Medical Research

Grant Abstracts 2018

Scripps Research Institute

Peter Schultz, Angad Mehta
La Jolla, CA
$800,000
December 2018

Almost five decades ago Crick, Orgel and others proposed that RNA might be able to support both genotype and phenotype.  Since then, the RNA world hypothesis has been extensively investigated and the function of RNA templates has been studied in terms of evolution, replication and catalysis.  Recently, investigators at the Scripps Research Institute engineered strains of E. coli in which a large fraction of 2’-deoxycytidine in the genome is substituted with the modified base 5-hydroxymethylcytidine.  Subsequently, they generated strains derived from these engineered bacteria, which show significant ribonucleotide content in their genomic templates.  In the proposed studies, the investigators will characterize the properties of these chimeric templates and corresponding strains to determine the circumstances under which E. coli can incorporate ribonucleotides into its genome.  They will also attempt to rationally engineer strains with similar high ribonucleotide content.  The team’s expectation is that such chimeras may provide deeper insights into the link between the RNA and DNA worlds.

University of California, San Francisco

Diana Laird, Andrew Brack, Saul Villeda
San Francisco, CA
$1,000,000
December 2018

Expansion of the aging population is creating major health and socio-economic challenges.  The nascent field of gerontology aspires to develop therapies to extend the human health span and mitigate chronic diseases of aging.  However, this goal is stymied by the sparsity of appropriate model organisms and by a lack of insight into mechanisms by which the more than 80 organs in the body regulate aging.  A team at the University of California, San Francisco proposes to devise a unique, new, tractable and generalizable model for interrogating the role of individual organs in determining the rate of aging using interspecies chimeras between the mouse and the naked mole rat (NMR). NMRs live >9-fold longer than laboratory mice, and the female reproductive lifespan is an astonishing 20-30 times longer.  The team will consider the specific role of the ovary in regulating aging, and its potential as a fountain of youth.  The aims of this project are to understand how the NMR ovary functions 30-fold longer than that of the mouse and to test the capacity of the ovary to prolong youth across the entire organism in chimeric mice with ovarian tissue from NMRs.  The investigators will introduce novel and powerful means to reveal and study integrated mechanisms of aging across all tissues and organs, with special emphasis on skeletal muscle and brain, and to evaluate the potential of NMR ovaries to decelerate or reverse aging.

University of Virginia

Michael Wiener, Lei Wang, Ken Dill
Charlottesville, VA
$1,000,000
December 2018

Structural biology is a critical component of modern biomedical research.  Multiple experimental techniques, primarily X-ray crystallography and cryo-electron microscopy (which has recently advanced remarkably), can yield macromolecular structure at atomic- or near-atomic resolution.  The current structural biology paradigm is that high information content samples, yielding large amounts of data per sample, are used to solve the structure.  However, obtaining such high information content samples, particularly for more complicated systems such as protein complexes, membrane proteins, or transient conformational states of macromolecules, is often very risky, with concomitantly large amounts of time, money, and effort required to maximize the likelihood of success.  An investigator at the University of Virginia, in collaboration with investigators at the University of California, San Francisco and Stony Brook University, proposes an alternative structural biology paradigm: multiple low information content samples, yielding small amounts of data per sample, are used to solve the structure.  This alternative structural biology paradigm will be actualized via development of a new integrated experimental/computational approach, Serial Solution Scattering Structure Determination (S4D). S4D will utilize atomic pairwise distances obtained by solution X-ray scattering from protein samples containing electron-dense “R-group” labels incorporated by in vitro chemical or in vivo unnatural amino acid incorporation methods.  These pairwise distances will be utilized by the “sparse constraint” Bayesian structure determination program termed Modeling Employing Limited Data (MELD).  The culmination of this approach would permit facile macromolecular structure determination in vitro and in vivo.  Success with this “alternative paradigm” for structural biology would enable true high-throughput structure determination that better keeps pace with the increasingly rapid acquisition of genomic and proteomic data.

