Award Abstract # 1054422
CAREER: Regulation and Function of STAT Signaling in Cell Adhesion and Detachment

NSF Org: IOS
Division Of Integrative Organismal Systems
Recipient: UNIVERSITY OF MARYLAND BALTIMORE COUNTY
Initial Amendment Date: January 26, 2011
Latest Amendment Date: April 23, 2015
Award Number: 1054422
Award Instrument: Continuing Grant
Program Manager: Matt Buechner
mbuechne@nsf.gov
 (703)292-4675
IOS
 Division Of Integrative Organismal Systems
BIO
 Directorate for Biological Sciences
Start Date: February 15, 2011
End Date: January 31, 2017 (Estimated)
Total Intended Award Amount: $650,000.00
Total Awarded Amount to Date: $650,000.00
Funds Obligated to Date: FY 2011 = $150,000.00
FY 2012 = $100,000.00

FY 2014 = $260,000.00

FY 2015 = $140,000.00
History of Investigator:
  • Michelle Starz-Gaiano (Principal Investigator)
    starz@umbc.edu
Recipient Sponsored Research Office: University of Maryland Baltimore County
1000 HILLTOP CIR
BALTIMORE
MD  US  21250-0001
(410)455-3140
Sponsor Congressional District: 07
Primary Place of Performance: University of Maryland Baltimore County
1000 HILLTOP CIR
BALTIMORE
MD  US  21250-0001
Primary Place of Performance
Congressional District:
07
Unique Entity Identifier (UEI): RNKYWXURFRL5
Parent UEI:
NSF Program(s): Animal Developmental Mechanism
Primary Program Source: 01001112DB NSF RESEARCH & RELATED ACTIVIT
01001213DB NSF RESEARCH & RELATED ACTIVIT

01001415DB NSF RESEARCH & RELATED ACTIVIT

01001516DB NSF RESEARCH & RELATED ACTIVIT
Program Reference Code(s): 1045, 1111, 1187, 9178, 9179
Program Element Code(s): 111900
Award Agency Code: 4900
Fund Agency Code: 4900
Assistance Listing Number(s): 47.074

ABSTRACT

When embryos develop, cells are often born in one location but required at another. Scientists are searching for the molecular mechanisms that govern the critical decision of a cell to move or stay in place. Dr. Starz-Gaiano and others have uncovered a pivotal role for a molecular cascade, called the Signal Transducer and Activator of Transcription (STAT) pathway, in determining whether a cell will become motile. This pathway is also essential for some cells to remain as stem cells instead of developing into another kind of cell. Dr. Starz-Gaiano's laboratory will use genetic, molecular, and mathematical approaches to understand how STAT signaling controls these cellular events. Fruit flies will be used in these studies because they have several advantages: rapid development, a small and well-characterized genome, many genetic methods, and transparent tissues that enable visualization of cells as they move. Dr. Starz-Gaiano expects to discover the mechanism by which STAT signaling is turned off in select cells, to identify the critical molecules that STAT employs to change the adhesiveness of cells, and to compare the properties of motile cells to those required for stem cell maintenance.

Unlocking the molecular mysteries of cellular decision-making is essential in understanding normal development, birth defects, and disease progression. Because over 80% of fruit fly genes are also found in humans, the molecular mechanisms identified in this project will likely be broadly applicable. This research will impact the fields of molecular signaling, cell motility, stem cell biology, and mathematical modeling of natural phenomena. The projects are also well-positioned to enhance education through interdisciplinary partnerships and will leverage UMBC's nationally-recognized programs that increase involvement of underrepresented students in science. Thus, the proposed activities will integrate widely relevant, interdisciplinary research with simultaneous, outstanding education for the next generation of citizens and potential scientists.

PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH

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David Stonko, Lathiena Manning, Michelle Starz-Gaiano, Bradford Peercy "A force-based biophysical model of collective cell migration in a three-dimensional, heterogeneous environment" PLOS One , v.10 , 2015 , p.e0122799
Lathiena Manning and Michelle Starz-Gaiano "Upright Imaging of Drosophila Egg Chambers" Journal of Visualized Experiments , v.97 , 2015 10.3791/52636
Monahan, A. and Starz-Gaiano, M. "Apontic regulates somatic stem cell numbers in Drosophila testes" BMC Developmental Biology , v.16 , 2016 , p.5 10.1186/s12861-016-0103-3
Monahan, A. and Starz-Gaiano, M. "Socs36E Limits STAT Signaling via Cullin2 and a SOCS-Box Independent Mechanism in the Drosophila Egg Chamber." Mechanisms of Development , v.138 , 2015 , p.313
Monahan, A.J.; Starz-Gaiano, M. "Socs36E attenuates STAT signaling to optimize motile cell specification in the Drosophila ovary" Developmental Biology , v.379 , 2013 , p.152 10.1016/j.ydbio.2013.03.022
Montell, Denise J.; Yoon, Wan Hee; Starz-Gaiano, Michelle "Group choreography: mechanisms orchestrating the collective movement of border cells" NATURE REVIEWS MOLECULAR CELL BIOLOGY , v.13 , 2012 , p.631-645
Saadin, A and Starz-Gaiano, M "Circuitous genetic regulation governs a straightforward cell migration" Trends in Genetics , v.32 , 2016 , p.660 10.1016/j.tig.2016.08.001
Saadin, A. and Starz-Gaiano, M. "Identification of Novel Regulators of the JAK/STAT Signaling Pathway in Border Cell Migration in the Drosophila Ovary" G3 , v.6 , 2016 , p.1991 10.1534/g3.116.028100

PROJECT OUTCOMES REPORT

Disclaimer

This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.

For an animal to develop normally from a fertilized egg, many changes must occur; for example, cells adopt different identities and some migrate to new locations to fulfill their functions in the organism.  How does encoded genetic information control these events?  To examine this question, we are taking advantage of Drosophila melanogaster, the fruit fly, to identify essential genes that regulate cellular decisions.  The genes in flies are very similar to those in other organisms, so results from this study provide a framework for increased understanding of development in general.  One known pathway integral to developmental processes is called JAK/STAT signaling, which is also important in human development, immune response, and disease progression. 

 

We have identified and characterized the roles of several new genetic regulators of STAT signaling activity.  Through genetic analysis, molecular biology, and mathematical modeling, we have built a clearer picture of how this cell-cell communication system works.  In ovarian cells, we have shown that the identified regulators are important for initiating signaling, determining the optimal number of migratory cells, and allowing the cells to move correctly, which is necessary for successful egg development. We have also leveraged mathematical modeling to develop a system to explain how groups of cells organize themselves and coordinate their movements. In the testes, we found that several of the same regulators function to limit STAT signaling and thereby determine stem cell number. To start the signaling cascade, some ovarian cells release activating molecules outside of themselves, and these molecules are detected by nearby cells to turn on STAT activity.  We developed a new strategy to image egg chambers, and, interestingly, found that the initiation of signaling could be influenced by the contours of neighboring cells, which create sinks or pools of signaling molecules.  The findings were further supported through mathematical modeling, which led to the same conclusions.  This influence of contour is likely to arise in many tissues where extracellular signaling molecules act – thus, these findings have broader impact on biological research in other contexts.   

 

In addition to our scientific goals, we have been dedicated to broadening participation in research and improving STEM education.  Through the funded project, I have mentored multiple students in laboratory research, including 3 PhD students, several other graduate students, and 18 undergraduates, and have continued to partner with diversity programs at my university to broaden participation.  Through these efforts, we have provided research training to over 14 under-represented minorities at the undergraduate level, and one at the graduate level.  In addition, we utilize the model we built for an Undergraduate Bio-Mathematics program to foster interdisciplinary research and training.  Two Master’s degree students in mathematics participated in this project.  In the classroom, I have adopted additional active learning/teaching strategies provided to over 250 students per year, developed improved assessment tools, trained undergraduates and graduate students in scientific teaching, and coached colleagues in seeking best practices for teaching and learning through the Teacher-Scholars Faculty Learning Community at UMBC.  The researchers on this project and I participated in multiple outreach activities in local K-12 schools and public science events to increase public interest and understanding of the work of biologists.


Last Modified: 04/06/2017
Modified by: Michelle Starz-Gaiano

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