A key objective of this mentored training program is to understand the impact of defective lamin A biogenesis on the musculoskeletal system-both at the cellular level and the whole-animal level. A second objective is to analyze potential strategies for treating human diseases associated with defects in the biogenesis of lamin A. My goal is to gain a deeper understanding of the pathophysiological relevance of lamin A/C in the musculoskeletal system, and in the process create a foundation for an independent academic research career. During the next few years, I will gain additional training and experience in mouse models, genetics, and molecular medicine, greatly expanding on my previous experience as a clinician and as a clinical investigator in the area of bone growth, bone biomechanics, and bone imaging. My mentor, Dr. Stephen Young, is an internationally recognized expert in the lamins and in molecular medicine; he has a very productive laboratory and a terrific record in mentoring young scientists. Furthermore, a team of consultants will provide additional expert career guidance as well as access to specialized expertise and equipment. The training program and institutional support at UCLA are outstanding. Proteins of the nuclear lamina have generated enormous interest with the realization that mutations in LMNA, the gene encoding prelamin A and lamin C, are linked to nine human diseases affecting skeletal muscle, peripheral nerve, adipose tissue, and bone. One of these diseases, Hutchinson-Gilford progeria syndrome (HGPS), causes a number of premature aging-like phenotypes, including severe atherosclerosis. Normally, mature lamin A is generated from prelamin A by a series of posttranslational processing steps, including endoproteolytic processing of prelamin A by Zmpste24, a zinc metalloproteinase of the endoplasmic reticulum. In Z/r""""""""pste24-deficient mice, no mature lamin A is generated, and farnesyl-prelamin A accumulates along the nuclear lamina. This accumulation of prelamin A is toxic, leading to a host of disease phenotypes resembling those in humans with HGPS, including ostoporosis, micrognathia, and alopecia. The disease phenotypes in Zmpste24-deficient mice can be eliminated by reducing the production of prelamin A. Interestingly, HGPS is caused by the accumulation of a mutant form of farnesylated prelamin A in cells. We have recently generated an authentic gene-targeted mouse model of HGPS.
My specific aims for the next few years are: (1) To better define the pathology associated with bone and muscle weakness in Zmpste24-deficient mice. (2) To determine if the bone abnormalities in Zmpste24-deficient mice differ from those in the gene-targeted mice with the Hutchinson-Gilford progeria allele. (3) To determine if reducing the amount of farnesyl-prelamin A at the nuclear envelope would eliminate the cellular and whole-animal disease phenotypes in the Z/T7pste24-deficient mice and the HGPS mice. ? ? ?
| Meta, Margarita; Yang, Shao H; Bergo, Martin O et al. (2006) Protein farnesyltransferase inhibitors and progeria. Trends Mol Med 12:480-7 |
| Young, Stephen G; Meta, Margarita; Yang, Shao H et al. (2006) Prelamin A farnesylation and progeroid syndromes. J Biol Chem 281:39741-5 |
