The Hartwell Foundation


2009 Biomedical Research Collaboration Award

Memphis, TN, December 05, 2009 -- The Hartwell Foundation officially announced the second winners of a Biomedical Research Collaboration Award, which provides funding to expand the frontiers of early-stage, innovative, and cutting-edge applied biomedical research through special collaboration. Charles E. Glatt MD, Ph.D., Weill Cornell Medical College of Cornell University and Jian Zuo, Ph.D., St Jude Children's Research Hospital, will receive $291,173 in combined direct cost over three years to pursue their proposed research for "Identification of Predisposing Factors in Childhood Depression: Using a Conditional Knock-In Mouse to Generate the Implicated Risk and Protective Variants of the Serotonin Transporter Gene." The Hartwell Foundation currently funds both researchers: Dr. Zuo is a 2006 Hartwell Investigator, while Dr. Glatt is a 2007 Hartwell Investigator. Cornell University and the St Jude Children's Research Hospital are both among The Hartwell Foundationís 2009 Top Ten Centers of Biomedical Research.

Serotonin is a universal signaling molecule involved in nerve communication and the serotonin transporter (SERT) protein is a major regulator of serotonin function. Notably, SERT is an important candidate gene for depression, because the most commonly used antidepressant medications all act by inhibiting the activity of this protein.

In pioneering research, Dr. Glatt has identified a variant in the gene responsible for SERT (polymorphism rs3813034) that alters how the gene is expressed. The polymorphism affects the balance between the two different molecular forms of serotonin transporter mRNA and leaves them distributed differently in the brain. One form appears to increase risk for depression while the other form protects against depression. The variant is a single nucleotide polymorphism that occurs in the polyadenylation signal for the distal form of SERT mRNA. It occurs in the signal sequence for processing the protective form in human brain and reduces the signalís effectiveness, thereby lowering the amount of the protective form relative to the risk form. Using a conditional knock-in mouse to generate the implicated risk and protective variants of the serotonin transporter gene, Glatt and Zuo plan to relate the changes induced during early biological development to the onset of depression.

"As a Hartwell Investigator, Jian Zuo is a leader in creating genetically engineered conditional knock-in mice. The Collaboration Award will provide us a unique opportunity to advance a new strategy to move the behavioral genetics of depression from a descriptive to a mechanistic approach. In the absence of an appropriate mouse model, understanding the genetic changes that predispose to depression in childhood would require access to living, human brain tissue," said Dr. Glatt.

The Glatt-Zuo collaboration will advance the current field of depression genetics because the animal model will enable controlled experiments to identify critical developmental periods with risk for depression and identification of windows of opportunity for clinical interventions. Surprisingly, the collaboration may also provide insight in how to regain hearing, as in their early discussion of mutual interests, it became apparent to both investigators that the auditory cells responsible for hearing express SERT and use serotonin to regulate cellular function.

"Together, we propose to design and create a mouse model that expresses only the high-risk form of a major candidate gene for depression, which can also be induced to re-express the protective form at specific developmental stages. In collaborating, we discovered an unexpected benefit from mutual interest in each otherís research focus," said Dr. Zuo.

The collaboration between Glatt and Zuo began when they met at The Hartwell Foundation 2008 Annual Meeting. The availability of Hartwell video conferences and mentoring fostered their progress. Early in their collaboration, they recognized that auditory cells responsible for hearing express SERT and use serotonin to regulate cellular function. At that time, Dr. Zuo began to wonder if alterations in SERT could change the survival of the auditory hair cells, which in his original Hartwell proposal he had proposed to regenerate following the loss of hearing. Discussions between investigators prompted many literature searches that went beyond the molecular biology of depression, elevating intriguing possibilities about how drugs that alter the function of SERT can restore vision in the brain after it is lost, how serotonin aids in cell survival and regeneration, and how drugs that block SERT cause hearing loss in children.

Depression is a disabling neurodevelopmental condition that often has its onset in adolescence. A major portion of the risk for depression in children and adolescents is due to genetic factors that an individual inherits from his or her parents, which are complex and poorly understood. The identification of genetic risk factors for depression would allow early identification of at-risk youth and aggressive intervention that could alter the course of illness. However, human genetic studies of depression have only identified minor risk factors that are not consistently replicated and thus not clinically useful. Genetic studies have focused on depression as a clinical rather than a biological entity and thus, the molecular effects contributed by genetic risk factors have not been specifically matched to the biological processes that contribute to depression.

Children undergoing chemotherapy and children overdosed with antibiotics often lose their hearing. This is mostly due to the loss of the auditory sensory cells in the inner ear. Humans and other mammals cannot replace damaged such sensory cells; however, chickens, fish, and amphibians can, by dividing neighboring cells derived from the same parental cells and adopting their sensory cell characteristics. Recent studies have highlighted the critical role of certain cell-cycle regulators to regenerate functional sensory cells in mammalian inner ears. The feasibility of manipulating key proteins in neighboring supporting cells to regenerate damaged sensory cells is in progress using animal models. Many factors will need to be studied, and genetic manipulations in such models offer unprecedented advantages.

2007 Hartwell Investigator Charles E. Glatt, MD, Ph.D., Weill Cornell Medical College of Cornell University

2006 Hartwell Investigator Jian Zuo, Ph.D., St Jude Children's Research Hospital

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