The School of Molecular and Cellular Biology at the University of Illinois at Urbana-Champaign

Our long-term objectives are to achieve a more thorough understanding of neutrophil polarity and chemotaxis by elucidating another key, but poorly defined cellular and molecular aspect of neutrophil migration - cell interactions with the extracellular matrix (ECM) substrate. Our recent experiments with primary human neutrophils and a unique human neutrophil culture model, aimed at dissecting the molecular program governing neutrophil adhesion and de-adhesion, led to the discovery of its potential key components. We hypothesize that these molecules cooperate to promote pseudopod adhesion and de-adhesion of the trailing edge. The results of these experiments will allow us to understand the signaling circuitry that controls neutrophil adhesion and de-adhesion and how these two responses integrate within the chemotactic signaling network leading to neutrophil polarity and directional migration. We also expect that the mechanism is likely to constitute a broadly conserved module for other amoeboid cells. Furthermore, we think that information from this study will help to identify potential targets for therapeutic interventions against inflammatory and autoimmune disorders. Moreover, because chemoattractant receptors have been shown to mediate tumor cell invasion and metastasis, we expect that results from this study may provide promising targets for the development of novel therapeutic strategies in the treatment of cancer.

Figure 1. Human neutrophils stimulated with chemoattractant exhibit polarized morphology and asymmetric cytoskeletal assemblies.

2. The molecular programs that control fate decisions of human embryonic stem cells
Although the field is only in its infancy, human embryonic stem cells (hESCs) can grow indefinitely as undifferentiated cells (Fig. 2) and can differentiate into nearly all types of cells in the body. These pluripotent cells have been hailed as a possible means for treating treat degenerative, malignant, or genetic diseases, injury due to inflammation, infection and trauma. Meanwhile, hESCs are an invaluable research tool that can serve as a platform to develop and test new drugs. However, to fully realize the therapeutic potential of hESCs, a better understanding of the conditions and molecular mechanisms for long-term self-renewal and efficient directed differentiation must be achieved.

Our long-term goal is to dissect the poorly understood molecular programs governing the fate decisions of hESCs. By screening a collection of pharmacological inhibitors, we identified potential key regulatory molecules that control hESC long-term self-renewal. We plan to expand our study to identify both positive and negative regulators of hESC pluripotency and thus to unravel the underlying signaling network. In addition, we will seek to induce directed differentiation of hESCs into the endoderm, mesoderm, or ectoderm lineage. The results of these experiments will provide insights into early human development and may contribute to effective strategies for tissue repair and regeneration.

Figure 2. Human embryonic stem cells (H7 cell line) cultivated under feeder-free conditions. The diameter of the cell colony is approximately 3 mm.