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Nucleocytoplasmic Interactions and Dynamics in Emery-Dreifuss Muscular Dystrophy

埃默里-德莱福斯肌营养不良症的核细胞质相互作用和动力学

基本信息

批准号：
8079051
负责人：
Howard J Worman
金额：
$ 34.51万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8079051
关键词：
Actins Affect Amino Acid Substitution Biological Models Bispecific Antibody 2B1 Cardiomyopathies Cell Nucleus Cells Centrosome Charcot-Marie-Tooth Disease Complex Cytoplasm Cytoskeleton Data Defect Disease Emery-Dreifuss Muscular Dystrophy Familial partial lipodystrophy Fibroblasts Fluorescence Genes Integral Membrane Protein Intermediate Filament Proteins Lamin Type A Lamins Lead Light Microscope Limb-Girdle Muscular Dystrophies Link Membrane Membrane Proteins Methods Movement Muscle Fibers Muscle function Muscular Dystrophies Mutation Myopathy Natural regeneration Nuclear Nuclear Envelope Nuclear Inner Membrane Nuclear Lamin Nuclear Outer Membrane Nuclear Structure Organ Pathogenesis Pathologic Pathway interactions Photobleaching Positioning Attribute Process Progeria Protein Dynamics Proteins Research Personnel Scapuloilioperoneal Atrophy with Cardiopathy Striated Muscles Syndrome Techniques Tissues X-linked Emery-Dreifuss muscular dystrophy emerin env Gene Products migration mutant myogenesis programs protein complex

项目摘要

DESCRIPTION (provided by applicant): Emery-Dreifuss muscular dystrophy (EDMD) results from mutations in two genes. Autosomal dominant EDMD, and infrequent autosomal recessive cases, result from mutations in LMNA. LMNA encodes A-type nuclear lamins, which are intermediate filament proteins associated with the inner nuclear membrane. Xlinked EDMD results from mutations in EMD, which encodes an integral protein of the nuclear envelope inner membrane called emerin. A commonly observed phenomenon in EDMD is defects in nuclear structure; however, little is known about how these structural defects relate to abnormal function. An emerging body of evidence demonstrates that the inside of the nucleus is connected to the cytoskeleton by a complex of interacting proteins termed the LING complex. These proteins include lamins, SUNs, which are transmembrane proteins of the inner nuclear membrane, and nesprins, some of which are transmembrane proteins localized to the outer nuclear membrane. Nesprins in turn can interact with cytoskeletal components such as actin. We hypothesize that mutations in the genes encoding A-type lamins and emerin cause a disruption of the LINC complex, which leads to abnormal nucleocytoskeletal connections and related defects in nuclear positioning and migration. Using a model system of fibroblasts undergoing polarization, we have obtained preliminary data showing that expression of lamin A mutants found in EDMD lead to nuclear movement defects. In Aim 1 of this project, we will carefully examine nuclear migration and centrosome positioning in cells expressing A-type lamins with amino acid substitutions that cause EDMD and related muscle disorders, cells lacking A-type lamins and cells expressing A-type lamins with amino acid substitutions that cause different diseases. In Aim 2, we will use fluorescence photobleaching techniques to determine the effects of mutations in A-type lamins on the dynamics of proteins of the LINC complex. In Aim 3, to link the pathogenic processes in autosomal EDMD to X-linked EDMD, we will examine the effects of emerin on nuclear movement and LINC complex protein dynamics. As nuclear positioning and nuclear migration are of critical importance in muscle fiber organization and differentiation, these studies will establish if defects in nucleocytoplasmic interactions lead to functional anomalies that can underlie the pathogenesis of autosomal and X-linked EDMD.

描述（由申请人提供）：

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nucleocytoplasmic connections and deafness.

DOI：
10.1172/jci67454
发表时间：
2013-02
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
H. Worman;N. Segil
通讯作者：
H. Worman;N. Segil

Emerin organizes actin flow for nuclear movement and centrosome orientation in migrating fibroblasts.

DOI：
10.1091/mbc.e13-06-0307
发表时间：
2013-12
期刊：
Molecular biology of the cell
影响因子：
3.3
作者：
Chang W;Folker ES;Worman HJ;Gundersen GG
通讯作者：
Gundersen GG

Muscular dystrophy-associated SUN1 and SUN2 variants disrupt nuclear-cytoskeletal connections and myonuclear organization.

DOI：
10.1371/journal.pgen.1004605
发表时间：
2014-09
期刊：
PLoS genetics
影响因子：
4.5
作者：
Meinke P;Mattioli E;Haque F;Antoku S;Columbaro M;Straatman KR;Worman HJ;Gundersen GG;Lattanzi G;Wehnert M;Shackleton S
通讯作者：
Shackleton S