The objective of this proposal is to use mouse models to test potential therapeutic strategies for Hutchinson-Gilford progeria syndrome (HGPS). Children with HGPS develop a host of aging-like disease phenotypes, including premature atherosclerosis. Most cases of HGPS are caused by a de novo point mutation in LMNA (the gene for prelamin A and lamin C). This mutation leads to the synthesis of a mutant prelamin A (commonly called progerin) that cannot be processed to mature lamin A by the endoprotease ZMPSTE24. Progerin is farnesylated at its carboxyl terminus. Because of the presence of this farnesyl lipid anchor, progerin accumulates at the nuclear rim (along the inner nuclear membrane) and causes grossly misshapen nuclei. Cells lacking ZMPSTE24 also accumulate farnesylated prelamin A at the nuclear rim and have grossly misshapen nuclei. We hypothesized that blocking protein farnesylation with a farnesyltransferase inhibitor (FTI) would mislocalize progerin (or prelamin A in the case of ZMPSTE24 deficiency) away from the nuclear envelope and reduce the frequency of misshapen nuclei. Indeed, this was the case, both for human and mouse cells with an HGPS mutation and for human and mouse cells lacking ZMPSTE24. These findings were extremely encouraging because they suggested a possible treatment strategy for HGPS. During the past year, we generated a mouse that produces lamin C but no lamin A or prelamin A. Remarkably, """"""""lamin C-only"""""""" mice are entirely healthy. This finding suggested that lamin A is dispensable and implied that it may be possible to treat any """"""""lamin A"""""""" disease, including HGPS, by reducing the synthesis of prelamin A/lamin A. Genetic experiments in mice have strongly supported this concept. A key goal of this proposal is to test the hypothesis that mislocalizing prelamin A or progerin away from the nuclear envelope with an FTI would prevent the progeria-like disease phenotypes in mouse models. Preliminary studies have strongly suggested that FTIs might indeed be efficacious. FTI treatment of HGPS results in the accumulation of a nonfarnesylated progerin. A second goal is to generate a new gene-targeted mouse model that expresses a nonfarnesylated version of progerin. By examining these new gene-targeted mice, we should be able to determine if the synthesis of nonfarnesylated progerin is associated with any adverse disease phenotypes. A third goal of the proposal is to determine if decreasing prelamin A synthesis with an antisense oligonucleotide could ameliorate progeria disease phenotypes in mouse models. Preliminary studies also suggest that this strategy is feasible. These studies stand a significant chance of identifying treatments for HGPS, which would be a welcome development for those affected by this disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL086683-03S1
Application #
7839423
Study Section
Special Emphasis Panel (ZRG1-GTIE-A (01))
Program Officer
Goldman, Stephen
Project Start
2009-07-15
Project End
2011-06-30
Budget Start
2009-07-15
Budget End
2011-06-30
Support Year
3
Fiscal Year
2009
Total Cost
$234,126
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Tapia, Olga; Fong, Loren G; Huber, Michael D et al. (2015) Nuclear envelope protein Lem2 is required for mouse development and regulates MAP and AKT kinases. PLoS One 10:e0116196
Yang, Shao H; Procaccia, Shiri; Jung, Hea-Jin et al. (2015) Mice that express farnesylated versions of prelamin A in neurons develop achalasia. Hum Mol Genet 24:2826-40
Jung, Hea-Jin; Tatar, Angelica; Tu, Yiping et al. (2014) An absence of nuclear lamins in keratinocytes leads to ichthyosis, defective epidermal barrier function, and intrusion of nuclear membranes and endoplasmic reticulum into the nuclear chromatin. Mol Cell Biol 34:4534-44
Young, Stephen G; Jung, Hea-Jin; Lee, John M et al. (2014) Nuclear lamins and neurobiology. Mol Cell Biol 34:2776-85
Degagné, Emilie; Pandurangan, Ashok; Bandhuvula, Padmavathi et al. (2014) Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs. J Clin Invest 124:5368-84
Jung, Hea-Jin; Tu, Yiping; Yang, Shao H et al. (2014) New Lmna knock-in mice provide a molecular mechanism for the 'segmental aging' in Hutchinson-Gilford progeria syndrome. Hum Mol Genet 23:1506-15
Lee, John M; Tu, Yiping; Tatar, Angelica et al. (2014) Reciprocal knock-in mice to investigate the functional redundancy of lamin B1 and lamin B2. Mol Biol Cell 25:1666-75
Young, Stephen G; Yang, Shao H; Davies, Brandon S J et al. (2013) Targeting protein prenylation in progeria. Sci Transl Med 5:171ps3
Ibrahim, Mohamed X; Sayin, Volkan I; Akula, Murali K et al. (2013) Targeting isoprenylcysteine methylation ameliorates disease in a mouse model of progeria. Science 340:1330-3
Jung, Hea-Jin; Lee, John M; Yang, Shao H et al. (2013) Nuclear lamins in the brain - new insights into function and regulation. Mol Neurobiol 47:290-301

Showing the most recent 10 out of 45 publications