As Director of Research, Dr. Kumar oversaw and directed the research activities, education, training, and major scientific and financial operations of the Conte Center. He also spearheaded several research projects including: 1) the characterization of the molecular genetic architecture of conduct disorder, one of the most prevalent forms of child and adolescent psychopathology, and; 2) evaluating candidate genes for autism and schizophrenia using human induced pluripotent stem cells (iPSCs) and neural progenitor cells together with combinatorial RNA intereference (RNAi) and CRISPR technologies.
Dr. Kumar joined The University of Chicago as a postdoctoral fellow in 2007 to investigate the genetics of neurodevelopmental disorders, including autism spectrum disorders, severe cortical malformations, and epilepsy. He and others demonstrated that 16p11.2 microdeletions are among the most frequent chromosomal abnormalities associated with autism, a discovery that represented one of the top ten scientific achievements in autism research in 2008 (Kumar et al, Human Molecular Genetics, 2008). This work also received the prize for 'Best Biological Research Paper' awarded by the International Society for Autism Research at their annual meeting in 2009. Dr. Kumar was also part of the team that demonstrated that 16p11.2 chromosomal imbalances are implicated in schizophrenia (McCarthy et al, Nature Genetics, 2009) and infantile seizure disorder (Bedoyan et al, American Journal of Medical Genetics, 2010).
In his most recent work with the Conte Center, Dr. Kumar and collaborators Dr. Benjamin Lahey and Dr. Jean Decety investigated the genetic and structural basis of conduct disorder using molecular genetics and functional magnetic resonance imaging (fMRI). Specifically, the team selected candidate genes that include ESR1 (estrogen receptor), OXTR (oxytocin receptor), GABRA2 (GABA receptor), MAOA (monoamine oxidase A), 5-HTT (serotonin transporter), AVPR1 (arginine vasopressin receptor), and COMT (catechol-O-methyltransferase). The team looked for associations between genetic variants in these genes and brain-behavioral phenotypes relevant to child and adolescent psychopathology.
During his doctoral work at The University of British Columbia in Vancouver, Ravinesh Kumar and colleagues demonstrated that pathologically violent 'fierce' mice are deleted for a single nuclear receptor gene called Nr2e1 (Kumar et al, Genesis, 2004). He went on to test the hypothesis that human NR2E1 underlies brain and behavioral development in neuropsychiatric and related disorders. To bolster this hypothesis, he used molecular, bioinformatic, and evolutionary genetic approaches to study NR2E1 in children with microcephaly (Kumar et al, Genes, Brain and Behavior, 2007), in children with microcepahtly, micropthalmia, ectrodactyly, and prognathism (MMEP) (Kumar et al, BMC Medical Genetics, 2007), and in adults with bipolar disorder, schizophrenia, and pathological aggression, including intermittent explosive disorder (Kumar et al, Neuropsychiatric Genetics, 2008).
During his postdoctoral studies, Dr. Kumar also identified three genetic risk factors for autism, including the seizure-related gene SEZ6L2 (Kumar et al, PLoS ONE, 2009) and two synaptic vesicle genes: APBA2 (Babatz et al, Autism Research, 2009) and RIMS3 (Kumar et al, Journal of Medical Genetics, 2010). In addition, he spearheaded a project that implicated mutations in the alpha tubulin gene TUBA1A with wide spectrum lissencephaly, making this the first major gene associated with 'lissencephaly with cerebellar hypoplasia (LCH)' (Kumar et al, Human Molecular Genetics, 2010). His postdoctoral work also involved the development of integrated bioinformatics platforms and computational networks-based disease models to provide a conceptual framework for systems-level exploration of complex genotype-phenotype relations in complex disorders.
New Silvio O. Conte Centers Address Brain Development, Disorders
With a mandate to use innovative, multidisciplinary research approaches to address important mental health questions, four newly funded centers have begun investigations of schizophrenia, brain development, and adolescent mood disorders. The four are the latest among NIMH's Silvio O. Conte centers, all of which have as their goal bringing together diverse expertise and cutting edge technology to gain new knowledge and improve the diagnosis and treatment of mental health disorders.
