Ester J. Kwon
Massachusetts Institute of Technology
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Publication
Featured researches published by Ester J. Kwon.
Molecular Psychiatry | 2013
Ester J. Kwon; Wenyuan Wang; Li-Huei Tsai
Validation of schizophrenia-associated genes CSMD1 , C10orf26 , CACNA1C and TCF4 as miR-137 targets
Learning & Memory | 2012
Wenyuan Wang; Ester J. Kwon; Li-Huei Tsai
MicroRNAs (miRNAs) represent a class of small regulatory noncoding RNAs ∼22 bp in length that mediate post-transcriptional silencing of gene expression via the recognition of specific sequences in target messenger (m)RNAs. The current body of literature suggests that miRNAs are fine-tuning regulators of gene expression profiles in a wide range of biological processes, from development to cancer. Many miRNAs are highly expressed in the adult nervous system in a spatially and temporally controlled manner in normal physiology, as well as in certain pathological conditions. These findings emphasize that gene regulation networks based on miRNA activities may be particularly important to brain function, and that perturbation of these networks may result in abnormal brain function. Indeed, miRNAs have been implicated in various aspects of dendrite remodeling and synaptic plasticity, as well as in experience-dependent adaptive changes of neural circuits in the postnatal developmental and adult brain. Recent advances in methods of next-generation sequencing, such as RNA-seq, offer the means to quantitatively evaluate the functions of miRNAs in a genome-wide manner in large cohorts of samples. These new technologies have already yielded valuable information and are expanding our understanding of miRNA-based mechanisms in higher-order brain processing, including learning and memory and cognition, as well as in neuropsychiatric disorders.
Bioconjugate Chemistry | 2008
Ester J. Kwon; Jamie M. Bergen; Suzie H. Pun
Endosomal release is an efficiency-limiting step for many nonviral gene delivery vehicles. In this work, nonviral gene delivery vehicles were modified with a membrane-lytic peptide taken from the endodomain of HIV gp41. Peptide was covalently linked to polyethylenimine (PEI) and the peptide-modified polymer was complexed with DNA. The resulting nanoparticles were shown to have similar physicochemical properties as complexes formed with unmodified PEI. The gp41-derived peptide demonstrated significant lytic activity both as free peptide and when conjugated to PEI. Significant increases in transgene expression were achieved in HeLa cells when compared to unmodified polyplexes at low polymer to DNA ratios. Additionally, peptide-modified polyplexes mediated significantly enhanced siRNA delivery compared to unmodified polyplexes. Despite increases in transgene expression and siRNA knockdown, there was no increase in internalization or binding of modified carriers as determined by flow cytometry. The hypothesis that the gp41-derived peptide increases the endosomal escape of vehicles is supported by confocal microscopy imaging of DNA distributions in transfected cells. This work demonstrates the use of a lytic peptide for improved trafficking of nonviral gene delivery vehicles.
Nature Neuroscience | 2015
Sandra Siegert; Jinsoo Seo; Ester J. Kwon; Andrii Rudenko; Sukhee Cho; Wenyuan Wang; Zachary Flood; Anthony Martorell; Maria Ericsson; Alison E. Mungenast; Li-Huei Tsai
Noncoding variants in the human MIR137 gene locus increase schizophrenia risk with genome-wide significance. However, the functional consequence of these risk alleles is unknown. Here we examined induced human neurons harboring the minor alleles of four disease-associated single nucleotide polymorphisms in MIR137. We observed increased MIR137 levels compared to those in major allele–carrying cells. microRNA-137 gain of function caused downregulation of the presynaptic target genes complexin-1 (Cplx1), Nsf and synaptotagmin-1 (Syt1), leading to impaired vesicle release. In vivo, miR-137 gain of function resulted in changes in synaptic vesicle pool distribution, impaired induction of mossy fiber long-term potentiation and deficits in hippocampus-dependent learning and memory. By sequestering endogenous miR-137, we were able to ameliorate the synaptic phenotypes. Moreover, reinstatement of Syt1 expression partially restored synaptic plasticity, demonstrating the importance of Syt1 as a miR-137 target. Our data provide new insight into the mechanism by which miR-137 dysregulation can impair synaptic plasticity in the hippocampus.
