Wolstein Research Building, Room ????
2103 Cornell Road, Cleveland, OH 44106
Lab phone: ???-???-????
Professor, Department of Pathology, School of Medicine
Co-Director, Harrington Rare Disease Program, School of Medicine
Email: mpa52@case.edu
OCRID: 0000-0003-4602-1811
Research Projects
Identify, Resolve Molecular-Circuit Mechanisms, and Develop Therapeutics for Unrecognized CD8 T-cell- based Behavioral Brain Diseases:
- CD8 cytotoxic T-cell immunity targeting hypothalamic feeding circuits in obesity (~40% of cases) (Ahrendsen et al. Acta. Neuropath. Comm. 2023)
- CD8 cytotoxic T-cell immunity targeting circuits in suicide and depression
- CD8 cytotoxic T-cell immunity targeting astrocyte glia limitans in autism (~65% of cases). (DiStasio et al. Ann. Neurol. 2019)
- Others
Molecular-Circuit Mechanisms and Therapeutics for Immune and Genetic Autisms:
- UBE3A underlies a genetic autism due to idic15/dup15q acting in the nucleus to cause behavioral symptoms and converging and synergizing with epilepsy to repress expression of synapse organizer CBLN1 to break autism gene-rich NRXN1-CBLN1-GRID1 transsynaptic complex (Smith et al. Sci. Trans. Med. 2011; Krishnan et al. Nature 2017; Nong et al. bioRxiv 2023)
- Molecular pathway overlap of sporadic (immune) autism and genetic autisms
- Sociability Circuits: Ventral tegmental area (VTA) glutamatergic neurons drive social behavior where UBE3A reduces CBLN1 to breaks glutamatergic synapse and impair sociability (Smith et al. Sci. Trans. Med. 2011; Krishnan et al. Nature 2017)
- Aggression/Irritability Circuits: Hypothalamic feedback inhibitory arcuate AgRP/NPY neurons inhibit irritability/aggression where UBE3A reduces CBLN1 to break a collateral glutamatergic synapses from aggression driving ventromedial hypothalamic neurons in the ventrolateral subdivision to arcuate AgRP/NPY neurons that provide feedback inhibition (Nong et al. bioRxiv 2023).
Molecular Mechanisms and Therapeutics for Central and Peripheral Axonal Diseases
Genetic neurodevelopmental disease resulting from MAPK8IP3 truncations and missense mutations
Human Brain Evolution Molecular Mechanisms
Human-specific SINE-VNTR-ALU (SVA) retrotransposon in microcephaly gene CDK5RAP2 intron represses its expression to slow progenitor to neuron maturation, potentially contributing to the slowed maturation, enlarged brain, and advanced cognitive and sensorimotor functions in human relative to their closest living relative the chimpanzee. Discovered the function of founding SVA-lncRNA gene family member, AK057321, a gene duplicated in rare cases of autism. It forms RNA:DNA heteroduplexes with genomic SVA sequences and decoy binds SVA repressive KRAB domain zinc finger transcription factor ZNF91 to release the CDK5RAP2 gene repression. SVA retrotransposon and SVA-lncRNA gene regulatory system regulates human genes underlying intellectual, social, and language abilities providing new insights into the genetic basis of human evolution. (Nadler et al. Commun. Biol. 2023).
Lab Members:
Brooke Mangano
BSTP Student
Email: brooke.mangano@case.edu
ORCiD: 0000-0002-4903-5779
Brooke is a first-year PhD student who graduated from the University of Georgia in December 2024 with Bachelor's Degrees in Biomedical Physiology, Biochemistry, and Molecular Biology. Her goal is to make progress in the medical field through translational research. She aims to focus on epigenetics and pharmacology to find treatments for behavioral neurological disorders such as autism, depression, and anxiety.
Sanjana Kumar
Undergraduate Researcher
Email: sanjana.kumar3@case.edu
Sanjana, a second-year student at CWRU, is majoring in neuroscience and minoring in psychology. As a pre-med student, she is eager to learn more about neuropsychiatric diseases.