DeBakey awardees explore diabetes, epigenetics, DNA recombination and mechanisms of ovulation

HOUSTON -- (November 6, 2009) -- The five recipients of the 2009 Michael E. DeBakey, M.D., Excellence in Research Awards at Baylor College of Medicine explore a variety of phenomena in their labs – gene therapy for diabetes, epigenetic inheritance, the mechanisms of DNA recombination and the regulation of ovarian follicular development, ovulation and subsequent events.

From left: Drs. Vijay Yechoor, Lawrence Chan, JoAnne Richard, Gregory Ira and Christophe Herman

This year's award recipients include:

Dr. Lawrence Chan, professor of medicine – endocrinology at BCM and director of the federally designated Diabetes and Endocrinology Research Center, and Dr. Vijay Yechoor, assistant professor of medicine – endocrinology.
Dr. Christophe Herman, assistant professor of molecular and human genetics.
Dr. Gregory Ira, assistant professor of molecular and human genetics.
Dr. JoAnne Richard, professor of molecular and cellular biology.

Each award winner receives a Michael E. DeBakey, M.D. Excellence in Research medallion, an unrestricted fund in support of his or her research as well as a celebration dinner for members of his or her laboratory. The awards are sponsored by the DeBakey Medical Foundation.

The research represented by this year's awards is widely diverse, but all represent key findings at the laboratory level.

Diabetes

The team of Chan and Yechoor developed a gene therapy that cured a form of type 1 diabetes in mice by inducing oval cells – liver stem cells – to change their fate to become a kind of beta cell that produces insulin indefinitely in the liver. Using a gene called Neurogenin 3 and an islet cell growth factor called betacellulin, the collaborators not only induced the oval cells to become essentially insulin-producing beta cells that reside in the liver. These cells make the non-insulin hormones characteristic of such cells as well, said Chan.

Epigenetics

Herman's work provides a new understanding of epigenetic inheritance. Epigenetics refers to an inheritable trait that is not totally directed by the sequence of DNA. In particular, his work looks at changes at the RNA level, specifically messenger RNA, which was thought to be so transient that alteration had no inheritable consequences. Herman's work showed that changes in the phenotype (the observable characteristics of a cell or organism) can occur when there are alterations in the messenger RNA that affect the genetic networks within the cells. His work uncovers new mechanism of regulating gene transcription (the process by which the genetic code is translated into a protein that carries out the work of the cell).

"We believe that Christophe is asking very novel questions that are central to the core of living things and biology," said Drs. Arthur Beaudet, chair of molecular and human genetics at BCM and Susan Rosenberg, professor of molecular and human genetics, in their letter nominating Herman for the honor.

DNA recombination

Ira's work focuses on the mechanisms of DNA recombination, the process by which one piece of DNA moves from one DNA molecule to another.

DNA recombination is a fundamental cellular process. One form called homologous recombination drives evolution by generating new combinations of alleles (one of the two genes organisms inherit from their parents) and maintains genomic stability by repairing DNA gaps and breaks in chromosomes, processes that can lead to cancer.

In their letter nominating Ira, Beaudet and Rosenberg wrote, "This topic is at the center of modern understanding of genomic instability that promotes cancer."

They pointed out that defects in the repair of the breaks in double-stranded DNA via homologous recombination are often seen in breast and ovarian cancers associated with BRCA mutations.

Ira and his laboratory colleagues identified the enzymes responsible for removal of one of the two DNA strands at a broken DNA end – the initiation stage of recombination. A single strand of DNA is a necessary component of repair.

In a second stage of his work, he and his laboratory identified the mechanism that regulates the crossover (the exchange of genetic material between homologous chromosomes that pair during cell division), diminishing its occurrence and reducing the risk of cancer.

Mechanisms of ovulation

Richards' work focuses on female fertility and cellular pathways critical to ovulation. In particular, she focuses on the molecular mechanisms by which follicle stimulating hormone (FSH) and luteinizing hormone (LH) regulate the processes of ovulation.

A recent publication by her and members of her laboratory in the journal Science identified two enzymes ERK1 and ERK2 (extracellular signal-regulated kinases) as critical to the cellular pathway that induces ovulation, maturation of the mammalian egg and other key activities in ovarian function and female fertility. Her laboratory also works with the oncogene KRAS and its effect on ovulation and the activities surrounding it as well as its relationship to ovarian cancer.

"ERK is an essential switch for meiosis (a form of cell division)," said Richards. "Altered RAS and ERK1/2 can lead to infertility and ovarian cancer.

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