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Exploring modulation of Lamin A/C protein lifetime as a novel axis of regulation in heath and disease

Award Number: R01AR084208
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: 04/15/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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Exploring modulation of Lamin A/C protein lifetime as a novel axis of regulation in heath and disease - Summary / Abstract The nuclear Lamins are intermediate filament proteins that underlie the nuclear envelope. Lamins assemble into bundled filaments that strengthen the nucleus and scaffold the genome. The LMNA locus encodes the Lamin A and C proteins; hundreds of mutations to LMNA have been linked to more than 10 distinct syndromes, collectively referred to as “laminopathies”. Disease-linked LMNA mutations are found in every domain of these proteins, and no clear genotype-phenotype correlations exist. LMNA-linked laminopathies primarily afflict the cardiovascular system, muscle, skin, connective tissue, bone, and fat. A major goal of our research program is to determine why specific tissues are especially vulnerable to LMNA mutations while the Lamin A/C proteins are broadly expressed. In this proposal, we present evidence that modulation of protein lifetime is a major novel axis that regulates both the function of Lamin A/C and the effects of laminopathy mutations. We have discovered that the lifetime of the Lamin A/C proteins varies over an order of magnitude across tissues, and these proteins are especially long- lived in the tissues that are most vulnerable to laminopathies. In the devastating laminopathy Hutchinson-Gilford progeria syndrome (HGPS), production of a toxic Lamin A isoform called “Progerin” disrupts nuclear function and causes accelerated aging. We determined that this mutation further slows the turnover of Lamin A in the diseased cardiovascular system, where it accumulates over time and interferes with the turnover of hundreds of other proteins. These findings raise key questions that will be addressed by our Aims. Firstly, while hundreds of mutations to LMNA are linked to human disease, we do not yet know how these other mutations affect Lamin A/C protein stability and/or aggregation within diseased tissues. We will leverage a novel in vivo metabolic labeling approach that we developed to probe the effect of another laminopathy mutation on protein turnover in the LmnaH222P mouse model (Aim 1). Secondly, we do not understand how Lamin A/C protein lifetime is modulated across tissues or in disease states. Differences in protein folding and/or assembly state often underlie differences in protein turnover rate, but we know very little about the structure of the Lamin A/C polymers in the cellular milieu or how variable these are across different tissue contexts. In Aim 2, we will use functional proteomics to probe the folded state of the Lamin A/C proteins in situ, and we will test the hypothesis that Lamins sense mechanical information – such as tissue strain – to alter their folded state. Thirdly, we know that the Lamins perform the important function of scaffolding heterochromatin at the nuclear periphery into repressive lamina-associated domains (LADs), yet we do not understand the consequences of variable Lamin A/C folded state on this Lamin function. In Aim 3, we will apply a novel genome binding analysis technique to map LADs and to define their repressive function within healthy and diseased tissues.


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 = $441,972 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	5/12/2026	NON-COMPETING CONTINUATION	$23,261
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	1/23/2026	NON-COMPETING CONTINUATION	$418,711
														Subtotal = $441,972

Issue Date FY: 2025 ( Subtotal = $418,631 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	2/19/2025	NON-COMPETING CONTINUATION	$418,631
														Subtotal = $418,631

Issue Date FY: 2024 ( Subtotal = $463,274 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	4/5/2024	NEW	$463,274
														Subtotal = $463,274

Grand Total All Awards = $1,323,877

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Exploring modulation of Lamin A/C protein lifetime as a novel axis of regulation in heath and disease

Award Number: R01AR084208

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: 04/15/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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