Since 1988, NIMH has encouraged scientists to seek funding for projects in which a unifying, well-defined scientific question would be approached from many angles and at many levels (for example, genetic, molecular, clinical, and behavioral) via its Centers for Neuroscience of Mental Disorders and Centers for Neuroscience Research. In 1993, these centers were renamed in memory of Rep. Silvio O. Conte, a champion of neuroscience research and the severely mentally ill. In keeping with the guidelines for Conte Centers, each of the four recently funded centers must be capable of conducting cutting edge research, with an eye for translation of basic research findings to mental health:
- Scientists at the University of Pittsburgh and Carnegie Mellon University are investigating the origins of cognitive deficits in schizophrenia. Problems with cognition are consistently present in schizophrenia, and while they may not be as dramatic as disordered perception, they are disabling. Research suggests that altered activity in a subset of neurons using the neurotransmitter GABA as the primary signaling molecule, may play a role these deficits. Center scientists will look for GABA-related gene products associated with changes in brain wave patterns seen in schizophrenia. Brain waves reflect the synchronized firing of neurons, which in turn underlie cognitive processes. The scientists will also test pharmacological agents to see if they restore normal GABA signaling. The project requires the participation of experts in disciplines as wide-ranging as neuroanatomy, electrophysiology, microscopy, state-of-the-art functional and structural imaging, computer modeling, and clinical neuroscience. The ultimate goal is to identify, based on knowledge of the underlying brain chemistry, novel treatments as well as biomarkers—features of biologic processes that can be used to assess function. Dr. David Lewis is the principal investigator at this center.
- Scientists at a Conte center at Johns Hopkins University aim to clarify exactly how changes in genetic susceptibility factors for schizophrenia regulate the development of the nervous system. Research suggests that schizophrenia alters developmental processes in the brain well before symptoms of the disease emerge in early adulthood. One key susceptibility factor, the protein DISC1, is reported to be a central player in such processes as the formation of synapses, the regulation of cell division, and the growth of new neurons in adulthood. This group will explore interactions of proteins involved in DISC1 molecular pathways. Genetic studies will identify genes related to the developmental cascades identified. The investigators will generate mice with targeted genetic changes and observe any behavioral effects. Elucidating the chain of events between gene products and disease will provide an information base for developing new and earlier interventions. Dr. Akira Sawa is the principal investigator.
- Scientists at another Conte center at Johns Hopkins University are studying the biochemistry and genetics behind how the brain responds to experience. Brain cells communicate with each other using chemical and electrical signaling between cells at specialized junctions called synapses. Long-term changes in the efficiency of this chemical and electrical signaling and associated changes in the configuration of synapses are thought to underlie brain development, the learning process, and changes in cognitive function in health and in disease. Scientists at this center will identify the molecular mechanisms involved in synapse formation, how signaling events at the synapse influence subsequent gene expression in the nucleus, and how these changes result in further long-lasting changes at synapses. Many of the drugs that are effective for treating mental health disorders are known to target synapses; further, malfunctions of synaptic mechanisms are implicated in disorders of cognition such as autism and schizophrenia. This work will help clarify the processes involved in normal communication among brain cells, and pave the way for identifying the mechanisms that go awry in mental health disorders. Dr. Richard Huganir is the principal investigator.
- The focus of the Conte center at the University of Wisconsin-Madison is a more complete understanding of the biologic and behavioral risk factors for anxiety and mood disorders in adolescence. The risk of adult anxiety and depressive disorders is substantially increased in adults who had symptoms in adolescence. Scientists at this center will study groups of adolescents, gathering detailed information on behavior, family environment, and any signs of mood disorders; levels of brain stress hormones, which can be both indicators of how the brain reacts to stress and markers of vulnerability to mood disorders; and structural and functional information from imaging studies on parts of the brain involved in emotional responses. Information on the dynamics of early stress, behavior, and the brain should provide insight into the variability of these disorders, risk factors for developing them, and possible treatment approaches. Dr. Richard Davidson is the principal investigator at this Conte center.
As research progresses, greater specialization is required to understand the complexities of biologic systems. Conte centers offer a context in which scientists can collaboratively address this complexity and translate the resulting knowledge into new methods of diagnosis and treatment.