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Molecular Genetics of Lyme Arthritis

Award Number: R01AR043521
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Molecular Genetics of Lyme Arthritis - PROJECT SUMMARY / ABSTRACT Lyme disease is caused by the tick borne spirochete Borrelia burgdorferi and there are estimated to be 300,000 cases/year in the US. It is associated with a spectrum of clinical symptoms of varying severities, ranging from localized skin lesion to disseminated infection including secondary skin lesions, arthritis, neuropathies, and carditis. It is apparent that genetically regulated responses of the host contribute to the severity of symptoms. We have taken a forward genetics approach to identify allelic genes that determine the difference in Lyme arthritis between the severely arthritic C3H mouse and the mildly arthritic C57BL/6 (B6) mouse. This analysis has identified Quantitative Trait Loci on several chromosomes, including the Bbaa1 locus on Chr 4, which encompasses the Type I IFN gene cluster. Congenic mouse lines in which the C3H Bbaa1 allele was introgressed onto the B6 background (B6.C3H-Bbaa1) confirmed the presence of a genetic element in this locus that regulates arthritis through expression of IFNβ, a Type I IFN. As the C3H and B6 IFNβ genes lack polymorphisms, any expression differences must be regulated by a linked genetic element. Advanced, interval specific recombinant congenic lines (ISRCL) have narrowed the physical region associated with Bbaa1 to 2.2 Mbp and identified the Cyclin Dependent Kinase Inhibitory gene, Cdkn2a, as a candidate regulator of IFNβ expression and determinant of the severity of Lyme arthritis. A variety of experiments demonstrated that the Bbaa1 impact on IFNβ expression was manifest through B. burgdorferi stimulation of myeloid cells, but that an additional, downstream mediator of arthritis required distinct activation of resident cells of the joint tissues. Independent studies characterized the arthritis-inducing activity of IFNβ as myostatin (MSTN). MSTN is well characterize as modulating skeletal muscle development, but has also been implicated in chronic disease and inflammation. We will utilize the B6.C3-Bbaa1 ISRCLs to characterize the mechanism by which products of the Cdkn2a locus regulate IFNβ production in myeloid cells, and, in turn, the mechanism by which the downstream effector MSTN modulates Lyme arthritis development. We propose a combination of lineage-specific expression analysis, silencing of gene expression, development of targeted KO mice, and the use of small molecule inhibitors in order to define the complex interactions involved in Lyme arthritis development. Our findings may provide insight into other pathologies driven by Type I IFN, which could also implicate unexpected pathways involving Cdkn2a and MTSN.


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 = $387,178 )
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	30	12/4/2023	NON-COMPETING CONTINUATION	$359,238
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	30	6/21/2024	NON-COMPETING CONTINUATION	$27,940
														Subtotal = $387,178

Issue Date FY: 2023 ( Subtotal = $399,814 )
2023	2023	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	29	2/22/2023	NON-COMPETING CONTINUATION	$39,981
2023	2023	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	29	12/13/2022	NON-COMPETING CONTINUATION	$359,833
														Subtotal = $399,814

Issue Date FY: 2022 ( Subtotal = $393,835 )
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	28	11/30/2021	NON-COMPETING CONTINUATION	$358,031
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	28	5/5/2022	NON-COMPETING CONTINUATION	$35,804
														Subtotal = $393,835

Issue Date FY: 2021 ( Subtotal = $386,544 )
2021	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	27	11/25/2020	NON-COMPETING CONTINUATION	$358,649
2021	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	27	5/17/2021	NON-COMPETING CONTINUATION	$27,895
														Subtotal = $386,544

Issue Date FY: 2020 ( Subtotal = $411,468 )
2020	2020	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	26	1/10/2020	COMPETING CONTINUATION	$411,468
2020	2018	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	25	3/11/2020	NON-COMPETING CONTINUATION	$0
2020	2018	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	25	1/7/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $411,468

Issue Date FY: 2018 ( Subtotal = $329,340 )
2018	2018	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	25	7/6/2018	NON-COMPETING CONTINUATION	$329,340
														Subtotal = $329,340

Issue Date FY: 2017 ( Subtotal = $329,340 )
2017	2017	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	24	6/30/2017	NON-COMPETING CONTINUATION	$329,340
														Subtotal = $329,340

Issue Date FY: 2016 ( Subtotal = $329,340 )
2016	2016	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	23	6/10/2016	NON-COMPETING CONTINUATION	$329,340
														Subtotal = $329,340

Issue Date FY: 2015 ( Subtotal = $329,340 )
2015	2015	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	22	6/11/2015	NON-COMPETING CONTINUATION	$329,340
														Subtotal = $329,340

Issue Date FY: 2014 ( Subtotal = $340,120 )
2014	2014	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	21	9/9/2014	COMPETING CONTINUATION	$340,120
2014	2013	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	20	9/8/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $340,120

Issue Date FY: 2013 ( Subtotal = $439,037 )
2013	2013	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	20	5/23/2013	NON-COMPETING CONTINUATION	$439,037
														Subtotal = $439,037

Issue Date FY: 2012 ( Subtotal = $463,672 )
2012	2012	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	19	6/14/2012	NON-COMPETING CONTINUATION	$463,672
														Subtotal = $463,672

Issue Date FY: 2011 ( Subtotal = $465,218 )
2011	2011	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	18	6/3/2011	NON-COMPETING CONTINUATION	$465,218
														Subtotal = $465,218

Issue Date FY: 2010 ( Subtotal = $474,733 )
2010	2010	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	17	6/11/2010	NON-COMPETING CONTINUATION	$474,733
														Subtotal = $474,733

Issue Date FY: 2009 ( Subtotal = $483,052 )
2009	2009	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	16	6/29/2009	COMPETING CONTINUATION	$483,052
2009	2008	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	15	6/29/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $483,052

Issue Date FY: 2008 ( Subtotal = $412,402 )
2008	2008	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	15	5/28/2008	NON-COMPETING CONTINUATION	$412,402
														Subtotal = $412,402

Issue Date FY: 2007 ( Subtotal = $408,559 )
2007	2007	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	14	5/23/2007	NON-COMPETING CONTINUATION	$408,559
														Subtotal = $408,559

Issue Date FY: 2006 ( Subtotal = $408,512 )
2006	2006	UNIVERSITY OF UTAH	201 S PRESIDENT'S CIR ROOM 406	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	13	5/31/2006	NON-COMPETING CONTINUATION	$408,512
														Subtotal = $408,512

Issue Date FY: 2005 ( Subtotal = $406,160 )
2005	2005	UNIVERSITY OF UTAH	201 S PRESIDENT'S CIR ROOM 406	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	12	5/23/2005	NON-COMPETING CONTINUATION	$406,160
														Subtotal = $406,160

Issue Date FY: 2004 ( Subtotal = $418,177 )
2004	2004	UNIVERSITY OF UTAH	201 S PRESIDENT'S CIR ROOM 406	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	8/2/2004	COMPETING CONTINUATION	$418,177
														Subtotal = $418,177

Issue Date FY: 2003 ( Subtotal = $371,669 )
2003	2003	UNIVERSITY OF UTAH	201 S PRESIDENT'S CIR ROOM 406	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10		NON-COMPETING CONTINUATION	$371,669
														Subtotal = $371,669

Grand Total All Awards = $9,990,985

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Molecular Genetics of Lyme Arthritis

Award Number: R01AR043521

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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