A5063781055- Mosquito-borne diseases and control
- Malaria Research and Control
- Heme Oxygenase-1 and Carbon Monoxide
- Autophagy in Disease and Therapy
- CRISPR and Genetic Engineering
- Insect Resistance and Genetics
- Invertebrate Immune Response Mechanisms
- Complement system in diseases
- Hemoglobin structure and function
- Parasites and Host Interactions
- Genetic Neurodegenerative Diseases
- Muscle Physiology and Disorders
- Sirtuins and Resveratrol in Medicine
- Crystallization and Solubility Studies
- Trace Elements in Health
- HIV/AIDS drug development and treatment
- Computational Drug Discovery Methods
- Research on Leishmaniasis Studies
- Insect symbiosis and bacterial influences
- RNA Interference and Gene Delivery
- RNA and protein synthesis mechanisms
- Drug Transport and Resistance Mechanisms
- Drug-Induced Hepatotoxicity and Protection
- X-ray Diffraction in Crystallography
- Evolution and Genetic Dynamics
Washington University in St. Louis
2017-2024
Massachusetts Institute of Technology
2014-2023
Abstract Synthetic posttranscriptional regulation of gene expression is important for understanding fundamental biology and programming new cellular processes in synthetic biology. Previous strategies regulating translation eukaryotes have focused on disrupting individual steps translation, including initiation mRNA cleavage. In emphasizing modularity cross-organism functionality, these systems are designed to operate orthogonally native control mechanisms. Here we introduce a broadly...
Plasmodium parasite entrance and exit Sweats fever are the hallmarks of malaria. Red blood cells replication factories for malaria parasites. Fever occurs when parasites' merozoite stages burst en masse from red into circulation. Nasamu et al. Pino discovered that two proteases, plasmepsin IX X, essential mass cell (see Perspective by Boddey). Plasmepsin X is also used merozoites to enter a fresh continue replicative cycle. These plasmepsins act regulating maturation enzymes required disrupt...
SIRT1 is a metabolic sensor and regulator in various mammalian tissues functions to counteract age-related diseases. Here we generated analyzed mice that express at high levels specifically skeletal muscle. We show transgenic muscle exhibits fiber shift from fast-to-slow twitch, increased of PGC-1α, markers oxidative metabolism mitochondrial biogenesis, decreased expression the atrophy gene program. To examine whether activity protects muscular dystrophy, degenerative disease, crossed mdx...
Establishing robust genome engineering methods in the malarial parasite, Plasmodium falciparum, has potential to substantially improve efficiency with which we gain understanding of this pathogen's biology propel treatment and elimination efforts. Methods for manipulating gene expression P. falciparum have been validated. However, a significant barrier fully leveraging these advances is difficulty associated assembling extremely high AT content DNA constructs required modifying genome. These...
Abstract Identifying how small molecules act to kill malaria parasites can lead new “chemically validated” targets. By pressuring Plasmodium falciparum asexual blood stage with three novel structurally-unrelated antimalarial compounds (MMV665924, MMV019719 and MMV897615), performing whole-genome sequence analysis on resistant parasite lines, we identify multiple mutations in the P. acyl-CoA synthetase (ACS) genes Pf ACS10 (PF3D7_0525100, M300I, A268D/V, F427L) ACS11 (PF3D7_1238800, F387V,...
Because Plasmodium falciparum replicates inside of a parasitophorous vacuole (PV) within human erythrocyte, parasite egress requires the rupture two limiting membranes. Parasite Ca2+, kinases, and proteases contribute to efficient egress; their coordination in space time is not known. Here, kinetics were linked specific steps with compartment markers, using live-cell microscopy parasites expressing PV-targeted fluorescent proteins, inhibitors. Several minutes before egress, under control...
Malaria parasites activate a broad-selectivity ion channel on their host erythrocyte membrane to obtain essential nutrients from the bloodstream. This conserved channel, known as plasmodial surface anion (PSAC), has been linked parasite clag3 genes in P. falciparum, but epigenetic switching between two copies of this gene hinders clear understanding how encoded protein determines PSAC activity. Here, we used linkage analysis falciparum cross where one parent carries single overcome effects...
