Postdoc, Ph.D., and M.Sc. Candidates

The Buxboim Lab for Mechanobiology invites applications for postdoc, Ph.D. and M.Sc. student positions for two interdisciplinary projects at the Hebrew University of Jerusalem, Israel.

P1: Mapping the interactions of Nuclear Lamins A and B1 Ig-fold domains using Designed Ankyrin Repeat Proteins

Despite their central role in development, regeneration, disease-causing mutations, and ageing, our understanding the nuclear lamina, chromatin and protein interactions, and a causal relation to pathology is lacking. Here, we utilize Designed Ankyrin Repeat Proteins (DARPins) that were screened and selected against lamins A and B1 motifs. The effects of expressing DARPin binders in cells on nuclear structure and nuclear lamina organization will be characterized and gain/loss-of-function studies will be performed to delineate direct and indirect interactions with nuclear lamina proteins. Chromatin interactions will be studied via lamina associated domain (LAD) mapping in combination with chromatin modifications and transcriptional profiling. By integrating aspiration and indentation-based rheology, we will characterize the implications on nuclear mechanics and how it affects cellular mechanosensitivity of extracellular elasticities. Based on the molecular and cellular measurements, functional studies will be performed to explore the impact on stem cell differentiation, cell senescence and rejuvenation. Transgenic murine models of premature and healthy ageing will be generated to study in vivo effects. Ultimately, a successful completion of our research aims will generate a mechanistic understanding of nuclear lamins, provide a molecular toolbox to study related pathologies, and highlight potential therapeutic strategies.

P2: Age-related niche stiffening effects on the regenerative capacity

of CNS progenitor cells

Normal central nervous system (CNS) functions depend on the life-long maintenance of myelin sheaths thereby providing insulation and metabolic support to the axons. Demyelination is an ongoing process that is linked with inflammation, viral infection, and trauma. Remyelination is medicated via oligodendrocyte progenitor cells (OPCs) that are recruited to demyelinating lesions, proliferate and differentiate to myelinating cells. Under normal conditions, remyelination successfully compensates for demyelination. However, the regenerative capacity of OPCs declines with ageing due to altered environmental cues, including age-related mechanical stiffening of the stem cell niche. Using a murine model, we found that changes in the expression levels of nuclear lamins not only affect nuclear lamina organization but also alters chromatin interactions. We will perform lamina associated domain (LAD) mapping that will be combined with single cell RNA profiling in young versus aged OPCs and in OPCs that will be exposed to soft versus stiff microenvironments. We expect to gain insights into the mechanobiological regulation of age-mediated effects on OPC regenerative capacity, which will provide means to identify therapeutic strategies. The expected impact stems beyond the regulation of CNS progenitor cells – it further addresses the role of nucleus mechanotransduction and niche stiffening in ageing and disease.

Responsibilities

Conduct experimental and/or computational research.

Qualifications

Candidates should have an undergraduate or graduate level training in cell and molecular biology, biophysics, computational biology or bioengineering. A comprehensive research facility and competitive scholarships are offered. Applications should include a CV, list of publication, updated grades sheet, and a short research interest statement (email to [email protected]).