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Synergistic Interaction of FTD Genes in Neuroinflammation and Neurodegeneration

Award Number: F99NS124183
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/12/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Synergistic Interaction of FTD Genes in Neuroinflammation and Neurodegeneration - Project Summary Frontotemporal dementia (FTD) is an early onset neurodegenerative disease, and the second most common cause of dementia in patients 60 years or younger. The majority of familial FTD are caused by intronic hexanucleotide (CCCCGG) repeat expansion in chromosome 9 open reading frame 72 (C9orf72) gene and by dominant mutations in the Progranulin (GRN) gene, causing haploinsufficiency in both genes, abnormal protein aggregate formation in neurons. Several functional and transcriptomic studies have shown that mice with null mutation in C9orf72 or Grn show abnormal microglia (resident CNS immune cells) activation mediated pathogenesis of neurodegeneration in FTD. While the exact functions for C9orf72 and Progranulin (PGRN [protein]) are still unclear, several studies have implicated both in autophagy and endolysosomal pathways in neurons and microglia, and concurrent mutations resulting in increased brain atrophy in patients. These results suggest a possible interaction between C9orf72 and PGRN in neurodegeneration during brain aging The goal of my project is to investigate the synergistic interaction of C9orf72 and Grn genes in glial homeostasis and neuronal degeneration using mouse models. In support of this, my preliminary data showed that C9orf72-/- ;Grn-/- DKO mice have significantly shortened lifespan, much shorter than C9orf72-/- mice, Grn-/- mice and control mice. Brain pathology examination in C9orf72-/-;Grn-/- DKO mice showed age-dependent gliosis as well as neuronal TDP-43 aggregates that are more pronounced and wide-spread than those in C9orf72-/- or Grn-/- mice. These results support my hypothesis and further indicate that loss of C9orf72 and Grn synergistically disrupt glia-neuron homeostasis and lead to more pronounced neurodegeneration phenotype. For the F00 phase, I propose to uncover the mechanism of C9 and PGRN in neurodegeneration in the aging brain via single-cell and bulk RNA-sequencing in 7 and 12 months old control, C9orf72-/-, Grn-/- and C9orf72-/-;Grn-/- DKO brain to determine how loss of these two FTD genes disrupts the homeostasis in glia-neuron interaction (Aim 2a). These transcriptomic data will be validated using in situ hybridization, immunohistochemistry and western blots (Aim 2b). Finally, I propose to develop in vitro cultures, including neuron-only cultures and glia-neuron co-cultures, which will provide more insights into the synergistic interaction between C9orf72 and PGRN in the autophagy- lysosome pathways and in glia-mediated toxicity to neurons (Aim 2c). For the K00 phase of this fellowship, I plan to develop induced pluripotent stem cells (IPSC)-derived 3D brain organoids as model systems to investigate disease mechanism and identify therapeutics for neurodegeneration. To identify signaling pathways that could be affected by diseases, I plan on using single-cell transcriptomics on patient IPSC derived glia-neuron organoids, followed by CRISPR/Cas9-based manipulation strategies on the signaling pathways dysregulated in these brain organoids to elucidate the diseases progression mechanisms.


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 = -$1,074 )
2025	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	10/23/2024	NON-COMPETING CONTINUATION	-$1,074
														Subtotal = -$1,074

Issue Date FY: 2023 ( Subtotal = $45,232 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	2/9/2023	NON-COMPETING CONTINUATION	$942
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/19/2023	NON-COMPETING CONTINUATION	$44,290
														Subtotal = $45,232

Issue Date FY: 2022 ( Subtotal = $43,693 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	6/23/2022	NEW	$716
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/6/2022	NEW	$42,977
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	1/6/2022	NEW	$0
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	1	7/14/2022	NEW	$0
														Subtotal = $43,693

Grand Total All Awards = $87,851

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Synergistic Interaction of FTD Genes in Neuroinflammation and Neurodegeneration

Award Number: F99NS124183

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/12/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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