DEPARTMENT OF PSYCHIATRY INVESTIGATORS JOIN THE UC DAVIS MIND INSTITUTE TO WIN COVETED NIH-FUNDED, AUTISM CENTER OF EXCELLENCE (ACE)
Department of Psychiatry Investigators, Joachim Hallmayer, MD, Sundari Chetty, PhD, and Ruth O’Hara, PhD, joined Autism expert David Amaral, MD, and his team at the UC Davis MIND Institute and were awarded a 5-year, Autism Centers of Excellence (ACE) grant. One of only five in the nation, their ACE Center is administered by the NIH National Institute of Child Health and Development. Their ACE aims to create a “Center for the Development of Phenotype-based Treatments of Autism Spectrum Disorder,” that takes a personalized medicine approach to addressing Autism Spectrum Disorder (ASD) treatment based on a child’s behavioral and biological characteristics with the goal of identifying and tailoring treatments that improve quality of life.
A primary emphasis of the newly funded ACE center is on patients with ASD who also have enlarged brains, known as megalencephaly. Megalencephaly is found in approximately 15 percent of boys with ASD, but it is less common in girls and may represent a subphenotype of ASD.
The Multiple Principal Investigator (MPI) team at Stanford University, Hallmayer, Chetty and O’Hara, will lead one of three ACE projects and produce induced pluripotent stem cells (iPSCs) from children with ASD and typical developing controls with and without megalencephaly. These iPSCs will be differentiated to produce various neuronal and glial cell types. The investigators will then be able to study whether these brain cells have alterations of genetic pathways or control mechanisms that may lead to the enlarged brain. Analysis of these cells may provide additional insights into potential treatment targets. A significant advance with respect to this ACE is that in addition to patients with ASD and megalencephaly, typical developing children with megalencephaly will also be recruited in order to more fully establish if the cellular phenotypes observed are specific to ASD or to megalencephaly in general.
Each member of the MPI team brings specific targeted expertise. Dr. Hallmayer, a leading expert in the genetic basis of Autism Spectrum Disorders, was one of the very first investigators to obtain NIMH funding to study neurons of individuals diagnosed with Autism with a known genetic mutation. Using this approach, Dr. Hallmayer’s team identified cellular and molecular phenotypes for rare but highly penetrant forms of autism, and also demonstrated that these could be rescued by treatment with specific pharmacologic agents acting on identified molecular targets. In collaboration with Dr. O’Hara and his team, he has established one of the largest known collections of iPSCs in rare variant and idiopathic ASD and other neurodevelopmental and psychiatric disorders, with iPSCs collected on over 400 patients and controls to date. He will be responsible for relating the cellular phenotypes to the genetic basis of the disorder.
Dr. Chetty and her laboratory have employed genome wide epigenetic and transcriptional profiling to demonstrate that important changes to the cell cycle and epigenetic state occur during pluripotent stem cell differentiation. Building upon these mechanistic insights, her lab has developed tools to prime pluripotent stem cells for differentiation across multiple lineages enhancing the prospects of using iPSCs for disease modeling and cell replacement therapy. The overarching goal of Dr. Chetty’s work will be to identify therapeutic targets by understanding the underlying cellular and signaling mechanisms involved in ASD. To achieve this goal, Dr. Chetty and her lab will differentiate the iPSC lines into various neuronal and glial cells and investigate changes at the cellular, functional, and mechanistic levels using a broad range of techniques from cell cycle analysis to RNA-sequencing.
Dr. O’Hara has extensive experience conducting multi-system investigations which integrate genetic, neurophysiological and in-depth clinical and behavioral phenotyping in a broad range of patient populations including neurodevelopmental disorders. Dr. O’Hara will be responsible for mapping the cellular phenotypes yielded onto the clinical, cognitive and neuroimaging phenotypes of the ASD patients, including structural imaging measures of gray matter, and diffusion tensor imaging measures of white matter connectivity.
The Center will also include an internal advisory committee with expertise in neurobiology, psychiatry, clinical medicine and administration, as well as an external advisory committee for periodic, scientific review, and a community advisory committee of individuals with ASD, parents, special needs teachers and public school teachers, public administrators and physicians.
In addition to Drs. Hallmayer, Chetty and O’Hara, ACE investigators include Marjorie Solomon, Christine Wu Nordahl, Susan Rivera, David Hessl, Breanna Winder-Patel, Sally Rogers, Clifford Saron and Gregory Young at the UC Davis Site; and Jeff Wood at UCLA.