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Generating LynA-/- and LynB-/- mice by CRISPR/Cas9 genome editing

Award Number: R03AI130978
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2017
PERIOD OF PERFORMANCE END DATE: 12/31/2018

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Generating LynA-/- and LynB-/- mice by CRISPR/Cas9 genome editing - Project Summary/Abstract Many debilitating and costly diseases are associated with inflammation and driven by macrophage signaling. Medical costs attributable to rheumatoid arthritis (RA) alone exceed $22.3 billion annually, and this incurable disease can severely impact patient quality of life, including the ability to work. Existing treatments for RA block macrophage inflammatory cytokine release or function and thereby also suppress antimicrobial immunity; the use of these treatments in patients suffering from infections is therefore problematic. Consequently, there is a pressing need for new therapies that target hypersensitive macrophages contributing to RA without impairing immune function. As a postdoctoral researcher I discovered a mechanism of macrophage signaling, through the protein LynA (but not a closely related protein, LynB), which functions only at sites of inflammation, as in the joints of RA patients, and is not required for antimicrobial immunity. This has led to the hypothesis that inhibition of LynA signaling could be an innovative new approach to relieving the symptoms of RA and other inflammatory diseases without suppressing immunity. LynA and LynB are thought to have opposing functions, with LynA pri- marily stimulating cell activation but LynB primarily initiating negative regulation. Dissecting their independent roles has been difficult, however, because existing Lyn-/- mice lack both LynA and LynB. We propose to overcome this obstacle to discerning the true functions of LynA and LynB in macrophage signaling and in inflammatory disease by generating LynA-/- (LynB-only) and LynB-/- (LynA-only) mice using CRISPR/Cas9 gene editing tech- nology. We will then perform experiments to test LynA and LynB function in macrophages from these mice, inducing antimicrobial signaling and hypersensitive signaling in an inflammatory environment in macrophages lacking LynA or LynB. Finally, we will test the progression of inflammatory arthritis in mice lacking LynA or LynB. We predict that LynA deletion will protect macrophages from inflammatory signaling and protect mice from de- veloping severe inflammatory arthritis, suggesting that inhibition of the LynA signaling pathway in the continued presence of LynB may be an effective strategy for treating autoinflammatory disease. Through the proposed approaches we aim to build the first definitive link between LynA, hypersensitive signaling, and inflammatory arthritis, while generating reagents and data to support a competitive R01 application. LynA-/- and LynB-/- mice will have long-term utility for mechanistic signaling and phosphoproteomics experiments to map unique roles of LynA and LynB in immune-cell signaling. These mice will be useful resources in which to begin the search for novel therapeutics targeting the LynA pathway in RA and other autoimmune diseases. Because this innovative therapeutic strategy is not expected to impair innate immunity to pathogens, it could expand treatment options for patients, make long-term suppressive treatment safer, and prevent disease recurrence.


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: 2019 ( Subtotal = $0 )
2019	2018	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	2	4/18/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $76,750 )
2018	2018	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	2	12/13/2017	NON-COMPETING CONTINUATION	$76,750
														Subtotal = $76,750

Issue Date FY: 2017 ( Subtotal = $76,250 )
2017	2017	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	1	1/5/2017	NEW	$76,250
														Subtotal = $76,250

Grand Total All Awards = $153,000

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Generating LynA-/- and LynB-/- mice by CRISPR/Cas9 genome editing

Award Number: R03AI130978

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2017

PERIOD OF PERFORMANCE END DATE: 12/31/2018

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