A5058059309- PI3K/AKT/mTOR signaling in cancer
- Tuberous Sclerosis Complex Research
- Pluripotent Stem Cells Research
- CRISPR and Genetic Engineering
- Retinal Development and Disorders
- Microbial Inactivation Methods
- Mitochondrial Function and Pathology
- Neuroscience and Neural Engineering
- Genetic and Kidney Cyst Diseases
- Fetal and Pediatric Neurological Disorders
- Virus-based gene therapy research
- RNA regulation and disease
- Epilepsy research and treatment
- Ion channel regulation and function
- Genetics and Neurodevelopmental Disorders
- stochastic dynamics and bifurcation
- Cerebrospinal fluid and hydrocephalus
- Neuroscience and Neuropharmacology Research
- Mast cells and histamine
Dartmouth College
2016-2025
Yale University
2020-2022
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a negative regulator of AKT/mTOR signaling pathway. Mutations in PTEN are found patients with autism, epilepsy, or macrocephaly. In mouse models, Pten loss results neuronal hypertrophy, hyperexcitability, seizures, ASD-like behaviors. The underlying molecular mechanisms these phenotypes not well delineated. We determined which the loss-driven aberrations form function orchestrated by downstream mTOR complex 1 (mTORC1)....
The causative link between focal cortical malformations (FCMs) and epilepsy is well accepted, especially among patients with dysplasia type II (FCDII) tuberous sclerosis complex (TSC). However, the mechanisms underlying seizures remain unclear. Using a mouse model of TSC- FCDII-associated FCM, we showed that FCM neurons were responsible for seizure activity via their unexpected abnormal expression hyperpolarization-activated cyclic nucleotide-gated potassium channel isoform 4 (HCN4), which...
Retroviruses expressing a fluorescent protein, Cas9, and small guide RNA are used to mimic nonsense PTEN mutations from autism patients in developing mouse neurons. We compare the cellular phenotype elicited by CRISPR-Cas9 those using shRNA or Cre/Lox technologies find that knockdown knockout (KO) produced corresponding moderate severe neuronal hypertrophy all cells. In contrast, Cas9 approach missense Pten mutations, resulting mix of KO-equivalent hypertrophic wild type-like phenotypes....
Phosphatase and tensin homolog (PTEN) is a major negative regulator of the phosphatidylinositol-3-kinase (PI3K)/Akt/mechanistic target rapamycin (mTOR) pathway. Loss-of-function mutations in PTEN have been found subset patients with macrocephaly autism spectrum disorder (ASD). loss neurons leads to somal hypertrophy, aberrant migration, dendritic overgrowth, increased spine density, hyperactivity neuronal circuits. These overgrowth phenotypes are present on Pten knock-out (KO) reconstitution...
SUMMARY Expansion of the cerebrospinal fluid (CSF)-filled cerebral ventricles (ventriculomegaly) is quintessential feature congenital hydrocephalus (CH) but also seen in autism spectrum disorder (ASD) and several neuropsychiatric diseases. PTEN frequently mutated ASD; here, we show a bona fide risk gene for development ventriculomegaly, including neurosurgically-treated CH. Pten -mutant associated with aqueductal stenosis due to hyperproliferation periventricular Nkx2.1 + neural precursors...