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W.M. Keck Foundation Grant Funds Reproductive Science Research

Northwestern has received a three-year, $1.6 million grant from the W.M. Keck Foundation to support reproductive science research focused on understanding the chemical and biological signaling events surrounding fertilization and early embryonic development.

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July 29, 2008 | by Megan Fellman
EVANSTON, Ill. --- Northwestern University has received a three-year, $1.6 million grant from the W.M. Keck Foundation to support reproductive science research focused on understanding the chemical and biological signaling events surrounding fertilization and early embryonic development.

The egg and sperm unite at the time of fertilization and create a new cell called the zygote. This single cell then divides many times, ultimately forming a new individual. How do the egg and sperm mature, and what is the underlying mechanism that controls cellular division and differentiation?

An interdisciplinary team of researchers at Northwestern believes that inorganic molecules -- zinc, calcium, iron and others -- may lie at the heart of this matter. The team's goal is to determine what critical roles these molecules, particularly zinc, play in signal processing. Based on preliminary studies, the team hypothesizes that fluxes in zinc ions mediate the first definitive signal in embryonic development.

Cells communicate by sending signals through networks of small molecules, but little is known about these networks in fertilization and early embryonic development. A better understanding of the role of inorganic molecules in signaling could help with fertility issues as well as shed light on the role of metal metabolism dysfunction in many diseases, including diabetes, cancer and Alzheimer's disease.

The project is being led by Thomas O'Halloran, Charles E. and Emma H. Morrison Professor in Chemistry in the Weinberg College of Arts and Sciences, and Teresa K. Woodruff, Thomas J. Watkins Memorial Professor of Obstetrics and Gynecology at the Feinberg School of Medicine. O'Halloran is an expert in how cells use essential metal nutrients such as zinc, copper and iron at the molecular level, and Woodruff's specialty is in ovarian biology and reproductive science.

"This research is focused on an unexplored area of egg and sperm biology, namely, the relationship of physiologically relevant metals to the events surrounding fertilization," said Woodruff. "The involvement of inorganic molecules in this process has not been examined, and the development of imaging technologies that are predicted to bring a new level of sensitivity and detection capability to this critical time in biology is exciting."

The team will use the Keck Foundation grant to purchase a custom-built scanning transmission electron microscope with multiple detectors for quantitative images of the inorganic elements in the mouse germ cells. No existing microscope can do this. Furthermore, the movement and flux of these ions will be tracked in live cells using confocal microscopy. New fluorescent "nanosensors" will be developed specifically for these studies.

The work lies at the interface of reproductive science, chemistry, biophysics and imaging technology. Also on the research team are Vinayak P. Dravid, professor of materials science and engineering at Northwestern and director of the University's NUANCE Center (Atomic and Nanoscale Characterization Experimental Center), and Jonathan Silverstein, M.D., associate professor of surgery and radiology at the University of Chicago Medical Center and associate director of the university's Computation Institute.

Dravid's expertise lies in advanced microscopy and analytical techniques; he will coordinate construction of the electron microscope and develop methods to use the equipment. Silverstein specializes in the application of computers and other technology to the analysis of vast biomedical databases; he will develop software to interpret the data collected using the microscope and will create 3-D images of the eggs showing amounts and distribution of the inorganic molecules.

The origin of the idea, that zinc in particular may play an important role in these signaling pathways, came from the research of graduate student Alison Kim, who is working with O'Halloran and Woodruff. She discovered that zinc was not uniformly distributed in eggs as they matured, which was unexpected.

"That got us all thinking," said O'Halloran. "Could zinc be a signal in the fertilization process? The evidence was strong enough for us to pursue. We first want to test whether there is a zinc signal pathway and then build a model of how zinc acts in the egg. This is very exciting because zinc's primary role in the body is typically thought to involve catalysis, not signaling."

The research project, titled "The Inorganic Signature of Life: Signaling Pathways in the Mammalian Oocyte," has received additional funding from Northwestern University and the Chicago Biomedical Consortium.

Based in Los Angeles, the W.M. Keck Foundation was established in 1954 by the late W.M. Keck, founder of the Superior Oil Company. The Foundation's grant making is focused primarily on pioneering efforts in the areas of medical research, science and engineering. The Foundation also maintains a program to support undergraduate science and humanities education and a Southern California Grant Program that provides support in the areas of health care, civic and community services, education and the arts, with a special emphasis on children and youth.