The Simons Foundation Autism Research Initiative (SFARI) is pleased to announce that it has selected six fellows in response to the 2021 Bridge to Independence Award (BTI) request for applications (RFA).
The BTI program is intended to help engage talented early-career scientists in autism research by facilitating their transition from mentored training positions to independent careers. Launched in 2015, the program is aimed at Ph.D.- and M.D.-holding scientists with an interest in autism research who are currently in training positions but intend to seek tenure-track faculty positions at a U.S. or Canadian research institution during the upcoming academic year. Fellows will receive a commitment of $495,000 over three years, activated upon assumption of their faculty positions. With the addition of the 2021 BTI cohort, the program now boasts 37 outstanding fellows.
The selected projects span a broad range of disciplines, tackling questions about the brain mechanisms that underlie features of autism, such as agitation and aggression, changes in attention and cognitive flexibility, as well as aspects of genetic and epigenetic regulation that may affect brain development. These studies will use a variety of experimental approaches, including human neuroimaging studies, genetic mouse and rat models of autism, and induced pluripotent stem cells.
Finalists were selected through a competitive review process. The scientific review panel included Helen Bateup, Ph.D. (associate professor, University of California, Berkeley), Kamran Khodakhah, Ph.D. (professor, Albert Einstein College of Medicine), Genevieve Konopka, Ph.D. (associate professor, University of Texas Southwestern Medical Center), Brian O’Roak, Ph.D. (associate professor, Oregon Health & Science University), Carlos Portera-Cailliau, M.D., Ph.D. (professor, University of California, Los Angeles) and Anne E. West (professor, Duke University). Members of the panel evaluated the quality of each applicant, the scientific merit of their research proposal and their commitment to autism research.
“The BTI Award is a unique program that provides invaluable funding and guidance to early-career scientists at a critical stage of their careers,” says West. “We reviewed many outstanding applications this year, and I have no doubt that the new BTI fellows will make important contributions to the field of autism in the coming years.”
Alongside research money, for the first time this year the BTI Award will also provide a $10,000 gift for the 2021 fellows to use, during their transition year, for a variety of professional development opportunities. Examples of activities include attendance at scientific conferences and professional development workshops, as well as informal visits to prospective faculty institutions. This initiative is part of SFARI’s broader effort to provide the BTI fellows with training and learning experiences that can help them navigate the many aspects of becoming a successful academic investigator. In the fall, the SFARI BTI program is also planning to offer additional training and networking opportunities, in conjunction with its sister BTI program recently launched by the Simons Collaboration on the Global Brain.
“Given the pandemic’s effects on the scientific workforce, the SFARI BTI program seems more relevant than ever,” says Alice Luo Clayton, SFARI senior scientist who oversees the BTI program. “I look forward to collaborating with these new fellows and supporting their academic and professional growth as they transition to research independence.”
The six awardees are:
Gabriella L. Boulting, Ph.D.
Research fellow in the laboratory of Michael Greenberg, Ph.D. (Harvard Medical School)
Autism heritability encoded in the primate-evolved experience-dependent regulome
Neuronal activity-dependent gene expression is essential for brain development. Transcriptional and epigenetic effects of neuronal activity have been extensively explored in mice. However, a recent study from Gabriella Boulting and colleagues has shown that more than one hundred autism-associated genes have previously unreported activity-inducible expression in human stem cell-derived neurons1, suggesting that the neuronal activity-dependent gene program has evolved differently in primates than in rodents. The current project aims to identify the neuronal activity-regulated genes of the primate genome, and the noncoding DNA regulatory elements that control them, in order to reveal evolved primate-specific genetic sequences that contribute to autism risk.
Alexander Li Cohen, M.D., Ph.D.
