Gliomas are incurable and are among the most fatal tumors in adult. Monoallelic mutations of IDH1 and IDH2, which encode isocitrate dehydrogenases (IDH) that convert isocitrate into ?-ketoglutarate (?KG), have been detected in nearly all secondary glioblastoma multiforme (GBM) and in 80% of low grade (WHO grade II) gliomas (LGGs). However, because IDH mutation-bearing glioma cells are difficult to isolate and propagate, an experimental system that allows dissection of the roles of IDH mutations and the subsequent genetic events in gliomagenesis is currently unavailable. Our overall goal is to understand the molecular mechanism underlying gliomagenesis and to identify novel targets to treat gliomas. It is generally believed that gliomas are originated from brain progenitor cells such as neural progenitor cells (NPCs). However, these cells are inaccessible for experimentation. Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), have the potential to differentiate into every somatic cell types. Therefore, we hypothesize that hPSCs serve as an alternative source for human brain progenitor cells, which can be used to dissect the roles of IDH mutations and other associated genetic events in LGGs. The objective of this proposal is to establish a novel stem cell model for LGGs, which will allow assessing the roles of IDH1 mutations and other glioma-associated genetic alterations in disease-relevant cell types. The rationale is that by establishing such a LGG model, we will be able to dissect the underlying molecular mechanism of gliomagenesis. These discoveries will ultimately facilitate identification of novel therapeutic targets and strengthen our capacity for therapeutic intervention. To achieve the objective, two specific aims are proposed.
In Aim 1, we will genetically engineer normal hPSCs to enable conditional expression of the mutant IDH1 in disease-relevant cell types.
In Aim 2, we will reprogram IDH mutation-bearing primary LGG cells into iPSC and assess cellular and molecular features of the LGG-iPSC-derived NPCs in a brain organoid model. If successfully completed, we expect to establish a novel stem cell model for LGGs, which will enable us to assess the specific roles of IDH mutations and other glioma-associated early genetic alterations. The project will ultimately facilitate identification of novel drug targets and development of new therapies to treat gliomas.

Public Health Relevance

The proposed research is relevant to public health because development of a novel an experimental system that allows dissection of the roles of IDH mutations and the subsequent genetic events will be critical to understand the underlying mechanisms of gliomagenesis, which would facilitate identification of novel drug targets and development of new therapies to treat this category of brain tumors. Therefore, the proposed research is relevant to the mission of NINDS that seeks fundamental knowledge about the brain and the nervous system and uses the knowledge to reduce the burden of neurological disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS106430-02
Application #
9776621
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Fountain, Jane W
Project Start
2018-09-15
Project End
2020-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Biochemistry
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294