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Vanderbilt's Sudhansu Dey on the Role of miRNAs in Embryo Implantation

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Name: Sudhansu Dey
Position: Professor, pediatrics/cell and developmental biology/pharmacology — Vanderbilt University Medical Center
 
Background:
- Professor, physiology, University of Kansas Medical Center — 1986-2002
- Professor, obstetrics/gynecology, University of Kansas Medical Center — 1984-1994
- Associate professor, physiology, University of Kansas Medical Center — 1981-1986
- Associate professor, obstetrics/gynecology, University of Kansas Medical Center — 1981-1984
- Postdoc, University of Kansas Medical Center — 1973-1975
- PhD, University of Calcutta — 1972
 

 
This week, Vanderbilt University Medical Center researcher Sudhansu Dey published data in The Proceedings of the National Academy of Sciences showing that two microRNAs are expressed in the mouse uterus during embryo implantation.

Additionally, Dey and his colleagues found that these miRNAs regulate expression of cyclooxygenase-2, a gene critical in the implantation process that has also been linked to a number of cancers.

 
This week, RNAi News spoke with Dey about his findings.
 
What is the focus of your lab?
 
My lab focuses primarily on embryo-uterine interactions during implantation. We are also working on uterine and ovarian cancers.
 
The paper said that you started these experiments speculating that microRNAs might have some role to play in the embryo implantation process. What triggered that hypothesis?
 
There were some reports that microRNAs play roles during embryogenesis, so I thought that may be it would be a good idea to see whether microRNAs are expressed, at least, in the uterus to influence uterine gene expression in the context of embryo implantation.
 
We did the microarray analysis of 400 microRNAs [looking for] microRNAs that target Cox-2 because Cox-2 is critical for implantation.
 
What is the specific role of cyclooxygenase-2?
 
Cox-2 is an enzyme that makes prostaglandins. The cyclooxygenase system has two isoforms, Cox-1 and Cox-2. We found previously using knockout mouse models that Cox-2-derived prostaglandins are critical for embryo implantation in the mouse.
We looked at several microRNAs that are up-regulated and down-regulated, and found that two — miR-101a and miR-199a — target Cox-2.
 
Had you worked with microRNAs before?
 
No.
 
Because of that, did you collaborate with anyone with experience in this field?
 
Yes. Henry Furneaux [of the University of Connecticut Health Center who co-authored the PNAS paper] has experience working with microRNA.
 
When we got the first results [from microarray expression profiling], we contacted him to see what he thought. He was very excited with the results.
 
After you found the two microRNAs that target Cox-2, what was your next step?
 
We wanted to know where they are expressed in the uterus because the uterus is comprised of heterogeneous cell types, primarily the myometrium and the endometrium, which contains the stroma and epithelium.
 
Where the miRNAs are expressed, and when during pregnancy, were our questions. We found that these two microRNAs are expressed at the same sites as Cox-2. We were very excited about that, because it means that these two microRNAs are probably regulating the Cox-2 protein levels.
 
Cox-2 protein levels should be tightly regulated. If the level is too high, it might cause abnormal uterine biology because Cox-2 is over-expressed in many solid tumors. During implantation, which is a highly regulated process, Cox-2 expression should be highly regulated.
 
I thought that these microRNAs might regulate Cox-2 protein levels by regulating the translation of Cox-2 mRNA.
 
What happens if you knock out either one of these microRNAs?
 
That is our next project. We are trying to get hold of people who could provide us with [miRNA inhibitors such as Alnylam Pharmaceuticals’] antagomirs. Then we can get in vivo data.
 
Although my attempts to contact Alnylam for help did not materialize, I am now in contact with Gianluigi Condorelli, whose group at [Istituto Superiore di Sanita in Italy] has used antagomirs for their work and has a lot of experience, and he has agreed to help me.
 
Thinking long term, what are the implications of this work?
 
I am intrigued by these findings because Cox-2 is known to be involved with many cancers and that’s where the implications lie — whether this microRNA could be targeted for potential human disease [such as] endometrial cancer.
 
So cancers of the female reproductive organs like uterine cancer?
 
Right.
Once you start tuning down the different microRNAs in a mouse model, what is the step after that? Do you start looking at human cells in culture?
 
Right. We will start looking at human endometrial cancer samples. We [also] have cell lines in which we will conduct more functional studies — loss-of-function/gain-of-function studies.
 
Other than Alnylam, have you had talks with other industry people who might be interested in collaborating with you?
 
Not really. I haven’t done anything yet because I didn’t want to get involved before the [PNAS] paper came out.
 
Given the initial success of your work with microRNAs, are you thinking about investigating these small RNAs in other aspects of your research?
 
Yes. I have lot of ideas, but we need to write a grant first and get some funding. One of my junior faculty members is preparing a grant on endometrial cancer and microRNAs.

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