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Signaling Pathways that Regulate Scaling and Regeneration of the Cerebellum

Award Number: R01NS092096
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: 02/01/2015
PERIOD OF PERFORMANCE END DATE: 06/01/2025

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Signaling Pathways that Regulate Scaling and Regeneration of the Cerebellum - The cerebellum, consisting of 80% of the neurons in the human brain, is involved in balance and motor coordination, and also modulates language, reasoning and social processes via its forebrain circuits. The developing cerebellum is particularly sensitive to factors that impact on growth (or cause injury) around birth, since much of its growth occurs in the third trimester and continues after birth. The postnatal cerebellar cortex has two proliferating stem/progenitor populations, one dedicated to making excitatory granule cells and the other to interneurons and astrocytes. Whereas great advances have been made in defining the stem/progenitor cells and lineages that generate the developing cerebellum, little is known about the ability of the cerebellum to produce new cells following injury. We recently discovered that the mouse cerebellum has a large capacity to replenish cells killed around birth. First, we found that Nestin-expressing progenitors (NEPs) that normally are dedicated to the astrocyte lineage are reprogrammed to become granule cell precursors (GCPs) when the latter are killed by irradiation or genetic approaches. Furthermore, at least two spatially and transcriptionally distinct NEP subtypes that are lineage-restricted have different responses to the loss of GCPs to achieve proper scaling of cell types after injury. Second, Purkinje cells (PCs), which are born by embryonic day 13.5, are rapidly replaced via proliferation of rare immature Purkinje cells (iPCs) following PC killing, and replenishment of PCs is age-dependent. Finally, signals released by dying cells, such as reactive oxygen species (ROS), and cells in the microenvironment can have critical influences on repair responses of progenitor cells. Preliminary results showed that cells in microenvironment have distinct cellular responses in each of our injury models. We will address two critical questions for both injuries: i) What are the gene expression changes that underlie the cellular transitions necessary for cell replenishment and ii) what are the roles of dying cells, immune cells and glia in regeneration. Our central hypothesis is that cerebellar progenitors and rare immature neurons maintain distinct transcriptional plasticity and along with cells in the microenvironment respond differently to killing of GCPs and PCs. Our specific aims are to: 1) Uncover the transcriptional signatures of NEP subtypes and iPCs during development and regeneration, and identify pathways required for proliferation and neuron production using single cell and mutant analyses. 2) Determine how the microenvironment influences NEP and iPC injury responses.


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: 2026 ( Subtotal = $0 )
2026	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	12/2/2025	TERMINATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	11/14/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $491,349 )
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	10	4/9/2024	NON-COMPETING CONTINUATION	$35,458
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	1/31/2024	NON-COMPETING CONTINUATION	$455,891
														Subtotal = $491,349

Issue Date FY: 2023 ( Subtotal = $506,544 )
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	2/28/2023	NON-COMPETING CONTINUATION	$506,544
														Subtotal = $506,544

Issue Date FY: 2022 ( Subtotal = $506,544 )
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	1/31/2022	NON-COMPETING CONTINUATION	$455,886
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	6/23/2022	NON-COMPETING CONTINUATION	$50,658
														Subtotal = $506,544

Issue Date FY: 2021 ( Subtotal = $506,544 )
2021	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	2/2/2021	NON-COMPETING CONTINUATION	$506,544
														Subtotal = $506,544

Issue Date FY: 2020 ( Subtotal = $506,544 )
2020	2020	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	1/31/2020	COMPETING CONTINUATION	$506,544
2020	2020	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	6/22/2020	COMPETING CONTINUATION	$82,460
2020	2019	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	6/22/2020	NON-COMPETING CONTINUATION	-$82,460
														Subtotal = $506,544

Issue Date FY: 2019 ( Subtotal = $462,493 )
2019	2019	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/7/2019	NON-COMPETING CONTINUATION	$462,493
														Subtotal = $462,493

Issue Date FY: 2018 ( Subtotal = $452,965 )
2018	2018	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/23/2018	NON-COMPETING CONTINUATION	$407,669
2018	2018	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/27/2018	NON-COMPETING CONTINUATION	$45,296
														Subtotal = $452,965

Issue Date FY: 2017 ( Subtotal = $452,965 )
2017	2017	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/23/2017	NON-COMPETING CONTINUATION	$407,669
2017	2017	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	6/7/2017	NON-COMPETING CONTINUATION	$45,296
														Subtotal = $452,965

Issue Date FY: 2016 ( Subtotal = $452,965 )
2016	2016	SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/5/2016	NON-COMPETING CONTINUATION	$452,965
														Subtotal = $452,965

Issue Date FY: 2015 ( Subtotal = $452,965 )
2015	2015	SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/15/2015	NEW	$452,965
														Subtotal = $452,965

Grand Total All Awards = $4,791,878

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Signaling Pathways that Regulate Scaling and Regeneration of the Cerebellum

Award Number: R01NS092096

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: 02/01/2015

PERIOD OF PERFORMANCE END DATE: 06/01/2025

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