Modeling complex neurological disorders with human induced pluripotent stem cells / Sean Kerry Ryan.

Format:

Book

Thesis/Dissertation

Author/Creator:

Ryan, Sean Kerry, author.

Contributor:

University of Pennsylvania. Department of Cell and Molecular Biology, degree granting institution.

Anderson, Stewart A., degree supervisor.

Jordan-Sciutto, Kelly L., degree supervisor.

Language:

English

Subjects (All):

Cellular biology.

Cell and molecular biology--Penn dissertations.

Penn dissertations--Cell and molecular biology.

Local Subjects:

Cellular biology.

Cell and molecular biology--Penn dissertations.

Penn dissertations--Cell and molecular biology.

Genre:

Academic theses.

Physical Description:

1 online resource (219 pages)

Contained In:

Dissertations Abstracts International 81-10B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2020.

Language Note:

English

System Details:

Mode of access: World Wide Web.

text file

Summary:

The etiology of many complex neurological disorders, including schizophrenia (SZ) and HIV-Associated Neurocognitive Disorders (HAND), are still unknown, partly due to a lack of accurate models. Human-induced pluripotent stem cells (HiPSCs), which can be differentiated into any cell type and capture the genetic variation across humans, may serve as a powerful model to elucidate the mechanisms behind such disorders. In this thesis we have explored mechanistic and cellular phenotypes of the complex disorders Schizophrenia and HAND. First, we studied 22qDS, a hemizygous microdeletion that occurs at chromosome 22q11.2 and leads to complex neuropsychiatric phenotypes including SZ in 25% of 22qDS individuals. Since 6 of the 40 genes deleted in 22qDS encode for proteins that directly localize to mitochondria, we tested the hypothesis that SZ and 22qDS are associated with mitochondria defects. We found that HiPSC-derived neurons from 22qDS+SZ indeed have mitochondria deficits. We further discovered that haploinsufficiency of only the 22qDS gene MRPL40, a component of the mitochondrial ribosome, sufficiently replicated the mitochondria deficits. Another important gene in the 22q region, CLDN5 functions in tight junctions in the blood-brain barrier (BBB). We hypothesized that there would be deficits in HiPSC-derived BBB in 22qDS+SZ. We found impaired BBB function and increased inflammation. Impaired mitochondria function and BBB integrity may synergistically collaborate leading to increased chance of neuropsychiatric development. Third, to study the interactions between HiPSC-derived cell types in a disease process, we focused on the study of HIV, which leads to HAND in over half of HIV-infected individuals despite antiretroviral treatment (ART). We systematically combined independently differentiated neurons, astrocytes, and microglia to generate a tri-culture with or without HIV-infection and ART. We found that infection led to activation of EIF2 in all three cell types, which was largely resolved by treatment with the antiretroviral compound efavirenz (EFZ). However, EFZ treatment enhanced distinct inflammation signatures and TNFa production in HIV-infected microglia. These findings validate the tri-culture and reveal potential therapeutic targets for HAND. In sum, this thesis provides evidence that HiPSCs can be used in complex cultures to study the cellular and molecular mechanisms behind complex neuropsychiatric and neurocognitive disorders.

Notes:

Source: Dissertations Abstracts International, Volume: 81-10, Section: B.

Advisors: Anderson, Stewart A.; Jordan-Sciutto, Kelly L.; Committee members: Dennis Kolson; Matthew Weitzman; Ronald Collman; David Lynch.

Department: Cell and Molecular Biology.

Ph.D. University of Pennsylvania 2020.

Local Notes:

School code: 0175

ISBN:

9798607313425

Access Restriction:

Restricted for use by site license.

This item must not be sold to any third party vendors.