27;19(4):190.    
• Gestational lipid profile as an early marker of metabolic syndrome in later life: a population-based prospective cohort study. Adank MC, Benschop L, van Streun SP, Smak Gregoor AM, Mulder MT, Steegers EAP, Schalekamp-Timmermans S, Roeters van Lennep JE. BMC Med. 2020 Dec 23;18(1):394
• Dietary Sargassum fusiforme improves memory and reduces amyloid plaque load in an Alzheimer’s disease mouse model. Jeroen Bogie, Cindy Hoeks, Melissa Schepers, Assia Tiane, Ann Cuypers, Frank Leijten, Yupyn Chintapakorn, Thiti Suttiyut, Surachai Pornpakakul, Dicky Struik, Anja Kerksiek, Hong-Bing Liu, Niels Hellings, Pilar Martinez-Martinez, Johan W. Jonker6, Ilse Dewachter, Eric Sijbrands, Jochen Walter, Jerome Hendriks, Albert Groen, Bart Staels, Dieter Lütjohann, Tim Vanmierlo & Monique T. Mulder. Sci Rep. 2019;9:4908. IF: 4.997
• Statin treatment increases lipoprotein(a) levels in subjects with low molecular weight apolipoprotein(a) phenotype. Reyhana Yahya, Kirsten Berk, Adrie Verhoeven, Sven Bos, Leonie van der Zee, Jeanette Touw, Gertraud Erhart, Florian Kronenberg, Reinier Timman, Eric Sijbrands, Jeanine Roeters van Lennep, Monique Mulder. Atherosclerosis. 2019;289:201-205.

Pharmacology (dr. A. Roks)

Internal Medicine (dr. J. Roeters van Lennep)

Geriatrics (prof. dr. F. Mattace Raso)

Neuroscience (dr. D. Jaarsma, dr. M. Schonewille)

Immunology (dr. P. Leenen, dr. W. Dik)

Epidemiology (dr. M Meester-Smoor)

Dietetics (dr. K. Berk)

Ophthalmology (prof. dr. C.C.W. Klaver)

Clinical Genetics (dr. G. Ruijter)

Heelkunde (dr. I. van der Pluijm)

Clinical Chemistry (dr. A. Tintu)

NWO-TTW

Alzheimer NL/AFI

TKI-PPP

Oogprojecten: Uitzicht, RSB, IRRF, Henkes Foundation

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  M.T. (Monique) Mulder, PhD