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Amanda Wong
e-mail address: aowong@umich.edu

Mentor: Michele Swanson, Ph.D. and Joel Swanson, Ph.D.

 

Research Description

In its capacity as a professional phagocyte, the macrophage is susceptible to intracellular membrane damage incurred by the substances it ingests.  Agents capable of inducing such membrane damage include environmental irritants, such as asbestos or silica particles, and intracellular pathogens for which escape from the phagosome is an integral part of their pathogenesis.  Damage to the macrophage’s endocytic compartments, whether the result of shear mechanical injury or more sophisticated mechanisms utilized by pathogens, can lead to inflammatory or infectious pathologies in the tissue in which the phagocyte resides.  Given the high risk for membrane damage in the lifetime of a macrophage, and its pathological consequences, it is likely that dedicated mechanisms exist to prevent or counteract such damage. 

The discovery in our lab of a form of resistance to membrane damage to lysosomes within activated macrophages supports the notion that maintenance of intracellular membrane integrity is important for proper macrophage function.  We use the term “inducible renintence” (IR) to describe the phenomenon we observe when we treat macrophages with factors known to induce classical macrophage activation (eg. LPS, IFN-γ, TNF-α) and then subsequently expose these activated macrophages to agents that induce membrane damage.  Macrophages that are activated before being subjected to damage induction suffer less membrane damage to their lysosomal compartments compared to resting macrophages that have not been activated.  Characterization of the phenomenon was achieved using quantitative, fluorescence microscopy-based methods for measuring lysosomal damage in live bone marrow-derived macrophages.  With this method we have identified IR as a property of activated macrophages, as well as some chemical mediators that induce IR.  Our goal now is to determine the mechanism(s) underlying IR. 

My thesis work will be based in this question, with the broad goal of achieving a more complete understanding of how macrophages respond to membrane damage.  Questions extending from this central question, especially as they relate to macrophage cell biology in the context of innate immunity – on the role of renitence in restricting intracellular bacterial infection, for example – will also be explored.


Publications

Raben N., Wong A., Ralston E., Myerowitz R. (2012) Autophagy and mitochondria in Pompe disease: Nothing is so new as what has long been forgotten. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 160C(1), 13-21.

Ramey, V.H., Wong, A., Fang, J., Howes, S., Barnes, G., Nogales, E. (2011) Subunit organization in the Dam1 kinetochore complex and its ring around microtubules. Mol Biol Cell 22, 4335-4342.

Ramey, V.H., Wang, H.W., Nakajima, Y., Wong, A., Liu, J., Drubin, D., Barnes, G., Nogales, E. (2011). The Dam1 ring binds to the E-hook of tubulin and diffuses along the microtubule. Mol Biol Cell 22, 457–466.

Raben, N., Barden, M., Wong, A., Plotz, P. (2011) Pompe Disease and the Contribution of Autophagy to its Pathogenesis. CML Lysosomal Storage Diseases 9, 1-7.


Abstracts

Wong, A., Barden, M., Li, H.M., Ralston, E., Plotz, P., Raben, N. Modulation of Autophagy as a Therapeutic Approach to a Lysosomal Storage Disorder – Pompe Disease. NIAMS Intramural Research Program (IRP) Retreat, Bethesda, MD, May 2011. (Outstanding Poster Award)

 

Awards

 

 


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