The Hartwell Foundation


2011 Biomedical Research Collaboration Award

Memphis, TN, June 05, 2011 -- The Hartwell Foundation officially announced the winners of its fourth Biomedical Research Collaboration Award to provide funding to expand the frontiers of early-stage, innovative, and cutting-edge applied biomedical research through special collaboration. 2007 Hartwell Investigator Anjali M. Rajadhyaksha, Ph.D., Assistant Professor of Pediatrics and Neuroscience, Weill Cornell Medical College of Cornell University, together with 2006 Hartwell Investigator Andrew A. Pieper, MD, Ph.D., Assistant Professor of Psychiatry and Biochemistry, UT Southwestern Medical Center, will receive $431,684 in combined direct cost over three years to pursue their proposed research for "Pharmacologic Agents for Treatment of Anxiety in Autism: Cav1.2-deficient Mice as a New Animal Model of Autism". Dr. Pieper was a previous recipient of a Hartwell Collaboration Award in 2008. Both Cornell and UT Southwestern were recently named to The Hartwell Foundationís 2011 Top Ten Centers of Biomedical Research.

One of the primary reasons for the absence of effective pharmacologic treatments for autism is the complete lack of animal models that faithfully replicate autism-associated anxiety, one of the most salient features of this childhood neurological disease. Recently, however, Dr. Rajadhyaksha serendipitously discovered unique manifestations of anxiety in mice genetically engineered to lack the Cav1.2 gene. The mice exhibit anxiety-like behaviors using three separate mouse behavioral assays, with no manifestation of compulsive repetitive behaviors. Affected mice display impaired social interaction and a prominent state of high anxiety reminiscent of the behavior in autistic children. Importantly, mutations in this gene are also known to be present in some children affected with autism.

As a 2007 Hartwell Investigator, Dr. Rajadhyaksha proposed combining human genetic studies with mouse models to understand the biological basis of what causes autism, with the ultimate goal of developing medications to treat autistic children. She was particularly interested in the biochemical and functional consequences of mutated genes that cause aberrant neuronal calcium (Ca2+) signaling. Such altered signaling could affect synaptic transmission and disrupt communication between nerve cells, which could contribute to abnormal brain development. Anjali proposed that perturbations in the developmental regulation of the Cav-BKca channel complex responsible for controlling the movement of calcium ions probably converge in some final common pathway to produce a subset of disorders known to be associated with autism.

As a 2006 Hartwell Investigator, Dr. Pieper proposed an innovative whole animal model for discovery of small molecules having neurogenic efficacy for treatment of childhood schizophrenia. Unlike conventional drug screens, which deploy binding or cell based assays in vitro, he successfully demonstrated how to identify compounds that were both pharmacologically active and non-toxic in living animals, quickly elevating promising candidates for new drugs to a very early stage of development. Screening in vivo not only provides an opportunity for accurate and reproducible assessment of the corrective effects of small molecules being screened on the phenotype, but also provides information about how effectively the drugs are tolerated by living mice. In Andrew's search to identify a drug that would ameliorate the phenotype in his mouse model of schizophrenia, he  discovered 8 potent, non-toxic, small drug-like molecules that stimulated neurogenesis in the hippocampus. The most promising compound could be administered orally to mice, had a blood circulation half life of approximately 6-7 hours and crossed both the blood brain and placental barriers. Administration of this compound to a mouse model of schizophrenia completely corrected morphologic abnormalities in the structure of the hippocampus. This effect correlated with restoration of normal electrophysiologic circuitry within the hippocampus, which is important in learning and memory. Dr. Pieperís discovery thus holds great promise for the development of new pharmacologic agents that might improve hippocampal structure and function in schizophrenia and other related conditions.

Previously, in 2008, Andrew shared the first Hartwell Collaboration Award along with 2006 Hartwell Investigator, Guoping Feng, Ph.D., from Duke University for "Rapid Discovery of Small Molecules for Drug Development in an Animal Model of Obsessive-Compulsive Disorder." They proposed using Fengís unique mouse model of obsessive-compulsive disorder together with the unconventional and technically demanding whole animal approach developed and successfully deployed earlier, by Pieper. Recently, Pieper and Feng obtained promising results that suggest they may have identified a novel pharmacologic agent to treat the compulsive repetitive grooming phenotype. To date, Andrew has also independently used his biologic screening approach in an animal model of Rett syndrome to successfully discover new compounds that may lead to the development of novel pharmacologic approaches to treating this autism-spectrum disorder as well.

Together, Drs. Rajadhyaksha and Pieper will collaborate to utilize the innovative drug discovery approach developed by Pieper for the unique Cav1.2 mouse model of autism-associated anxiety described by Rajadhyaksha. They seek to behaviorally and neuroanatomically characterize this unique anxiety phenotype as a model of autism, and to apply screening in vivo to identify novel compounds that will ameliorate anxiety in these mice. Their hope is that this will form the basis for the development of new drugs to treat anxiety in children with autism. Once an efficacious small drug-like molecule is identified, they intend to work closely with synthetic organic chemists in the UTSWMC Department of Biochemistry to synthesize and screen new chemical variants to improve biologic efficacy, while simultaneously conferring a more favorable profile of adverse off-target activity. Other substances based on the initial chemical structures can then be synthesized to help discern the mechanism of action of the newly discovered molecule, which will also contribute to understanding the underlying disease process.

The Rajadhyaksha-Pieper collaboration brings together new opportunities conveyed by a unique mouse model of anxiety in autism with an innovative, technically sophisticated, cutting edge approach to drug discovery.

"Since anxiety cannot be recapitulated in a cell or a test tube, it must be modeled in intact living animals. My unique mouse model appears to represent for the first time a genetic model of autism that replicates autism-associated anxiety," said Dr. Rajadhyaksha.

"The importance of characterizing these mice in order to gain valuable insights into the autism disease process can not be underestimated. This animal model could provide an unprecedented opportunity to discover new drugs for treating the debilitating anxiety associated with autism in children," related Dr. Pieper.

Fostering collaborations between investigators of complementary scientific strengths is one of the objectives of The Hartwell Foundation Mission to fund innovative, early-stage applied biomedical research with the potential to benefit children.




2007 Hartwell Investigator Anjali Rajadhyaksha, Ph.D., Weill Cornell Medical College of Cornell University

2006 Hartwell Investigator Andrew Pieper, MD, Ph.D., University of Texas Southwestern Medical Center

Biomedical Research Collaboration Awards

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Top Ten Centers