- Post Doctoral
MIT Unit Affiliation:
- Health Sciences and Technology
Post Doc Sponsor / Advisor:
Date PhD Completed:
Top 3 Areas of Expertise:
My long-term goal is to build my own independent research group that builds biologically-responsive nanotechnology tools to study and treat traumatic brain injuries (TBIs). I am motivated by recent evidence that TBIs, survivors of which suffer from long-term disability, are more prevalent in the general population than estimated, yet there are few options to improve disease outlook for these patients. There is a critical need for new technology to diagnose and treat TBIs; I believe emergent properties at the nanoscale – both new material properties and altered interactions with host biology – can be harnessed to tackle the challenges present in TBI research. In particular, I plan to leverage the damaged and dysregulated blood-brain barrier that occurs in TBIs as a gateway to probe injured brain tissue and as a target for engineered therapies using peptide-based nanosystems.
I believe my experience speaks to my ability to significantly contribute to the field of developing new technologies for TBI research. Throughout my training, I have had diverse opportunities to engineer different nanoparticulate scaffolds (polymeric, biologic, inorganic) that interact with living organisms via peptides. As a graduate student in Dr. Suzie Pun’s lab at the University of Washington, I developed polymeric gene delivery systems that escape endocytic vesicles via membrane-interacting peptides (Kwon et al., Bioconj. Chem 2008; Kwon et al., Mol Pharm 2010) and target neural stem cell niches in the adult mouse brain via cell-specific peptides (Kwon et al. Biomaterials 2010). As a postdoctoral fellow in Dr. Sangeeta Bhatia’s lab at MIT, I evolved this idea and have worked on several “tandem-peptide” nanosystems that coordinate the action of two peptides to improve efficacy and specificity of action. Due to my interest in developing translational research, I have applied this idea to several mouse models of disease, including penetrating brain injuries (Kwon et al., ACS Nano 2016), Pseudomonas pneumonia, and ovarian cancer to develop both therapeutic and diagnostic systems. Furthermore, as a Research Scientist in Dr. Bhatia’s lab, I currently lead a team that is developing peptide-based platforms that (1) modify the host immune response and (2) deliver antibiotics, both for the treatment of bacterial infections.
Throughout the course of my graduate and postdoctoral training, I have been building the leadership, mentorship, and grant writing skills that will be the basis for launching my own independent research group. In Dr. Bhatia’s lab, I direct a 4 person research team, help lead post- and pre-graduate nano-focused members of the Bhatia lab, and have directly mentored 10 trainees at all levels on their individual projects. Throughout my training I have supervised 13 undergraduates and technicians, and I am delighted that 12 have chosen to pursure graduate level study in STEM fields. As an example of my grantsmanship, I have secured both personal funding (e.g. pre- and post-doctoral NRSAs, Simons Fellowship) and contributed to funded research grants (DARPA, NIH). Beyond application for funds, I have been responsible for reporting research progress to funding agencies and directing research projects to fulfil milestones. In order to support my future research, there are diverse funding avenues available for TBI-related research (NIH, DOD/DARPA, Brain Research Foundation).
As a member of the Koch Institute at MIT – a unique research environment which was designed to maximize interaction between engineers and biologists – and my participation in a multi-PI DARPA grant where collaboration enabled new technologies, I can appreciate the enormous benefit that a highly collaborative environment stimulates. My expertise in endowing peptide-based biological function to nanosystems can cross-fertilize with fields of tissue engineering, drug delivery, and materials development and furthermore, my interest in TBI research would be energized by alternate engineering solutions such as mechanical and chemical measurement probes.
Expected End Date of Post Doctoral Position:
I have experience in both my graduate and post-graduate research in modifying nanomaterials with peptides to exert biological function. Peptides can display a diverse array of biological functions – as evidenced by numerous peptides found in nature – and can be combined in nanoparticles to confer multi-functionality. In my doctoral work with Suzie Pun at the University of Washington, I synthesized peptide-functionalized polymeric systems to target and traffic nucleic acid cargoes to cellular targets. In particular, I showed that a targeting peptide was able to traffic the majority of delivered plasmid DNA to neural progenitor cells in the subventricular zone when delivered into the brain. In another class of peptide functions, I investigated a membrane-interactive peptide taken from the coat protein of HIV to improve vesicular release of cargo from endocytic compartments. In unpublished work, I identified peptides that bind to cultured adult neural progenitor cells using phage display.
