Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


37986.pdf (8.16 MB)

ETD Abstract Container

Abstract Header

Shared PI3K signaling abnormalities in brain tumors and epilepsy: PI3K inhibition in PTEN-deficient disorders of the brain

White, Angela R
http://orcid.org/0000-0001-9299-8303
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1603712831970142

Abstract Details

2020, PhD, University of Cincinnati, Medicine: Molecular and Developmental Biology.
Deficiency in Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN) (also referred to as MMAC1/TEP1) is known to contribute to multiple diseases of the brain including brain tumors, autism spectrum disorders and epilepsy. PTEN is a dual-specificity phosphatase that negatively regulates the phosphatidylinositol 3-kinase (PI3K) pathway by dephosphorylating phosphatidylinositol (3,4,5)-trisphosphate (PIP3), generating phosphatidylinositol (4,5)-bisphosphate (PIP2). Overactive PI3K signaling increases PIP3 leading to accelerations in cell cycle transition, proliferation and cell size. In this body of work, I assessed PTEN deficiency in the brain in the context of both cancer and neurodevelopmental disorders. In the first studies presented here (Chapters 2 and 3) we assess high grade gliomas. In Chapter 4, we assess PTEN deficient autism and epilepsy. Each project has the commonality of utilizing inhibition of the PI3K pathway to counteract the effects of PTEN deficiency but the therapeutic strategies used for each disorder will differ. For Chapter 2, we found a subset of tumors which have a favorable response to PI3K pathway inhibition, as assessed by proliferation and apoptosis in a novel genetically engineered mouse model which is PTEN deficient. This work seeks to identify the molecular differences in tumors which are reported as responsive to PI3K inhibition as compared to tumors that were not responsive. In Chapter 3, we describe a novel mouse model which represents a subset of pediatric high grade glioma. Due to the driving mutations in the PI3K pathway, including a mutation in PTEN, we assessed both monotherapy PI3K inhibition as well as a monotherapy downstream effector of PI3K (mTOR). Although preliminary, the tumors showed a marked reduction in proliferation. Finally, in Chapter 4, we assessed a therapeutic approach derived from PTEN-deficient cancers and apply it to PTEN-deficient autism and seizure disorders in a neuron-specific PTEN-deficient mouse model. We reported a significant reduction in several phenotypes including increased protein synthesis, seizures, and certain aspects of macrocephaly. The broad therapeutic approaches utilized for each PTEN-deficient disorder here are all inhibiting either PI3K or a downstream effector. The specific therapeutic approach is variable and will be better presented in each chapter. Overall, we find potential therapy approaches which will need to be more thoroughly elucidated for their respective disorder.
Christina Gross, Ph.D. (Committee Chair)
Lionel Chow, M.D. (Committee Member)
Steve Danzer, Ph.D. (Committee Member)
Charles Vorhees, Ph.D. (Committee Member)
Ronald Waclaw, Ph.D. (Committee Member)
268 p.
Biology
PTEN; seizure; autism

Recommended Citations

Citations

  • White, A. R. (2020). Shared PI3K signaling abnormalities in brain tumors and epilepsy: PI3K inhibition in PTEN-deficient disorders of the brain [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1603712831970142

    APA Style (7th edition)

  • White, Angela. Shared PI3K signaling abnormalities in brain tumors and epilepsy: PI3K inhibition in PTEN-deficient disorders of the brain. 2020. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1603712831970142.

    MLA Style (8th edition)

  • White, Angela. "Shared PI3K signaling abnormalities in brain tumors and epilepsy: PI3K inhibition in PTEN-deficient disorders of the brain." Doctoral dissertation, University of Cincinnati, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1603712831970142

    Chicago Manual of Style (17th edition)

ucin1603712831970142
223
© 2020, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.