Aging cells change their metabolic rates, vesicular trafficking, and signaling – all of these factors contribute to the onset and progression of human diseases, such as Alzheimer’s or cancer.
We use mouse models and cellular reprogramming techniques to model human diseases in a cell culture dish. We generate iPSC-derived or fibroblast-derived human neurons to study metabolic control of stemness, differentiation, proliferation, and degeneration.
Implications for Alzheimer’s disease
Alzheimer’s disease (AD) is the most common and severe neurodegenerative disease of our time. With well-characterized general disease hallmarks, molecular mechanisms underlying AD pathogenesis remain elusive. Recently, inhibition of the lysosomal system has been described among the earliest changes in AD brains, likely preceding the well-known aggregation of amyloid and Tau tangles and having yet unknown consequences. Impaired lysosomal system and consequently molecular trafficking and cellular signaling are linked to AD and neurodegeneration. Our lab focuses on the role of lysosomal pathways in the formation of disease hallmarks and the onset of AD. In particular, we seek to understand the chronic up-regulation of mTORC1 signaling, transport of signaling complexes and autophagy in AD neurons.
Regulation of cellular metabolism and its implications for aging
Among others, Insulin growth factor 1 (IGF-1), mTOR, Sestrin 2, and S6K1 mutants are associated with longevity and healthy aging. All of the mentioned proteins merge at the mTORC1 signaling hub to regulate cellular metabolism. We seek how this important cellular kinase itself is regulated by incoming cellular signals and specific metabolites, such as amino acids. Deregulation of mTORC1 activity is associated with a number of human neurodegenerative diseases and cancer. We explore how early cellular changes result in the formation of disease hallmarks to identify ways to specifically prevent disease onset. We assess changes in molecular trafficking, kinase activity, phospho-Tau formation, amyloid processing, and secretion. We aim to identify new components of the pathway to understand sustained metabolic changes reducing life quality and shortening lifespan.
Implications for regeneration after brain injury
We seek to understand the long-term consequences of traumatic brain injury (TBI) and the onset of AD-like symptoms. We seek to modify molecular stress-sensing pathways to promote neuronal regeneration and prevent injury-induced phospho-Tau buildup after TBI.
We are developing compounds to boost regenerative processes in the ailing brain and engineer stem cells for transplantations. Our brain injury studies are realized in collaboration with Drs Haesun Kim (Rutgers), Steven Levison (NJMS), and Bryan Pfister (NJIT).