As a postdoctoral fellow in the lab of Sangeeta Bhatia at MIT, I continued to evolve my approach of peptide-based nanotechnology. I was in particularly interested in building technology that is responsive to the host biology in living systems. Exploring a “tandem peptide” approach – wherein two peptides combined into a single entity confer specific activity – and leveraging properties of nanomaterials (e.g. biodistribution, multi-valent structures, biodegradation), I built several peptide-based nanosystems as diagnostics and therapeutics. I have built these nanosystems for three disease applications: (1) bacterial pneumonia, (2) traumatic brain injury, and (3) ovarian cancer. Across these systems, a thematic finding is that the tandem peptide structure enables new function and/or increased activity. For example, when screening for an agent to kill the gram-negative bacteria, P. aeruginosa, I found that concatenating a peptide which interacts with the membrane of gram-negative bacteria with a bacteria toxin improved the selectivity and activity of either domain alone ~30-fold. The most potent peptide identified in the screen was loaded in porous silicon nanoparticles and was able to decrease bacterial titers in a mouse model of P. aeruginosa pneumonia. In two applications for siRNA delivery, combining targeting ligands with an intracellular trafficking domain allowed for cell-specific uptake and silencing in mouse models of traumatic brain injury and ovarian cancer. Lastly, a diagnostic system which detects ectopic protease expression in ovarian cancer via a protease sensitive peptide that accumulates in the urine leverages ligand-targeting to enable detection of ultra-low burden tumor burdens. I believe the expertise I have gained through my pre- and post-doctoral training will be a template to instruct the development of new technologies for TBI in my own research group.
Gene delivery to neurons has the potential to make a significant impact on the treatment
of central nervous system diseases. The delivery of transgenes that encode proteins that
can promote the division, survival, and migration of new neurons is a promising approach
to mitigate neurodegeneration that is observed in these diseases. This work describes the
development of a synthetic, polymer-based delivery vehicle that incorporates peptides to
mediate intracellular trafficking to neurons. First, a targeting peptide is evaluated for its ability
to transfect specific cell-types after delivery to the mouse brain. Then, a novel
membrane-active peptide is employed to improve the efficiency of vehicles by mediating
endosomal escape and a shortened sequence is investigated. Together, this targeting
peptide and endosomal escape peptide are incorporated in a single vehicle and evaluated
for in vitro and in vivo transfection efficiency.
Top 5 Awards and honors (name of award, date received):
5 Recent Papers:
Lo JH*, Kwon EJ*, Zhang AQ, Singhal PS, Bhatia SN, (2016) "A comparison of modular PEG incorporation strategies for stabilization of peptide-siRNA nanocomplexes," Bioconj Chem. Pub Sep1.
Kwon EJ, Skalak M, Lo Bu R, Bhatia SN, (2016), "A Neuron-Targeted Nanoparticle for siRNA Delivery to Traumatic Brain Injuries," ACS Nano, 10 (8), 7926–7933.
Mann AP, Scodeller P, Hussain S, Joo JM, Kwon EJ, Braun G, Molder T, She ZG, Kotamraju V, Ranscht B, Krajewski S, Teesalu T, Bhatia SN, Sailor MJ, Ruoslahti E, (2016), "A peptide for targeted, systemic delivery of imaging and therapeutic compounds into acute brain injuries," Nat Commun, 2016; 7:11980.
Kwon EJ, Lo JH, Bhatia SN, (2015), "Smart Nanosystems: Bio-inspired Technologies that Interact with the Host Environment," Proc Natl Acad Sci U S A. 2015 Nov 24;112(47):14460-6.
Kwon EJ, Lasiene J, Jacobson BE, Park IK, Horner PJ, Pun SH, (2010), "Targeted nonviral delivery vehicles to neural progenitor cells in the mouse subventricular zone," Biomaterials. 31(8):2417-24.