Washington University in St. Louis

Weikai Li, Rui Zhang
St. Louis, MO
$1,000,000
December 2018

Structure determines function.  A new protein structure is often the milestone that transforms our understanding of basic biological processes.  Four Nobel Prizes have been awarded to the scientists who deciphered the structures of membrane proteins, which constitute about one third of all proteins.  Membrane proteins, however, are notoriously difficult for structural studies due to their hydrophobicity and instability.  The structures of only ~2% of human membrane proteins have been solved, significantly impeding the understanding of their functions.  New out-of-the-box approaches for determining their structures would be nothing short of revolutionary for science and medicine.  Two investigators at Washington University in St. Louis propose a “termini coupling” method to stabilize membrane proteins for purification and structural determination.  Building upon their recent success applying termini coupling to X-ray crystallography, they will develop this novel concept for cryo-electron microscopy, a revolutionary structural tool that overcomes many limitations of crystallography.  The team’s proposed approach can be universally applied to solve the structures of almost any membrane protein, which will allow them and others to address fundamental questions about the multitude of processes that occur on or through cell membranes.  The structures will reveal how signals move between the external and internal environment, how nutrients and ions are sensed and transported, how enzymes catalyze reactions at the membrane interface, and how cells identify and interact with each other to execute a coordinated action.  Termini coupling will allow scientists to finally ‘see’ how human membrane proteins are built and how their functions are executed.  Termini coupling is expected to fundamentally transform the current understanding of biology.

Center for Infectious Disease Research

Alexis Kaushansky, Noah Sather
Seattle, WA
$1,000,000
June 2018

Recently, several promising experimental vaccines have failed to achieve efficacy in the field after they demonstrated high levels of protection in human clinical trials involving pathogen naïve individuals.  Early clinical trials typically study the first exposure to infection while in the field, people are often infected with a pathogen multiple times before vaccination.  Investigators at the Center for Infectious Disease Research in Seattle, Washington, hypothesize that the resultant partial “immunity” alters the engagements between the pathogen and the host.  This impacts the development of potent immune effector cells and in turn reduces the efficacy of vaccine-induced protection.  Each of these processes is complicated by the reality that, while most studies evaluate bulk measurements, infection and immunity are both driven by a very small number of individual cells whose characteristics are likely lost in the context of bulk measurements.  The team proposes to evaluate changes that occur in host-parasite interactions as a result of pre-existing humoral immunity to malaria infection, as well as determine the impact of these changes on vaccine efficacy.  Importantly, assessments will occur at the single cell level, allowing evaluation of how parasites, host target cells and antibody responses interact to yield protection or susceptibility to infection.

The Rockefeller University

Erich Jarvis, Shiaoching Gong, Michael Long, Ofer Tchernichovski
New York City, NY
$1,000,000
June 2018

Spoken language is critically dependent on the ability to imitate sounds heard, a complex trait known as vocal learning.  Despite its independent evolution in only a handful of distantly related avian and mammalian lineages, vocal learning between these lineages shows remarkable convergence in behavioral mechanisms, neurocircuitry, and associated brain gene expression specializations.  These specializations include a finite set of over 50 genes that Rockefeller University researchers recently identified as showing convergent, differential expression within vocal circuits in the brains of vocal-learning songbirds and humans.  The investigators posit that evolutionary changes in the regulation of these genes are responsible for the emergence of vocal learning and other brain circuits for related complex traits.  They will test this hypothesis by developing new molecular tools to modify a rudimentary vocal brain circuit in mice.  The researchers will engineer the human versions of these genes into mouse vocal circuits and then determine whether these animals exhibit enhanced vocal-learning associated traits as measured by circuit connectivity, physiology, and vocal behavior.  Such studies may generate genetically tractable mouse models with greater vocal learning capacity for studying and repairing human communication disorders, as well as tools for genetically engineering circuits for other complex traits.

