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Principal Investigator: Xiaosi Han
Organization: BIRMINGHAM VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
Project Summary/Abstract
Gliomas are incurable and are the number two cause for tumor mortality in adult under 40 years old.
Monoallelic mutations of IDH1 and IDH2, which encode isocitrate dehydrogenases (IDH) that convert
isocitrate into α-ketoglutarate (αKG), have been detected in 80% of low grade gliomas (LGG) and nearly
all secondary glioblastoma multiform (GBM). 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), such as human embryonic stem cells and induced pluripotent stem cells
(iPSCs), have the potential to differentiate into different somatic cell types and organoids including
brain organoid. Brain organoids possess primitive brain structure with different cell types and therefore
may provide a microenvironment permissive for gliomagenesis. We hypothesize that iPSCs derived
brain organoids serve as an alternative source for human brain 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 brain organoid model for LGGs allowing assess 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, three specific aims are
proposed. In Aim 1, we will assess the roles of IDH and TP53 mutations in gliomagenesis using the
brain organoid LGG model. We will first generate brain organoid from iPSCs and then introduce
genetic changes including IDH1 mutation and TP53 knock-down. In Aim 2, we will assess the role of
ATRX mutation in brain organoid based gliomagenesis in vitro. In Aim 3. We will characterize brain
organoid-derived xenograft tumor in comparison to genetically engineered brain organoids and patient
LGGs. If successfully completed, we expect to establish a novel brain organoid model for LGGs, which
will enable us to assess the specific roles of IDH mutations and other glioma-associated genetic
mutations in tumorigenesis. The project will ultimately facilitate identification of novel drug targets
and development of new therapies to treat gliomas.
Terms: <2-ketoglutarate><2-oxoglutarate><21+ years old><ATRX><ATRX gene><Adult><Adult Human><Animal Model><Animal Models and Related Studies><Antioncogene Protein p53><Architecture><Astrocytes><Astrocytus><Astroglia><Brain><Brain Neoplasia><Brain Neoplasms><Brain Nervous System><Brain Tumors><Cancer Cause><Cancer Etiology><Cell Body><Cell Survival><Cell Viability><Cells><Cellular Tumor Antigen P53><Cessation of life><DNA><DNA Alteration><DNA Sequence Alteration><DNA mutation><Death><Deoxyribonucleic Acid><Diagnosis><Disease><Disorder><Dissection><Encephalon><Engineering / Architecture><Ensure><Enzyme Gene><Enzymes><Event><Family><Gene Expression><Generalized Growth><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Genetic defect><Genetic mutation><Genomics><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioblastoma><Glioma><Gliomagenesis><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Growth><Heterograft><Heterologous Transplantation><Human><Hydroxylases><In Vitro><Inhibition of Cell Proliferation><Intervention><Intervention Strategies><Investments><Isocitrate Dehydrogenase><Isocitrates><Lead><Mixed Function Oxidases><Mixed Function Oxygenases><Modeling><Modern Man><Molecular><Monooxygenases><Mutation><Negative Control of Cell Proliferation><Negative Regulation of Cell Proliferation><Nerve Cells><Nerve Unit><Neural Cell><Neural Stem Cell><Neurocyte><Neuroglial Neoplasm><Neuroglial Tumor><Neurons><Oncogenesis><Oncoprotein p53><Organoids><P53><Pathway interactions><Patients><Pb element><Phosphoprotein P53><Phosphoprotein pp53><Progenitor Cells><Proliferating><Protein TP53><Publishing><Recombinant DNA Technology><Research><Role><Sequence Alteration><Somatic Cell><Source><Structure><System><TP53><TP53 gene><TRP53><Therapeutic Intervention><Tissue Growth><Transplantation><Tumor Promotion><Tumor Protein p53><Tumor Protein p53 Gene><Xenograft><Xenograft procedure><Xenotransplantation><adult youth><adulthood><alpha ketoglutarate><alpha thalassemia mental retardation X-linked gene><alpha-oxoglutarate><astrocytic glia><brain cell><cell type><drug development><epigenome><genetically engineered><genome mutation><genomic alteration><genomic profiles><glial-derived tumor><glioblastoma multiforme><glioma genesis><hESC><heavy metal Pb><heavy metal lead><human ES cell><human ESC><human embryonic stem cell><human pluripotent stem cell><iPS><iPSC><iPSCs><improved><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><intervention therapy><interventional strategy><knock-down><knockdown><model of animal><mortality><mouse model><murine model><mutant><nerve stem cell><neural precursor><neural precursor cell><neural progenitor><neural progenitor cells><neuro-oncology><neuroglia neoplasm><neuroglia tumor><neuron progenitors><neuronal><neuronal progenitor><neuronal progenitor cells><neuronal stem cells><neurooncology><neuroprogenitor><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><ontogeny><p53 Antigen><p53 Genes><p53 Tumor Suppressor><pathway><permissiveness><progenitor biology><progenitor cell biology><protein p53><shRNA><short hairpin RNA><small hairpin RNA><social role><spongioblastoma multiforme><stem and progenitor biology><stem cell biology><stem cells><transplant><tumor><tumor xenograft><tumorigenesis><tumorigenic><tumors in the brain><xeno-transplant><xeno-transplantation><young adult><young adulthood><α-ketoglutarate><α-oxoglutarate><α-thalassemia mental retardation X-linked gene><αKG>