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Brain Elasticity in Multiple Sclerosis and implications in mechanomodulation of oligodendrocytes: a cellular and clinical approach

Propriedades viscoelásticas do cérebro em Esclerose Múltipla e implicações em mecanomodulação de oligodendrócitos: uma abordagem celular e clínica

Reference
PTDC/MED-NEU/29516/2017
Project Start Date
2018-07-26
Project End Date
2022-07-25
Principal Investigator
Coinvestigator
Scientific Area
Medical and health sciences
Funding Program
Concurso para Financiamento de Projetos de Investigação Científica e Desenvolvimento Tecnológico em Todos os Domínios Científicos - 2017

Abstract

Cells and extracellular matrix (ECM) interact to maintain homeostasis and tissue mechanostasis (mechanical homeostasis). Intracellular contractility scales with extracellular stiffness in vivo and in vitro, and cells respond to mild changes in ECM composition and tissue mechanical properties by adequately secreting ECM elements or favoring degradation. Upon pathological changes, cells may engage fibrosis - producing excessive ECM upon excessive loading-, or undergo apoptosis - in case of excessive mechanical unloading. Recently, the noninvasive technique magnetic resonance elastography (MRE) showed that brain softening occurs with physiological ageing. Strikingly, individuals with Multiple Sclerosis (MS) present exacerbated softening when compared with age-matched controls, presumably due to deregulated ECM, cell death and consequent loss of mechanostasis. We recently reported that oligodendrocytes are mechanosensitive, displaying impaired morphological, differentiation& maturation markers when cultured on substrates with excessive or insufficient stiffness, comparing with brain compliant matrices. We propose that ECM remodeling/degeneration and cell death occurring in MS cause deregulation of cell-ECM mechanostasis and consequent functional impairment, promoting disease progression. The brain ECM is highly complex, hence unsuitable for direct therapy on its multiple deregulated components. Instead, we propose using soluble modulators of key proteins involvedin intracellular contractility to mimic physiological stiffness in a deregulated-ECM context, putatively achieving (i) enhanced oligodendrocyte survival and function, and (ii) normalized production of ECM components by distinct cell types. We aim to tackle the implications of brain softening in MS and test innovative ideas that will open new avenues for future therapeutic intervention. We will unveil mechanisms underlying mechanomodulation of oligodendrocyte differentiation& survival in a context of intracellular contractility, and test several soluble modulators of mechanotransduction using our in vitro setup, aiming to mitigate the negative effects of excessive softness on oligodendrocytes. An observational longitudinal study will be conducted with MS patients. Brain stiffness will be assessed by MRE (complemented with clinical assessment) during routine magnetic resonance performed immediately before engaging treatment with a second-line disease modifying agent(DMA) that we consider being a good candidate as a potential mechamodulator leading to increased intracellular contractility, being the first-line DMA (dimethyl fumarate)-treated patients the clinical control group. Reassessment will occur 12 months later, to evaluate progression of each individual?s brain stiffness before and after treatment.

Institutions

Main Institutions

  • Universidade de Coimbra Centro de Neurociências e Biologia Celular (CNC-UC)

Other Institutions

  • Universidade de Coimbra (UC)
  • Universidade de Coimbra Centro de Neurociências e Biologia Celular (CNC-UC)

Funding 238.740,36 €

Fundação para a Ciência e a Tecnologia (FCT) - Portugal

238.740,36 €
  • 2018-01-01 a 2024-12-31
  • PTDC/MED-NEU/29516/2017