Salk Institute for Biological Studies

Janelle Ayres
La Jolla, CA
$1,000,000
June 2018

Host-microbe interactions have traditionally been viewed as antagonistic, with most investigators focusing on understanding host resistance mechanisms that kill pathogens.  Salk researchers have been characterizing host-microbe interactions from a fundamentally distinct perspective—how do animals survive when interacting with microbes?  Health is traditionally believed to be a passive homeostatic state and disease occurs when there’s disruption in the system, such as the presence of a pathogen.  It would then follow that removal of the pathogen would return the system back to a healthy state.  However, in many scenarios, the collateral damage associated with pathogen elimination can do more harm than the pathogen itself, as is seen with sepsis and influenza infection.  Salk investigators hypothesize that maintaining health during infection is an active process, involving mechanisms that coordinate cooperative interactions between the host and pathogens.  This is based on Salk researchers’ discoveries of co-operative defenses that protect the host during infections by alleviating physiological damage without killing the pathogen.  The investigators plan to develop an approach to perform systems level analyses to elucidate the mechanisms contributing to co-operative defenses against two infections in the elderly: sepsis induced by intestinal perforation and influenza.  They will also identify novel methods to manipulate these defenses and strategies to determine how cooperative defense therapies influence pathogen virulence, evolution and attenuation. The project could generate a fundamentally different perspective on understanding and treating many infectious diseases.

University of California, Davis

Ben Montpetit, Priva Shah, Christopher Fraser, Richard Wozniak
Davis, CA
$1,000,000
June 2018

Zika, Hepatitis C, Dengue, and West Nile of the Flaviviridae virus family infect hundreds of millions of people, causing widespread morbidity and mortality.  A prominent example is the recently discovered congenital Zika syndrome characterized by severe microcephaly and other developmental defects.  Except for Hepatitis C, there are no approved anti-viral treatments for these viruses, despite decades of research.  A central tenet of Flaviviridae biology, and one that defines therapeutic strategies, is that virus replication occurs within the cytoplasm of host cells.  Investigators from the University of California, Davis and the University of Alberta in Canada are challenging this dogma by showing, using highly sensitive and specific detection techniques, that the RNA genomes (vRNAs) of Zika and Hepatitis C enter and leave the host cell nucleus during the course of an infection.  This breakthrough requires a paradigm shift away from a cytoplasm centric view of Flaviviridae biology and a re-evaluation of how researchers study and combat these viruses.  However, before the team can leverage this knowledge for societal benefit (e.g. therapeutics), they must understand, at a molecular and mechanistic level, why these viral RNAs travel through the nucleus and engage nuclear processes, and how this benefits the virus.  They will tackle these questions using highly innovative approaches that will allow them to construct dynamic and cell specific systems-level interaction networks between vRNAs and host cell nuclear factors.  The investigators expect these high-risk, high-reward endeavors will produce new paradigms and foster novel pan-Flaviviridae therapeutic opportunities.

University of Chicago

Tao Pan, Murat Eren, Eugene Chang, Mitchell Sogin
Chicago, IL
$1,000,000
June 2018

Genomics-enabled microbiome science has revealed amazing snapshots of globally distributed taxonomic and metabolic diversity, yet current molecular technologies do not describe the dynamic response of microbiomes to environmental shifts.  Biological systems generally respond to environmental flux via regulated protein synthesis where transfer RNA (tRNA) serves a key role in decoding genetic information on-demand.  These adapter molecules also undergo posttranscriptional, chemical modifications that add distinct regulatory aspects in decoding as well as reflect levels of microbial metabolic activity.  A multidisciplinary team of investigators propose a transformative approach that utilizes high-throughput sequencing technology with novel molecular and computational components that simultaneously report tRNA abundance, modification, and charging states that translate into measures of specific taxon expression and activity levels.  The researchers will develop this platform for the application of minute amounts of microbiome samples and generate a complete bioinformatics pipeline integrated into metagenomics platforms such as Anvi’o.  The team will also carry out three biological driver studies as proof-of-principle of applying tRNA-Seq for new biological insights and discoveries.  These studies will empower investigations of rapid dynamic taxonomic and functional shifts in microbial populations in various biomedical and ecological contexts.

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