Upon infecting a red blood cell (RBC), the malaria parasite Plasmodium falciparum drastically remodels its host by exporting hundreds of proteins into RBC cytosol. This protein export program is essential for survival. Hence export-related could be potential drug targets. One enzyme in this pathway plasmepsin V (PMV), an aspartic protease that processes export-destined endoplasmic reticulum (ER) at element (PEXEL) motif. Despite long-standing interest enzyme, functional studies have been...
Following each round of replication, daughter merozoites the malaria parasite Plasmodium falciparum escape (egress) from infected host red blood cell (RBC) by rupturing parasitophorous vacuole membrane (PVM) and RBC (RBCM). A proteolytic cascade orchestrated a serine protease, subtilisin-like protease 1 (SUB1), regulates breakdown. SUB1 activation involves primary autoprocessing 82-kDa zymogen to 54-kDa (p54) intermediate that remains bound its inhibitory propiece (p31) postcleavage. second...
The eradication of malaria remains challenging due to the complex life cycle Plasmodium and rapid emergence drug-resistant forms falciparum vivax. New, effective, inexpensive antimalarials against multiple stages parasite are urgently needed combat spread malaria. Here, we synthesized a set novel hydroxyethylamines investigated their activities in vitro vivo. All compounds tested had an inhibitory effect on blood stage P. at submicromolar concentrations, with best showing 50% concentrations...
Identification of novel chemotypes with antimalarial efficacy is imperative to combat the rise Plasmodium species resistant current drugs. We have used a hybrid target-phenotype approach identify and evaluate for malaria. In our search drug-like aspartic protease inhibitors in publicly available phenotypic databases, we identified GNF-Pf-4691, 4-aryl- N-benzylpyrrolidine-3-carboxamide, as having structure reminiscent known proteases. Extensive profiling two terminal aryl rings revealed...
Malaria parasites have evolved unusual metabolic adaptations that specialize them for growth within heme-rich human erythrocytes. During blood-stage infection,
Malaria parasites have evolved unusual metabolic adaptations that specialize them for growth within heme-rich human erythrocytes. During blood-stage infection, Plasmodium falciparum internalize and digest abundant host hemoglobin the digestive vacuole. This massive catabolic process generates copious free heme, most of which is biomineralized into inert hemozoin. Parasites also express a divergent heme oxygenase (HO)-like protein (PfHO) lacks key active-site residues has lost canonical HO...
Malaria parasites have evolved unusual metabolic adaptations that specialize them for growth within heme-rich human erythrocytes. During blood-stage infection, Plasmodium falciparum internalize and digest abundant host hemoglobin the digestive vacuole. This massive catabolic process generates copious free heme, most of which is biomineralized into inert hemozoin. Parasites also express a divergent heme oxygenase (HO)-like protein (PfHO) lacks key active-site residues has lost canonical HO...
Malaria parasites have evolved unusual metabolic adaptations that specialize them for growth within heme-rich human erythrocytes. During blood-stage infection, Plasmodium falciparum internalize and digest abundant host hemoglobin the digestive vacuole. This massive catabolic process generates copious free heme, most of which is biomineralized into inert hemozoin. Parasites also express a divergent heme oxygenase (HO)-like protein (PfHO) lacks key active-site residues has lost canonical HO...
Functional characterization of the multitude poorly described proteins in human malarial pathogen, Plasmodium falciparum, requires tools to enable genome-scale perturbation studies. Here, we present GeneTargeter (genetargeter.mit.edu), a software tool for automating design homology-directed repair donor vectors achieve gene knockouts, conditional knockdowns, and epitope tagging P. falciparum genes. We demonstrate GeneTargeter-facilitated six different types knockout knockdown constructs...
ABSTRACT Establishing robust genome engineering methods in the malarial parasite, Plasmodium falciparum , has potential to substantially improve efficiency with which we gain understanding of this pathogen’s biology propel treatment and elimination efforts. Methods for manipulating gene expression P. have been validated. However, a significant barrier fully leveraging these advances is difficulty associated assembling extremely high AT content DNA constructs required modifying genome. These...
Malaria parasites have evolved unusual metabolic adaptations that specialize them for growth within heme-rich human erythrocytes. During blood-stage infection, Plasmodium falciparum internalize and digest abundant host hemoglobin the digestive vacuole. This massive catabolic process generates copious free heme, most of which is biomineralized into inert hemozoin. Parasites also express a divergent heme oxygenase (HO)-like protein (PfHO) lacks key active-site residues has lost canonical HO...