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Douglas N. Robinson
Department Affiliation: Primary: Cell Biology; Joint: Medicine; Secondary: Pharmacology and Molecular Sciences; Chemical and Biomolecular Engineering
Degree: Ph.D., Yale University School of Medicine
Telephone Number: 410-502-2850
Fax Number: 410-955-4129
E-mail address: firstname.lastname@example.org
Home Page URL: http://robinsonlab.cellbio.jhmi.edu/
School of Medicine Address: 100 Physiology Building, 725 N. Wolfe Street, Baltimore, MD 21205
Understanding Cytokinesis and Cell Shape Control
Multi-cellular living organisms grow from single cells into multicellular, complex systems composed of highly diverse cell-types organized into tissues, which in turn form organs and organ systems. To organize and maintain this complex architecture, the organism must undergo constant renewal through cell proliferation and elimination of unwanted cells. This process of tissue development and homeostasis requires chemical and mechanical information to be sensed by the cells within the tissues, and in turn, interpreted to guide their decision making: to divide, migrate, constrict, or die. Failure in these processes leads to diverse diseases, such as hypertension, degeneration, and cancer. We have been studying cytokinesis (cell division) as a model cell behavior that incorporates internally generated signals with external mechanical cues to drive healthy cell shape change.
Using a simple model organism Dictyostelium discoideum, we have discerned the mechanics that drive cytokinesis, and identified how the cell senses external forces (mechanosensing) and transmits them to changes in the chemical signaling pathways that guide cytokinesis. Working with computational biologist Pablo Iglesias (JHU Electrical and Computer Engineering), we have reached the point where we have a highly quantitative understanding of cytokinesis and cellular mechanosensing, which is based on measured parameters and has predictive power. We continue to pursue important fundamental questions using this model organism and cell process.
While we study how these processes direct cytokinesis, we are also learning how these same principles apply to diseases such as cancer and chronic lung disease. To accomplish such broad goals, we collaborate closely with a several basic and clinical scientists. For example, working with Bob Anders (JHU Pathology), we are examining how changes in cell mechanics correlate with pancreatic ductal adenocarcinoma cancer (PDAC) progression. With Ramana Sidhaye (JHU Pulmonology), we are exploring the acute changes to cellular architecture that occur in the lung epithelia in response to insults such as cigarette smoke, which can ultimately lead to diseases such as chronic obstructive pulmonary disease (COPD) and lung cancer.
We are also leveraging our sophisticated understanding of cell shape control to identify and develop small molecule modulators (i.e. possible future drugs) of cell mechanics. Such tools will be invaluable for dissecting tissue mechanics during normal development, tissue homeostasis, and pathological situations such as tumor formation and metastasis. Towards this goal, we developed platform for high-throughput drug screening for cell mechanics modulators and have already identified one compound, 4-HAP, which shifts one of the major cell mechanics proteins myosin II onto the cell cortex where it increases cortical tension and elasticity. We then tested the compound in mouse models of metastatic pancreatic cancer and found that it reduced metastasis. We are continuing to pursue the range of studies with the overarching goal of moving fundamental discovery towards application.
- Duan, R., Kim, J.H., Shilagardi, K., Schiffhauer, E., Lee, D., Son, S., Li, S., Thomas, C., Luo, T., Fletcher, D.A., Robinson, D.N., Chen, E.H. Spectrin is mechanoresponsive protein shaping fusogenic architecture during myoblast fusion. Nat. Cell Biol. 20, 688–698, 2018. Pub Med Reference
Liu, Y. and Robinson, D.N. Recent advances in cytokinesis: Understanding the molecular underpinnings. F1000Research 7(F1000 Faculty Rev): 1849, 2018.
Kothari, P., Srivastava, V., Aggarwal, V., Tchernyshyov, I., Van Eyk, J., Ha, T., and Robinson D.N. Contractility kits promote assembly of the mechanoresponsive cytoskeletal network. J. Cell Sci. 132(2): 1-12, 2019. Pub Med Reference
Schiffhauer, E.S., Ren, Y., Iglesias, V., Kothari, P., Iglesias, P.A., Robinson, D.N. Myosin IIB assembly-state determines myosin IIB mechanosensitive dynamics. J. Cell Biol. 218(3): 895-908, 2019. Pub Med Reference
Kothari, P., Johnson, C., Sandone, C., Iglesias, P.A., Robinson, D.N. How the mechanobiome drives cell behavior, viewed through the lens of control theory. J. Cell Sci. 132:1-10. jcs234476, 2019. Pub Med Reference
Surcel, A., Schiffhauer, E.S., Thomas, D.G., Zhu, Q., DiNapoli, K., Herbig, M., Otto, O., West-Foyle, H., Jacobi, A., Kräter, M., Plak, K., Guck, J., Jaffee, E.M., Iglesias, P.A., Anders, R.A., Robinson, D.N. Targeting mechanoresponsive proteins in pancreatic cancer: 4-hydroxyacetophenone blocks dissemination and invasion by activating MYH14. Cancer Res. 79: 4665-4678, 2019. Pub Med Reference
Crews, D.C., Wilson, K.L., Sohn, J., Kabacoff, C.M., Poynton, S.L., Murphy, L.R., Bolz, J., Wolfe, A., White, P.T., Will, C., Collins, C., Gauda, E., Robinson, D.N. Helping scholars overcome socioeconomic barriers to medical and biomedical careers: Creating a pipeline initiative. Teach. Learn. Med. 1-12. DOI: 10.1080/10401334.2020.1729161, 2020. Pub Med Reference
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