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Principal Investigator: Ju Chen
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $521,263
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Mutations in genes encoding nuclear envelope (NE) components cause an array of diseases referred to as
nuclear envelopathies that often manifest as cardiomyopathies. The NE separates the nucleoplasm from
cytoplasm and is composed of outer and inner nuclear membranes. The nuclear lamina (NL) is an extensive
network of lamin polymers and associated proteins that are embedded in the inner nuclear membrane (INM).
Functionally, NL and INM proteins not only provide mechanical stability to the nucleus but also serve as the
anchoring point for chromatin at the nuclear periphery, playing a critical role in chromatin organization and
regulation of gene expression via interaction with and modulation of epigenetic machinery components. The
LAP2-Emerin-MAN1-domain (LEM-D) family of proteins play an important role in the association between the
NL and chromatin. LEMD2 (LEM domain-containing protein 2), is a transmembrane protein located in the INM,
involved in nuclear integrity and perinuclear tethering and transcriptional silencing of heterochromatin.
Recently, it has been reported that a single amino acid substitution of leucine 13 to arginine (L13R) in LEMD2
leads to autosomal recessive human cardiomyopathy. However, despite its clinical relevance, little is known as
to the specific role of LEMD2 in cardiomyocytes (CMs), and mechanisms by which the L13R mutation leads to
cardiomyopathy. To address this gap in knowledge, we have generated three mouse models: constitutive CM-
specific Lemd2 knockout (cKO), inducible CM-specific Lemd2 knockout (icKO), and LEMD2 L13R knock-in
mice. We will also utilize a human induced pluripotent stem cell (iPSC)-derived CM model of the LEMD2 L13R
mutation to address the impact of L13R mutation in LEMD2 on human CMs. Preliminary studies revealed that
loss of LEMD2 in embryonic or adult CMs is detrimental, and LEMD2 L13R mutation affects cardiac function in
a murine model, indicating that LEMD2 plays a critical role in maintaining normal CM structure and function in
developing and adult hearts. Thus, we hypothesize that LEMD2-mediated maintenance of NE integrity and/or
regulation of heterochromatin tethering and silencing is essential for CM structure and function, and LEMD2
L13R mutation impairs specific aspects of LEMD2 function leading to cardiomyopathy. Accordingly, Our
Specific Aims are: 1. To determine the role of LEMD2 in the developing and adult myocardium by analyzing
constitutive (cKO) and inducible (icKO) Lemd2 CM-specific knockout mice for heart morphogenesis, structure
and function, and the progression of cardiomyopathy; and 2. To elucidate molecular mechanisms underlying
cardiomyopathy consequent to the L13R mutation in LEMD2 by detailed analyses of LEMD2 L13R knock-in
mice and human induced pluripotent stem cell (iPSC)-derived LEMD2 L13R mutant CMs.
Terms: <21+ years old><Ablation><Address><Adult><Adult Human><Affect><Age><Amino Acid Substitution><Apoptosis><Apoptosis Pathway><Arginine><Biological Function><Biological Process><Birth><Body Weight><CD154><CD40L><CD40LG><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac defect><Cardiocyte><Cardiomyopathies><Cell Nucleus><Chromatin><Cytoplasm><Dilatation><Dilatation - action><Disease><Disorder><Dysfunction><Embryo><Embryonic><Envelope Protein><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Functional disorder><Gene Action Regulation><Gene Expression Regulation><Gene Inactivation><Gene Regulation><Gene Regulation Process><Gene Silencing><Genes><Genetic Alteration><Genetic Change><Genetic defect><Goals><Heart><Heart Muscle Cells><Heart myocyte><Heterochromatin><Human><Impairment><Integral Membrane Protein><Intrinsic Membrane Protein><KI mice><KO mice><Knock-in Mouse><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Knowledge><L-Arginine><Lamins><Leanness><Leucine><Link><MLC2 gene product><Maintenance><Mechanics><Mediating><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Modeling><Modern Man><Molecular><Morphogenesis><Mutant Strains Mice><Mutation><Myocardial Diseases><Myocardial Disorder><Myocardiopathies><Myocardium><Myosin A><Myosin Heavy Chains><Myosin IIA><Non-Muscle Myosin Type IIA><Nonmuscle Myosin Type IIA><Nuclear><Nuclear Envelope><Nuclear Inner Membrane><Nuclear Lamina><Nuclear Membrane><Nucleoplasm><Nucleus><Null Mouse><Parturition><Pattern><Physiologic><Physiological><Physiopathology><Platanna><Play><Polymers><Programmed Cell Death><Protein Family><Proteins><Regulation><Reporting><Role><STA protein><Shapes><Structure><Surface Proteins><System><TNFSF5><TNFSF5 gene><TRAP Gene><Thick><Thickness><Thinness><Transmembrane Protein><Transmembrane Protein Gene><Type V IF Protein><Ventricular><Weight><Xenopus laevis><adulthood><ages><autosome><cardiac MLC2><cardiac function><cardiac muscle><cardiomyocyte><clinical relevance><clinically relevant><emerin><env Antigens><env Gene Products><env Polyproteins><env Protein><epigenetically><function of the heart><genome mutation><heart defect><heart function><heart muscle><hiPSC><histone modification><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><iPS cell derived cardiomyocytes><iPSC derived cardiomyocytes><induced human pluripotent stem cells><induced pluripotent stem cell derived cardiomyocytes><insight><knockin mice><man><mechanic><mechanical><morphogenetic process><mouse model><mouse mutant><murine model><mutant><myocardium disease><myocardium disorder><myosin heavy chain><myosin light chain 2><myosin light chain 2 gene product><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pathophysiology><polymer><polymeric><social role><transcriptional silencing><weights>