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Elucidating cellular pathways controlling the reactive state of astrocytes in Alzheimer's Disease

Award Number: F30AG066418
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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Elucidating cellular pathways controlling the reactive state of astrocytes in Alzheimer's Disease - PROJECT SUMMARY/ABSTRACT Astrocytes perform essential homeostatic functions in the brain. In response to local tissue injury, astrocytes become “reactive”, a process classically characterized by morphological hypertrophy and upregulation of GFAP. Reactive astrocytes are a defining feature of Alzheimer's disease (AD) neuropathology and are strongly correlated with cognitive decline in AD. However, mechanisms controlling astrocyte reactivity are not well understood. Recent studies have identified a form of reactive astrocyte induced by inflammatory activation (“inflammatory reactivity”, a.k.a. “A1” reactivity) that may play a role in AD. Inflammatory reactive astrocytes are characterized by loss of normal homeostatic functions such as phagocytosis of CNS substrates as well as gain of neurotoxic properties. Importantly, they are found in a mouse model of AD as well as normal aged mice. Furthermore, human post-mortem AD brains are enriched for astrocytes expressing a marker of inflammatory reactivity. To elucidate mechanisms controlling inflammatory reactivity and its functional outputs in human astrocytes, in my preliminary work I implemented pooled CRISPRi loss-of-function screening in human iPSC- derived astrocytes (iAstros). From a preliminary screen, I identified myosin phosphatase as a potential regulator of the decreased phagocytic activity in inflammatory astrocytes. Furthermore, I leveraged existing astrocyte RNA-seq datasets to infer transcriptional regulators of inflammatory reactivity. In my first aim, I propose to determine how regulation of myosin phosphatase leads to decreased phagocytosis in inflammatory reactive astrocytes. In my second aim, I propose integrate genome-wide CRISPRi screening and coexpression analysis of existing astrocyte RNA-seq datasets to discover cellular pathways controlling inflammatory reactivity, followed by connecting these pathways to functional outputs of astrocyte reactivity. My sponsor Dr. Martin Kampmann, who co-developed the CRISPRi screening technology, and my co-sponsor Dr. Sergio Baranzini, an expert in neuroinflammation and the integration and analysis of transcriptomic datasets, are ideally positioned to support my proposed research. Furthermore, my collaborator Dr. Erik Ullian is an expert on the differentiation of high- quality astrocytes from human iPSCs, which further supports the feasibility of the proposed work. In addition to my two sponsors and my collaborator Dr. Ullian, I will also receive mentorship from Dr. Aimee Kao, a physician- scientist and practicing neurologist with whom I will undergo longitudinal clinical training in neurology, and Dr. Bruce Conklin, a global leader in iPSC-based technologies and genome surgery. Overall, the work proposed in this fellowship should contribute towards the development of drugs that can selectively modulate different functional outputs of astrocyte reactivity for the treatment of AD. Furthermore, through this work I will develop expertise in uncovering disease mechanisms with iPSC-derived models and functional genomics which will strengthen my training as a physician-scientist.


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 = -$780 )
2024	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Aging Research	000	4	9/23/2024	NON-COMPETING CONTINUATION	-$780
														Subtotal = -$780

Issue Date FY: 2023 ( Subtotal = $40,507 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	001	4	2/15/2023	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	Aging Research	000	4	11/21/2022	NON-COMPETING CONTINUATION	$39,565
														Subtotal = $40,507

Issue Date FY: 2022 ( Subtotal = $39,328 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	001	3	5/2/2022	NON-COMPETING CONTINUATION	$717
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	000	3	11/19/2021	NON-COMPETING CONTINUATION	$38,612
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	002	3	7/18/2022	NON-COMPETING CONTINUATION	-$1
														Subtotal = $39,328

Issue Date FY: 2021 ( Subtotal = $38,387 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	000	2	11/13/2020	NON-COMPETING CONTINUATION	$37,871
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	001	2	3/10/2021	NON-COMPETING CONTINUATION	$516
														Subtotal = $38,387

Issue Date FY: 2019 ( Subtotal = $36,779 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	001	1	9/11/2019	NEW	$0
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Aging Research	000	1	9/11/2019	NEW	$36,779
														Subtotal = $36,779

Grand Total All Awards = $154,221

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Elucidating cellular pathways controlling the reactive state of astrocytes in Alzheimer's Disease

Award Number: F30AG066418

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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