Biomaterials | 2010
Ester J. Kwon; Jurate Lasiene; Berit E. Jacobson; In-Kyu Park; Philip J. Horner; Suzie H. Pun
Targeted gene therapy can potentially minimize undesirable off-target toxicity due to specific delivery. Neuron-specific gene delivery in the central nervous system is challenging because neurons are non-dividing and also outnumbered by glial cells. One approach is to transfect dividing neural stem and progenitor cells (NSCs and NPCs, respectively). In this work, we demonstrate cell-specific gene delivery to NPCs in the brains of adult mice using a peptide-modified polymeric vector. Tet1, a 12-amino acid peptide which has been shown to bind specifically to neuronal cells, was utilized as a neuronal targeting ligand. The cationic polymer polyethylenimine (PEI) was covalently modified with polyethylene glycol (PEG) for in vivo salt stability and Tet1 for neuron targeting to yield a Tet1-PEG-PEI conjugate. When plasmid DNA encoding the reporter gene luciferase was complexed with Tet1-PEG-PEI and delivered in vivo via an injection into the lateral ventricle, Tet1-PEG-PEI complexes mediated increased luciferase expression levels in brain tissue when compared to unmodified PEI-PEG complexes. In addition, cells transfected by Tet1-PEG-PEI complexes were found to be exclusively adult NPCs whereas untargeted PEG-PEI complexes were found to transfect a heterogenous population of cells. Thus, we have demonstrated targeted, nonviral delivery of nucleic acids to adult NPCs using the Tet1 targeting ligand. These materials could potentially be used to deliver therapeutic genes for the treatment of neurodegenerative diseases.
Molecular Pharmaceutics | 2010
Ester J. Kwon; Sylvie Liong; Suzie H. Pun
HGP is a 24-amino acid peptide derived from HIV gp41 that increases vesicular escape when incorporated into gene delivery vehicles. The typical yield of HGP from solid phase peptide synthesis is low due to its length and hydrophobicity. The goal of this work was to investigate truncated sequences that maintained activity in order to improve the ease and yield of synthesis. A shortened, 15-amino acid sequence retained comparable lytic activity and the ability to interact with lipids when compared to the full length peptide. A scrambled peptide showed poor lytic activity, confirming that the activity of these endosomal escape peptides is sequence specific. Peptides were covalently attached to polyethylenimine (PEI) and used to condense plasmid DNA to form nanoparticulate carriers. When delivery efficiencies of PEI-peptide conjugates were compared in vitro, PEI modified with the truncated HGP sequence increased transgene expression over unmodified PEI and full length HGP.
Advanced Materials | 2016
Jinyoung Kang; Jinmyoung Joo; Ester J. Kwon; Matthew Skalak; Sazid Hussain; Zhi-Gang She; Erkki Ruoslahti; Sangeeta N. Bhatia; Michael J. Sailor
Calcium ions react with silicic acid released from dissolving porous silicon nanoparticles to create an insoluble calcium silicate shell. The calcium silicate shell traps and protects an siRNA payload, which can be delivered to neuronal tissues in vitro or in vivo. Gene delivery is enhanced by the action of targeting and cell-penetrating peptides attached to the calcium silicate shell.
Journal of Controlled Release | 2008
Ester J. Kwon; Jamie M. Bergen; In-Kyu Park; Suzie H. Pun
Neuron-targeted nucleic acid delivery systems are important technologies for realizing the potential of gene therapy for nervous system disorders. However, neurons are difficult cells to transfect using non-viral vectors due in part to the specific and unique delivery challenges present in these cells. We have investigated several bioactive peptides for their ability to assist in overcoming delivery barriers in mammalian cells. We summarize here our recent progress in developing and applying peptide-modified polycations for nucleic acid delivery. In addition, we present data demonstrating the potential of using multicomponent, peptide-modified polycations for nucleic acid delivery to neurons.
Protein Science | 2007
Jason Cellitti; Manuel Llinás; Nathaniel Echols; Elizabeth A. Shank; Blake Gillespie; Ester J. Kwon; Scott M. Crowder; Frederick W. Dahlquist; Tom Alber; Susan Marqusee
Small proteins are generally observed to fold in an apparent two‐state manner. Recently, however, more sensitive techniques have demonstrated that even seemingly single‐domain proteins are actually made up of smaller subdomains. T4 lysozyme is one such protein. We explored the relative autonomy of its two individual subdomains and their contribution to the overall stability of T4 lysozyme by examining a circular permutation (CP13*) that relocates the N‐terminal A‐helix, creating subdomains that are contiguous in sequence. By determining the high‐resolution structure of CP13* and characterizing its energy landscape using native state hydrogen exchange (NSHX), we show that connectivity between the subdomains is an important determinant of the energetic cooperativity but not structural integrity of the protein. The circular permutation results in a protein more easily able to populate a partially unfolded form in which the C‐terminal subdomain is folded and the N‐terminal subdomain is unfolded. We also created a fragment model of this intermediate and demonstrate using X‐ray crystallography that its structure is identical to the corresponding residues in the full‐length protein with the exception of a small network of hydrophobic interactions. In sum, we conclude that the C‐terminal subdomain dominates the energetics of T4 lysozyme folding, and the A‐helix serves an important role in coupling the two subdomains.
Proceedings of the National Academy of Sciences of the United States of America | 2015
Ester J. Kwon; Justin H. Lo; Sangeeta N. Bhatia
Nanoparticle technologies intended for human administration must be designed to interact with, and ideally leverage, a living host environment. Here, we describe smart nanosystems classified in two categories: (i) those that sense the host environment and respond and (ii) those that first prime the host environment to interact with engineered nanoparticles. Smart nanosystems have the potential to produce personalized diagnostic and therapeutic schema by using the local environment to drive material behavior and ultimately improve human health.