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Shared mechanisms of astrocyte maturation in development and glioblastoma

Award Number: R01NS123562
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Shared mechanisms of astrocyte maturation in development and glioblastoma - Project Summary Glioblastoma (GBM) is the most common and deadliest primary brain tumor in adults. Recent work continues to support the idea that this cancer (like many others) echoes the proliferation and differentiation programs from earlier developmental stages. The possibility that neurological cancers like GBM are essentially `locked in' to a developmental program and retain the controls that instruct these cell populations during development opens new and exciting opportunities. Furthermore, it places an emphasis on the need to identify the molecular triggers that govern the transition of immature progenitor cells to quiescent mature astrocytes during development. In this project we will test the hypothesis that master transcriptional regulators are sufficient for driving astrocyte maturation and that these factors can be used to jump-start stalled maturation within GBM-astrocytes. The ability of individual or small groups of transcription factors to drive cell fate or maturation changes has been demonstrated in a variety of cell types, including neurons and glia. To begin, we used existing transcriptomic, epigenomic, and DNA-binding data to identify a targeted set of candidate transcription factors that we hypothesize catalyze the astrocyte maturation process. We will test whether these transcription factors are capable of inducing precocious maturation in immature human astrocytes by manipulating their expression using schemes that mirror their developmental activity. As a model system, we are using human iPSC-derived cortical organoids, which provides a multicellular platform in which astrogenesis and maturation occurs endogenously along a timescale analogous to what is observed in the fetal and early postnatal human brain. We will also ask how the developmental trajectory of astrocyte maturation is perturbed in the setting of GBM by comparing epigenomic profiles of maturing human astrocytes from the organoid system with single cell data from surgical GBM resections. This comparison will place GBM-astrocyte differentiation in the context of the normal developmental trajectory and reveal potential transcription factors whose absence may contribute to stalled maturation. An important possibility in the pathobiology of gliomagenesis is that the heterogeneous mutations accumulated within GBM-astrocytes render them unreceptive to maturation-inducing transcription factors. Thus, in a final set of experiments, we will use isogenic iPSC lines harboring driver GBM mutations to test their influence on the receptivity to maturation-inducing transcription factors. Together, these studies will help teach us how and where GBM cells are stalled in their developmental programs and offer novel avenues to pursue differentiation schemes to mitigate these deadly tumors.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $394,688 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	7/28/2025	NON-COMPETING CONTINUATION	$394,688
														Subtotal = $394,688

Issue Date FY: 2024 ( Subtotal = $382,849 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/28/2024	NON-COMPETING CONTINUATION	$382,849
														Subtotal = $382,849

Issue Date FY: 2023 ( Subtotal = $394,688 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/10/2023	NON-COMPETING CONTINUATION	$394,688
														Subtotal = $394,688

Issue Date FY: 2022 ( Subtotal = $392,106 )
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/30/2022	NON-COMPETING CONTINUATION	$392,106
														Subtotal = $392,106

Issue Date FY: 2021 ( Subtotal = $385,650 )
2021	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/24/2021	NEW	$385,650
														Subtotal = $385,650

Grand Total All Awards = $1,949,981

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Shared mechanisms of astrocyte maturation in development and glioblastoma

Award Number: R01NS123562

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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