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Characterizing Tissue Specific Regulation of Mutant Lamin Protein Degradation

Award Number: R15AG074113
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2016
PERIOD OF PERFORMANCE END DATE: 08/30/2025

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Characterizing Tissue Specific Regulation of Mutant Lamin Protein Degradation - Project Summary Laminopathies are a wide range of disorders that include both multisystem disorders such as the aging disorder Hutchinson Guilford Progeria and tissue specific disorders such as Emery-Dreifuss Muscular Dystrophy and the neuropathy Charcot-Marie-Tooth disease. All of these different disorders can be caused by mutations in the LMNA gene, however, how mutations in one gene give rise to such different disorders is incompletely understood. Mutant forms of lamin protein have been found to aggregate, and this aggregation is associated with impaired cellular function and disease phenotypes. Therefore, we hypothesize that certain tissues are susceptible to specific lamin mutations due to the inability of tissue specific quality control mechanisms to degrade those mutant forms, leading to protein aggregation and cellular toxicity. We will test this hypothesis using the fruit fly Drosophila melanogaster as our model system. Drosophila allow us to manipulate gene expression in specific tissues, enabling experiments to tease apart how different lamin protein mutations are degraded in specific tissues. Flies have two homologues of the human LMNA gene, LamC and Lam Dm0, and mutations in these genes mimic human disorders. In addition, introducing the equivalent mutations that cause human disease into LamC results in lamin protein aggregation and disease-like phenotypes. Furthermore, AMPK signaling, which is downregulated in muscle biopsies from patients, has been found to reduce mutant LamC aggregation in the fly muscle. On the other hand, we find that Lam Dm0 aggregates in the muscle during aging, and that p38 MAPK (p38Kb) and the CASA complex regulate the degradation of Lam Dm0. One difference between LamC and Lam Dm0 is that while with both lamins are expressed in muscle, only Lam Dm0 is expressed in neurons. As LamC and Lam Dm0 have different tissues specificities, we can also assess if specific protein quality control mechanisms are able to target certain mutant forms of lamin in each tissue. This will allow us to determine if disease tissue specificity is due to the failure of protein quality control machinery to degrade certain mutant forms of lamin protein, resulting in muscular dystrophy rather than neuropathy, for example. Therefore, we will 1) determine if p38Kb and the CASA complex regulate the aggregation of specific forms of mutant LamC proteins and how this contributes to muscle defects, 2) characterize how specific disease mutations in Lam Dm0 affect aggregation in muscles and neurons, and 3) determine if AMPK and p38Kb act in the same or different pathways to regulate mutant lamin aggregation. We expect that our proposed study will provide new insights into how mutant forms of lamin result in a disease state and if activating different protein quality control mechanisms could prove to be an effective therapeutic mechanism.


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: 2026 ( Subtotal = -$73,834 )
2026	2021	BOARD OF TRUSTEES OF ILLINOIS STATE UNIVERSITY	CAMPUS BOX 1100	NORMAL	IL	61790	MCLEAN	USA	Aging Research	000	2	1/28/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$73,834
														Subtotal = -$73,834

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	BOARD OF TRUSTEES OF ILLINOIS STATE UNIVERSITY	CAMPUS BOX 1100	NORMAL	IL	61790	MCLEAN	USA	Aging Research	000	2	8/9/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	BOARD OF TRUSTEES OF ILLINOIS STATE UNIVERSITY	302 HOVEY HALL	NORMAL	IL	61790	MCLEAN	USA	Aging Research	000	2	8/16/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $442,936 )
2021	2021	BOARD OF TRUSTEES OF ILLINOIS STATE UNIVERSITY	302 HOVEY HALL	NORMAL	IL	61790	MCLEAN	USA	Aging Research	000	2	9/22/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$442,936
														Subtotal = $442,936

Grand Total All Awards = $369,102

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Characterizing Tissue Specific Regulation of Mutant Lamin Protein Degradation

Award Number: R15AG074113

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2016

PERIOD OF PERFORMANCE END DATE: 08/30/2025

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