Integration of cellular metabolism and signaling = homeostasis...?

    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.

    2. 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 aim to identify new components of the pathway to understand sustained metabolic changes reducing life quality and shortening lifespan. In collaboration with Drs Gal Haspel (NJIT) and Hieronim Jakubowski (ICPH, NJMS), we conduct longevity and locomotion assays as functional readout for fitness in C. elegans as well as biochemical and high-resolution microscopy of the aging mouse brain. These analyses help us to assess the role of amino acid metabolites on aging and fitness.

    3. 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, 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 onset of AD. In patricular, we seek to understand the chronic up-regulation of mTORC1 signaling in AD neurons, fine-tune its activity to physiological levels to prevent disease progression.

    4. Implications for regeneration after brain injury
    We seek to understand the long-term consequences of traumatic brain injury (TBI) and onset of AD-like disease. We characterize and modify the status of Wnt/GSK3 transduction pathway to promote neuronal regeneration and prevent injury-induced phospho-Tau formation and 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 Kevin Pang (VA, NJMS), Steven Levison (NJMS), and Bryan Pfister (NJIT).

mTORC1 signaling2

      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.

The mechanistic target of Rapamycin complex 1 (mTORC1) in involved in the regulation of catabolic and anabolic processes in the cell. 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 disease 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.

1. Regulation of protein synthesis and degradation at the lysosome

pTau staining
TBI peptides

Dobrowolski Lab

Federated Department of Biological Sciences

Rutgers University-Newark and  New Jersey Institute of Technology

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