Defining JNK-associated neurodevelopmental disorders - PROJECT SUMMARY This proposal aims to investigate the role of the c-Jun N-terminal kinase (JNK) signaling pathway in neurodevelopmental disorders (NDDs). NDDs, such as autism and intellectual disability, affect individuals across the lifespan and present diagnostic and medical management challenges. Despite advancements in genomic diagnostics and precision therapies, their application to NDDs remains limited. A key obstacle in improving care is the inability to provide a molecular diagnosis for most affected individuals, hindering the understanding of pathomechanisms and development of precision therapies. Loss-of-function variants in several genes involved in the JNK pathway, including MAP2K4 and MAP4K4 identified by our group, were recently shown as causative in NDDs. While the JNK pathway is known to play critical roles in neurodevelopment, its relevance to NDDs remains underexplored. I hypothesize that disrupted JNK signaling is a feature shared across an emerging class of NDD, and plays a role in non-syndromic neurologic disorders across the lifespan. I will test this hypothesis through two main approaches: induced pluripotent stem cell (iPSC)-based disease models to understand the effects of MAP4K4 and MAP2K4 deficiencies on the JNK pathway in the neuronal context, and a biobank-scale investigation of individuals with rare variants among JNK-associated genes to test if novel gene-disease relationships are identified. The Aim 1 of this proposal will thoroughly examine neuronal cellular and organoid phenotypes in iPSC disease models, and evaluate whether JNK pathway disruption underlies the observed phenotypes, as suggested by my preliminary data. The experimental approach will include rescue experiments for each sub-Aim to further determine this relationship. The Aim 2 of the proposal will evaluate other genes integral to the JNK pathways as candidate disease genes, and will leverage biobank-scale data to test if novel gene-disease relationships could be determined. Completion of this project will lead to better understanding of genetics of NDDs and improve the diagnostic yield of genetic testing for cases of NDDs. The JNK pathway is heavily researched as a drug target in other contexts, including cancer therapeutics, and my project could nominate a subset of genetic NDDs as potential therapeutic targets. Lastly, the genotype-first disease discovery pipeline I am developing can be repurposed to investigate additional gene-disease relationships that extends beyond NDDs. Through the 5-year funding period, I plan to identify and describe 3 or more novel Mendelian NDDs, and comprehensively describe JNK-associated NDDs as a distinct disease group. I plan to emerge from this period as a leader in disease discovery with broad expertise from basic neuroscience to biobank-scale data management and analysis. I will use the experience and discoveries as the foundation for the next stage in my career as an independent R01-funded translational researcher with a focus on the genetics of NDDs, as well as on therapeutic approaches inspired by the data that I will generate throughout the funding period.
