2019-20 CBI Trainees

Raymond Berkeley 

Chemistry and Biochemistry
Galia Debelouchina Lab

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CBI Appointment Period: 2018-20
Grant Year: [4,5*]

*San Diego Fellowship Recipient

Chemical tools for the study of intrinsically disordered proteins

Intrinsically disordered proteins (IDPs) play key roles in numerous cellular processes. These proteins often condense into discrete intracellular droplets that are required for these proteins to carry out their function. Despite the central role of these protein droplets in cell biology and disease, the mechanisms that underlie protein phase separation are poorly understood. The dynamic nature of these protein droplets makes nuclear magnetic resonance (NMR) the ideal tool for their study, but the low sensitivity of NMR makes it difficult to study IDPs in their native environment. Our lab uses dynamic nuclear polarization to circumvent the sensitivity problem. My work focuses on the design of probes that are capable of delivering polarization agents to intracellular protein droplets in order to selectively enhance the NMR signal from these condensed proteins. These probes will enable the study of the structural basis for phase separation in cells without requiring any chemical modification to the proteins under study.

 

Jeffrey Chen

Chemistry and Biochemistry
Michael Burkart Lab

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CBI Appointment Period: 2019-20
Grant Year: [5]

Engineering protein-protein interactions in algal fatty acid biosynthesis

Fatty acids are primary metabolites made in all living organisms that can be converted into commodity chemicals such as plastics and biofuels. They are naturally produced through iterative cycles of two-carbon extensions of the acyl chain, followed by product release from the carrier protein by a thioesterase once the appropriate chain length has been reached. Most fatty acids in organisms are grown with acyl chains of 14-18 carbons, but medium-chain fatty acids (MCFAs) with aliphatic tails of 6-12 carbons are the most suitable for chemical conversion. We believe that protein-protein interactions between the fatty acid carrier protein and the thioesterase are important for determining the instant of product release. My work aims to crosslink the carrier protein and thioesterase from the algae Chlamydomonas reinhardtii, thereby trapping the interacting residues at the interface. These residues will then be identified using x-ray crystallography, allowing us to engineer the interface interactions for increased levels of MCFA production in photosynthetic algae.

 

Garland Jackson

Chemistry and Biochemistry
Kamil Godula Lab

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CBI Appointment Period: 2019-20
Grant Year: [5]

Development of Glycosylation Modulators Targeted to the Golgi Apparatus.

Carbohydrates are one of the four macromolecular building blocks of the cell. They are an essential structural feature of nucleic acids, a source of energy for the cell, and a component of glycoproteins and glycolipids presented at the cell surface. These glycoconjugates are central to cellular signaling and the interaction of the cell with its environment. Engineering the glycan display of the cell allows for specific control of important signaling processes and can enhance detection and treatment of disease. My research seeks to develop tools that target the Golgi Apparatus, by utilizing the lipid recycling pathway, to modulate glycosylation events in this organelle prior to glycoconjugate presentation to the cell surface. Development of small molecules that can localize to the Golgi and deliver payloads to chemically engineer these structures will be a resourceful tool in glycobiology research.

 

Brodie Ranzau 

Chemistry and Biochemistry
Alexis Komor Lab

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CBI Appointment Period: 2018-20
Grant Year: [4*, 5]
*San Diego Fellowship Recipient

Repurposing RNA-modifying enzymes for genome editing

Single-point mutations are the genotypic cause of the vast majority of genetic diseases. Genome editing is one method of treating genetic diseases by mutating the pathogenic allele into a healthy allele. Current genome editing techniques create double-stranded DNA breaks (DSBs) at target locations in the genome, which are recognized by DNA repair pathways that may incorporate a supplied DNA strand and lead to successful genome editing. This process is inefficient, especially when attempting to substitute a single base pair, and may create other harmful insertions or deletions at the DSB. My work aims to circumvent the use of DSBs by creating precision base editing tools that can chemically modify target nucleobases. Base editors capable of causing C-to-T and A-to-G mutations have already been created. By directing the evolution of RNA modifying enzymes, new base editors will be created that cover other modifications and mutations, vastly increasing the utility of these tools for editing the genome.

 

Matthew Shin

NanoEngineering
Nicole Steinmetz Lab

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CBI Appointment Period: 2019-20
Grant Year: [5]
San Diego Fellowship Recipient

Novel Bio-Nanoparticle Conjugates to Treat Cardiovascular Disease

Nanomedicine lies at the heart of nanoscale engineering, biology, chemistry, and medicine. The crosstalk of these disciplines has yielded promising, scalable nanomaterials which can be engineered to improve the efficacy of cardiovascular drug delivery. Our work is aimed at utilizing plant-virus based nanomaterials to treat atherosclerotic plaques in cardiovascular disease (CVD). These bio-derived nanoparticles host an arsenal of aspect ratio shapes and sizes, each with their own unique set of properties, which can be exploited for applications in nanomedicine. For example, tobacco mosaic virus (TMV) nanorods have a high aspect ratio dimensions which exhibit favorable flow and preferential margination in blood circulation, thus enhancing targeting of the vessel wall. Further, plant-virus coat protein scaffolds can be genetically ‘tuned’ upstream to confer ‘chemical handles’ on the interior and exterior of the viral nanoparticle for bioconjugation or electrostatic loading purposes. Such a precisely controlled spatial assembly and display of functional groups are not yet attainable with current synthetic chemistries, and therefore we exploit this bioinspired advantage afforded by nature. For the proposed study, we utilize TMV nanoparticles engineered to display therapeutic peptides; the goal is to demonstrate that these designer nanoparticles enhance cholesterol efflux from lipid-rich, atherosclerotic plaques through design principles that leverage both margination and avidity. We nanoengineer at the chemical-biology interface using plant-virus based technologies to generate impactful, nanomedicine solutions that overcome the efficacy and safety barriers presented in cardiovascular drug delivery.

 

Holly Sullivan 

Bioengineering
Karen Christman Lab

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CBI Appointment Period: 2018-20
Grant Year: [4, 5]

Inhalation of polymeric nanoparticles for therapeutic delivery after myocardial infarction

Every year, nearly 800,000 people in American have a heart attack. Many of these patients will now be in heart failure— 5 million people are living with congestive heart failure, and on average they will die within 5 years of diagnosis. The mounting prevalence of heart disease related deaths creates the need for more efficient methods of treatment. Nanoparticles present a non-invasive, targeted method of delivering therapeutic small molecules and peptides to the infarcted region of heart post myocardial infarction (MI). Our work, in collaboration with the Gianneschi lab at Northwestern University, is aimed at developing degradable polymeric nanoparticles that localize in the infarct after being cleaved by matrix metalloproteinases that are upregulated after MI. The nanoparticles preferentially enter the infarct via the leaky vasculature and remain in the infarct following a morphological switch to micron-scale aggregates in response to enzymatic cleavage.  Inhalation of nanoparticles is highly translational and minimally invasive, making it a desirable form of administration moving forward.