Harvard University

university

Cambridge, MA

Total disclosed

$117,755,558

Award count

240

Distinct programs

First → last award

1992 → 2031

Disclosed awards

Showing 226–240 of 240. Public data only — SR&ED tax credits are confidential and not shown.

Mechanism-Function Studies of Ribonucleotide Reductase$876,200
NIH Research Projects · FY 2026 · 1992-04
Abstract A vast number of enzymes are now known to derive their function from radicals. Radical-based enzymes have particular relevance to human health as therapeutic targets with wide-ranging applications including chemotherapy, anti-retroviral and anti-bacterial drugs and anti-inflammatory agents. Radicals are produced by proton-coupled electron transfer (PCET), and consequently this mechanism is central to radical-based enzymology. As PCET is exquisitely sensitive to the proton transfer distance, radical pathways are a facile target of conformational gating in tertiary and quaternary structure. Of the many radical-based enzymes, ribonucleotide reductases (RNRs) are exceptional in their PCET-based biological function and are paramount to health, as the enzymes produce the DNA building blocks for life. Mis-regulation of RNR leads to disease states caused by imbalances in the intracellular nucleoside 5´-di(tri)phosophates (ND(T)Ps, N = A, U, C or G) pools available for replication and DNA repair, highlighting the enzyme's potential as a therapeutic target. Indeed, the central role of RNRs in nucleic acid metabolism has made class Ia human RNR the target of five clinically used therapeutics that inhibit RNR through distinct modes of action, thus promoting cytotoxicity for the treatment of cancer. The function of class Ia RNRs is derived from a reversible long-range radical transport (RT) pathway that spans 32 Å and two subunits (α and β) upon every turnover. The emergence of new structural details of class I RNR have formed the undergirding of three specific aims by allowing both the nature of subunit interactions and the networks of amino acids that connect the catalytic, specificity, and activity sites of the intact enzyme to be identified. Specific Aim 1 will explore the insertion the C-terminal tail of β into α to poise the tyrosine (Y356) residue that manages RT at the αβ interface. The specific C-terminal tail interactions and the dynamics of its insertion into α will be examined. Specific Aim 2 seeks to characterize the initial events of radical generation and transport within the β-subunit with a focus on W48, which resides between the diferric-tyrosyl radical cofactor Y122· and the interfacial Y356. Using a suite of tryptophan analogues at W48 with perturbed reduction potentials and unique spectroscopic signatures, we will determine if W48 is on the PCET pathway of RT as well as understand the redox potentials necessary for cofactor assembly. Specific Aim 3 seeks to develop methods to characterize interconversion between active and inactive forms of RNR, as this process is central for regulating the intracellular dN(D)TP pools and thus maintaining genome stability and cell viability. These specific aims will be examined with the use of site-specific unnatural amino acids (UAAs), steady-state and transient kinetics measurements of RT and the design of new biophysical and spectroscopic assays. The work undertaken to address Specific Aims 1–3 will reveal new modalities for the design of therapeutics that target the PCET pathway on physiologically relevant timescales and at a fundamental level will deliver a deeper understanding of the impact of PCET on biological function.
Riemannian Optimization: Manifold Learning, Analysis, and Applications$35,250
Other NSERC · FY 2024
Geometry, Riemannian Manifolds, Machine Learning, Non-Convex Optimization, Convex Optimization, High-Dimensional Probability, Algorithms, Deep Learning, Data Science, ManOpt Computational Package
Astrochemical Pathways to Nitrogen Containing Aromatics$40,000
Other NSERC · FY 2024
Astrochemistry, Interstellar Medium, Aromatic, N-Heterocycles, Ice Analogues
Enzyme-free Signal Amplification of Single Molecule Binding Events On-Bead$59,583
Other NSERC · FY 2024
Single Molecule Arrays, Disease Diagnostics, Protein Quantification, Signal Amplification, Bioanalytical chemistry, Polymer Chemistry
Dynamic Nanoscale Cellular Imaging via High-Pressure Freezing with Buffer Exchange$35,250
Other NSERC · FY 2024
High Pressure Freezing, Time resolved super-res microscopy, Structural biology, Biophysics, Applied physics, Bioengineering, Vitrification, Stress Granules
Deciphering the role of BMP4 signaling during early embryonic development using in vitro models and synthetic biology$20,000
Other NSERC · FY 2024
Developmental Biology, DNA Barcoding, Gastruloid, Gastrulation, Early Embryonic Development, BMP4 Signalling, Cell Lineage Tracing, Human Embryonic Stem Cells, Gene expression measurement, Genome editing
Liquid-infused windows for universal sunlight control$20,000
Other NSERC · FY 2024
smart buildings, energy efficiency, sustainable architecture, microfluidics, responsive materials, bio-inspired design, adaptive optics, sunlight control, heat transfer, built environment
Testing Lepton Flavor Universality with the ATLAS Experiment$38,417
Other NSERC · FY 2024
Computing, Statistics, Accelerator physics, Theoretical physics, High energy physics
An Integrated Perspective on the Tetrapod Water-to-Land Transition$40,000
Other NSERC · FY 2024
Vertebrate Palaeontology, Macroevolution, Biomechanics, Functional Morphology, Ecomorphology, Biorobotics, Adaptive Landscapes, Modularity & Integration
Establishing bulk-to-boundary connections in celestial holography: a new framework to constrain scattering amplitudes$33,667
Other NSERC · FY 2024
Holography, Scattering Amplitudes, Conformal Field Theory, Quantum Field Theory, Quantum Gravity, Celestial Holography, Gravity, Spacetime Symmetries
Turning up the Temperature in Conformal Field Theory$32,083
Other NSERC · FY 2024
quantum field theory, particle physics, collider physics, conformal field theory, theoretical physics
Machine learning guided CRISPR-Cas9 protein engineering$35,250
Other NSERC · FY 2024
CRISPR, directed evolution, protein engineering, machine learning, genome editing, protospacer adjacent motif
Personalized Control Strategy for Assistive Exoskeletons Using Stochastic Game Theory$35,000
Other NSERC · FY 2024
Human-Robot Interaction, Human Sensorimotor Control, Stochastic Control, Game Theory, Machine Learning, Time Series Estimation
Bioenergetics of Collective Behaviour: Bridging Biomechanics and Bio-robotics$70,000
Other NSERC · FY 2024
Elucidating the Mechanism of Proton Coupled Electron Transfer in the Beta Subunit of E. coli Class Ia Ribonucleotide Reductase$40,000
Other NSERC · FY 2024
Mechanistic Enzymology, Metalloenzymes, Radical Enzymology, Chemical Biology, Laser Spectroscopy, Electrochemistry, Bioinorganic Chemistry, PCET in Biology

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