# Identifying mTOR Dependent Periods During Brain Development > **NIH NIH R01** · VANDERBILT UNIVERSITY · 2020 · $397,556 ## Abstract Tuberous Sclerosis Complex (TSC) is a multi-organ disorder caused by mutations in the TSC1 or TSC2 genes. TSC is a challenging disease to approach as there are many involved organ systems, which have distinct profiles of symptom onset, disease progression, and in some cases even stability or regression of the benign tumors known as hamartomas. These multiple examples of distinct time courses in each organ system strongly suggest that the TSC1/TSC2 genes control cell signaling pathways that are tissue specific and developmentally regulated, resulting in lesions that present at different times in the lifetime of the patient. These pathways certainly include mTOR kinase signaling, but critical upstream and downstream regulators of this developmentally regulated process in specific tissues remain poorly understood. The neurological manifestations of TSC are typically severe at very early ages and include epilepsy, intellectual disability, autism, and behavioral/psychiatric disorders. Recent findings in human cell-derived model systems suggest that neural development is disrupted in TSC, and that proper regulation of mTOR signaling is especially important in human brain in comparison to other mammals. However, the cellular mechanisms connecting TSC1/2 mutation and the phenotypic outcomes of this mutation are not well understood. This project will use patient-derived cells and single-cell measurements of protein and RNA to measure altered signaling pathways in various cell types of the human brain and also address how these abnormalities impact specific developmental stages. Examined stages will span early neural progenitor cells to more mature neurons found in the postnatal brain. Human induced pluripotent stem cells (iPSCs) from patients carrying TSC2 mutations will be used to generate lineage-committed progenitors and differentiated neurons and glia. We will also use freshly resected human tubers as well as previously resected human tubers that have been fixed and stored, and will employ custom-designed computational pipelines to compare the developmental trajectories of TSC2-mutant cells to matched controls and larger published datasets. Using cutting edge cell imaging and analysis protocols, we will test the overarching hypothesis that tubers from patients with TSC and stem cell derivative neural cells and tissues have mTOR-dependent and mTOR- independent signaling abnormalities that are lineage- and temporally-restricted. Finally, we will quantitatively compare signaling dynamics in specific developmental stages and lineages between TSC2 mutant cells and cells derived from a second “mTORopathy” with overlapping but non-identical clinical features, to dissect the function of different components of this pathway in neural development and pathogenesis and reveal compensatory signaling after treatment of cells carrying TSC2 or DEPDC5 mutations. ## Key facts - **NIH application ID:** 10054882 - **Project number:** 1R01NS118580-01 - **Recipient organization:** VANDERBILT UNIVERSITY - **Principal Investigator:** KEVIN C ESS - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $397,556 - **Award type:** 1 - **Project period:** 2020-09-01 → 2025-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10054882 ## Citation > US National Institutes of Health, RePORTER application 10054882, Identifying mTOR Dependent Periods During Brain Development (1R01NS118580-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10054882. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*