Instructor of neurology (Boston Children’s Hospital, Harvard Medical School)
Using network mapping to identify neuromodulation targets for agitation and aggression in autism
Agitation and aggression are common, difficult-to-manage challenges for many individuals with autism. In the current project, Alexander Li Cohen plans to identify a specific brain network that has a causal relationship with agitation and aggression, and that is consistent across age and clinical cohorts, including individuals with autism. These studies will take advantage of neuroimaging data and behavioral measures of agitation and aggression that have already been collected from diverse clinical cohorts (including a total of 970 adults and 300 children and adolescents). Results from these studies are expected to inform mechanistic studies of how specific genetic alterations lead to increased agitation and aggression in autism, as well as neuromodulation studies to determine if altering brain activity in this network can reduce agitation and aggression, ultimately leading to novel treatment options.
Eirene Markenscoff-Papadimitriou, Ph.D.
Associate specialist in the laboratory of John Rubenstein, M.D., Ph.D. (University of California, San Francisco)
Mechanisms of chromatin regulation in autism
A significant proportion of high-confidence autism risk genes play a role in chromatin regulation, but it remains unclear how mutations in these genes cause autism2. In the current proposal, Eirene Markenscoff-Papadimitriou plans to focus on two autism risk genes, ADNP and POGZ, which encode chromatin regulators with similarities in their structures and functions. She hypothesizes that identifying enhancers dysregulated by heterozygous mutations in these genes can point to the neuronal cell types where autism vulnerability arises. To identify such enhancers, epigenetic and transcriptomic profiling will be performed in mouse models of Adnp and Pogz haploinsufficiency. The function of pathogenic missense and truncating variants will also be assessed in human stem-cell derived cortical neurons.
Marino Pagan, Ph.D.
Postdoctoral research associate in the laboratory of Carlos Brody, Ph.D. (Princeton University)
High-throughput dissection of the neural mechanisms underlying cognitive inflexibility in autism
Cognitive flexibility, the ability to rapidly switch our thinking and actions according to context, is a fundamental component of higher cognition. Changes in cognitive flexibility are common in autism, yet little is known about the underlying neural mechanisms. Marino Pagan has developed paradigms that allow rats to perform complex behaviors that require rapid executive control3. In the current project, he plans to leverage these behavioral paradigms to systematically characterize deficits across different domains of cognitive flexibility in genetic rat models of autism (including Fmr1 and Nrxn1 mutants). He then plans to investigate the neural mechanisms underlying cognitive inflexibility in these models. These studies will involve high-throughput electrophysiology and optogenetic experiments in freely moving, behaving animals.
Kartik Pattabiraman, M.D., Ph.D.
Clinical fellow in the laboratory of Nenad Sestan, M.D., Ph.D. (Yale University School of Medicine)
Connecting autism risk genes to circuits: Multi-level characterization of the cortical subplate
Functional genomic studies have identified disruption of cortical neurons and their associated circuits during mid-fetal development as a possible convergent etiology of autism. The largest structure in the mid-fetal human developing cortex is the subplate zone, a heterogenous layer of neurons associated cortical circuit assembly. Kartik Pattabiraman plans to perform a comparative multi-level characterization of this cortical layer with a focus on its role in circuit formation and autism pathology. Specifically, he plans to identify and study conserved and species-specific characteristics. He also plans to further characterize subplate-enriched genes, including ASD risk genes, and assess the effect of knockdown of select genes on cortical connectivity.
Zhuzhu Zhang, Ph.D.
Postdoctoral fellow in the laboratory of Joseph Ecker, Ph.D. (The Salk Institute for Biological Studies)
Epigenetics and environmental interaction in postnatal brain development
Many autism risk genes play a role in regulating the epigenetic machinery, including chromatin remodelers and writers and readers of DNA methylation. Exposure to potential environmental risk factors for autism can also remodel the epigenome. This suggests that disruption of the epigenetic landscape may be a converging contributor to autism pathogenesis. In the current study, Zhuzhu Zhang plans to characterize cell type- and circuit-specific epigenomic configurations during normal postnatal brain development in mice and investigate how the epigenomic configurations are altered in genetic mouse models of autism. These studies will provide a better understanding of the interplay of changes in the genome and epigenome in neurodevelopmental conditions.
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