Area of knowledge: Human Biology, Microbiology, Molecular Biology, Genetics, Cellular Biology, Genomics and Proteomics, Biochemistry
The extracellular matrix (ECM) is a critical and often overlooked component of the resident microenvironment of the central nervous system (CNS) that plays a pivotal role in neuronal maturation, signaling, ageing and injury (1). The ECM serves multiple functions such as providing structural support and integrity, acting as a reservoir of soluble factors such as cytokines and growth factors, and mediating cellular signaling (2,3). It modulates the transduction of cell surface receptors that internalize signals controlling a variety of functions including neuronal migration, survival, neurite sprouting, myelination of axons, and formation of circuits (4,5). Moreover, in the past years it has been shown that the composition of the spinal cord ECM undergoes important changes in response to injury, generating an inhibitory environment that blocks intrinsic as well as treatment-induced mechanisms of tissue regeneration and functional recovery. Our central hypothesis is that the presentation of a physiological, developmentally appropriate ECM cues will circumvent some of the aspects of the lesion after a spinal cord injury. The present study is focused on understanding the cell extrinsic determinants that drive human motor neurons (MN) degeneration and limits nervous tissue regeneration after traumatic spinal cord injury (SCI). Our proposed study seeks to target some of the ECM candidates of the native and injured spinal cord and understand their effects on MNs survival, growth sprouting and maturation. We will first utilize biochemical purification and quantitative mass spectrometry (MS)-based proteomics to define the composition and nature of remodeling of the mammalian spinal cord matrisome in vivo. We will then leverage our combined expertise in iPSC technologies and biomaterials to establish ECM mimetic matrices that can recapitulate the architecture and modulatory activity of the physiological matrisome to facilitate the survival, growth, and maturation of motor neurons (MNs) in vitro. Finally, our best combinatorial ECM approach will be injected into mouse spinal cord after a severe traumatic spinal cord injury.
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JOB POSITION DESCRIPTION
The candidate involved in this project will have the opportunity to be immersed in multidisciplinary activities in a variety of scientific fields including neuroscience, biomaterials, chemistry, tissue engineering, and regenerative medicine. The candidate will be characterizing the identities of proteins that comprise the spinal cord matrisome across early postnatal, adult, as well as injured spinal cord in mice. These invaluable datasets will highlight age-dependent matrisome alterations and inform the design of developmentally fitting ECM matrices for culturing iPSC-derived spinal motor neurons.
Human iPSCs-derived neurons culture and biochemistry techniques will also be part of the candidate´s work, in order to characterize the effect of native and injured ECM candidates on neuronal behavior in vitro. Finally, the candidate will be involved in the design of new hydrogels with orthogonal ECM candidates that favor neuronal sprouting, survival, and growth after a severe contusion in a mouse model of SCI. Scientific papers writing as well as conference attendance will be highly encouraged. International stays in other research centers are offered. Thus, a thorough formation in different skills (scientific writing, oral communication, IP protection, etc) will also be proposed by the institution.