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Single Cell Analyses of Neuroimmune Dysfunctions in the Thalamocortical Circuit in FTLD

Award Number: R01AA027074
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2023

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Single Cell Analyses of Neuroimmune Dysfunctions in the Thalamocortical Circuit in FTLD - PROJECT SUMMARY Aberrant glial activation is a prominent feature in neurodegenerative diseases. But, what triggers glial activation in the aging brain and how it contributes to neuronal degeneration remains unclear. The scientific premise of this proposal is based on previous studies that dominant mutations in human Progranulin gene (GRN [gene], PGRN [protein]) cause a drastic reduction in PGRN levels in CSF and brain tissues in patients with frontotemporal lobar degeneration (FTLD), leading to profound gliosis, aggregation of RNA binding protein TDP-43, and neurodegeneration. In support of this idea, our recent studies show that Grn knockout (Grn-/-) mice is a valid model that captures several key disease features in FTLD caused by GRN mutations (FTLD- GRN), including microglial activation, microglia-mediated synaptic pruning and dysfunction in the thalamocortical circuit. Our ongoing work further revealed that Grn-/- mice and FTLD-GRN patients also shows a robust astroglial activation that positively correlates with microglial activation. Similar to Grn-/- microglia, Grn-/- astrocytes exhibit an age-dependent up-regulation of innate immunity genes, including complements C3 and C4b, which together with C1qa from Grn-/- microglia, activate both classical and alternative complement pathways to promote neurodegeneration. Taken together, these results support the hypothesis that PGRN deficiency is a feasible disease model to uncover the intricate neuroimmune interactions and how perturbation to these interactions leads to neuronal degeneration. To test this hypothesis, we propose a comprehensive single cell transcriptomic approach to survey the dynamic changes of glial and neuronal cell types in the thalamocortical circuit that is most severely impacted by PGRN deficiency. This approach will provide critical insights into the intrinsic mechanism of glial activation, neuronal degeneration and neural circuit dysfunction in Grn-/- mice and in FTLD-GRN patients. This innovative strategy involves high throughput profiling of transcriptomic and physiological properties of glia and neurons using droplet-based capture technology, microscopy and dynamic imaging of cell intrinsic physiological responses. These results will provide an unprecedented resolution to directly test the hypothesis that disruptions to the dynamic neuroimmune interactions between microglia, astrocytes and neurons in the thalamocortical circuit lead to neurodegeneration in FTLD caused by PGRN deficiency.


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: 2024 ( Subtotal = -$40,605 )
2024	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Alcohol Research Programs	000	5	2/8/2024	NON-COMPETING CONTINUATION	-$40,605
														Subtotal = -$40,605

Issue Date FY: 2022 ( Subtotal = $646,000 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Alcohol Research Programs	001	5	6/21/2022	NON-COMPETING CONTINUATION	$646,000
2022	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Alcohol Research Programs	000	4	6/8/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $646,000

Issue Date FY: 2021 ( Subtotal = $739,282 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Alcohol Research Programs	001	4	7/21/2021	SUPPLEMENT FOR EXPANSION	$93,282
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Alcohol Research Programs	000	4	6/30/2021	NON-COMPETING CONTINUATION	$646,000
														Subtotal = $739,282

Issue Date FY: 2020 ( Subtotal = $646,000 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Alcohol Research Programs	001	3	8/19/2020	NON-COMPETING CONTINUATION	$0
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Alcohol Research Programs	000	3	7/1/2020	NON-COMPETING CONTINUATION	$646,000
														Subtotal = $646,000

Issue Date FY: 2019 ( Subtotal = $642,000 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Alcohol Research Programs	000	2	6/19/2019	NON-COMPETING CONTINUATION	$642,000
														Subtotal = $642,000

Issue Date FY: 2018 ( Subtotal = $640,000 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Alcohol Research Programs	000	1	9/12/2018	NEW	$640,000
														Subtotal = $640,000

Grand Total All Awards = $3,272,677

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Single Cell Analyses of Neuroimmune Dysfunctions in the Thalamocortical Circuit in FTLD

Award Number: R01AA027074

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2023

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