Medical Research

Grant Abstracts 2017

Fred Hutchinson Cancer Research Center

Cyrus Ghajar, Peter Nelson, Patrick Paddison, Slobodan Beronja, Stephen Tapscott, Kirk Hansen
Seattle, WA
$1,000,000
June 2017

The majority of cancer metastasis research is focused on uncovering why certain organs (or “soils”) are permissive to colonization by tumor cells.  But why other tissues only very rarely succumb to metastasis is almost completely ignored.  Using skeletal muscle (SkM) as a model of infertile soil, a team of investigators at the Fred Hutchinson Cancer Research Center and at the University of Colorado, Denver proposes a series of experiments at the biological and technological cutting edge to specify the molecular mechanisms by which SkM suppresses metastasis.  Their goal is to test whether ectopic expression of SkM-derived metastasis suppressors prevents colonization of susceptible sites.  The team plans to: (1) identify metastasis suppressors within SkM; (2) reverse engineer growth resistance using rare tumor cells that successfully colonize SkM; and, (3) express SkM-derived factors specifically within the lungs of mice to determine whether this converts the lung from a metastasis-prone site to a metastasis-suppressive one.  The innovation of this work is the application of sophisticated models and techniques – including some pioneered by the team – to address a long-standing biological mystery: how SkM suppresses metastatic outgrowth. Solving this mystery could hold the key to creating a new paradigm in metastasis research; one that is based on defining the molecular nature of tissue-driven tumor suppression, and applying this information to convert fertile tissues into resistant ones.

Mayo Clinic

Jan van Deursen, Darren baker, Atta Behfar, Hu Li, Andre Terzic
Rochester, MN
$1,200,000
June 2017

Humans and mice have the innate capacity to regenerate heart tissue, but the proliferative capacity of cardiomyocytes dramatically declines after birth, which is a key barrier to the use of regenerative medicine in the treatment of various heart diseases.  In contrast, lower vertebrates retain cardiac regenerative ability throughout life, which has spurred interest into the underlying molecular and cellular mechanisms with the intent to exploit the insights gained to reestablish cardiac homeostasis and repair in humans.  In zebrafish, the three layers that surround the myocardium, referred to as the pericardium, have been identified as a source of cells and signaling factors critical for cardiac regeneration.  A multidisciplinary team of Mayo Clinic investigators discovered that, in adult mice, senescent cells accumulate in the pericardium with aging and that the systemic elimination of senescent cells from midlife on attenuates fundamental aspects of cardiac aging, including cardiomyocyte hypertrophy, loss of stress tolerance and diastolic dysfunction, all of which are linked to heart failure.  These findings provide a rare, unexpected and promising entry point for closing the longstanding knowledge gap about the mechanisms that limit cardiac maintenance and repair as humans and mice age.  The investigators will exploit this opportunity by combining innovative mouse models and cell culture methods with advanced systems biology to identify pericardial signaling pathways that act to sustain myocardial architectural integrity and function.  They will also determine how bioactive factors secreted from pericardial senescent cells that accumulate with aging perturb these signaling networks.  Lastly, the team will evaluate the role of senescent cells in cardiac loss of function and regeneration in mice subjected to myocardial infarction.

Sanford Burnham Prebys Medical Discovery Institute

Duc Dong, Clyde Campbell, Joseph Lancman, Sean Zeng
La Jolla
$1,000,000
June 2017

The prevailing strategy for regenerative medicine is to transplant into patients, replacement cells that have been derived outside the body (in vitro), from pluripotent stem cells. However low survival and functional integration of these cultured cells, as well as the inherent risks associated with the process of transplantation and the use of differentiated stem cells which may have acquired tumorigenic defects, remain formidable obstacles for this approach to be considered effective and safe.  To bypass these obstacles, Sanford Burnham Prebys investigators plan to generate replacement cells by directly converting any cell of choice, while they remain in the body (in vivo).  To do this, the investigators must push the boundaries of induced in vivo lineage conversion, challenging the dogma that cells are lineage restricted in their native microenvironment.  Leveraging zebrafish genetics, they have developed a novel in vivo vertebrate platform to rapidly identify and optimize transcription factors that can induce differentiated cells to change into lineages of interest.  Using this in vivo platform, the researchers have been able to directly induce several differentiated vertebrate cells, including skeletal muscle and skin epidermal cells, to directly convert into unrelated gut lineages, disputing the longstanding model that differentiated cells in vivo are lineage restricted.  In this project, the investigators plan to determine whether most cells in the body, at any age, have the potential to be directly converted into any other cell types, and to uncover and exploit the molecular mechanisms involved in this in vivo cell lineage conversion process.  These studies may pave the way towards a vast new in vivo supply of replacement cells/organs: shifting the paradigm of using an in vitro derivation, stem cell-dependent approach to using an in vivo lineage conversion, stem cell-independent approach to advancing regenerative medicine.

Stony Brook University

Lilianne R. Mujica-Parodi, Ken Dill, Steven Skiena, Steven Stufflebeam, Jacob Hooker
Stony Brook, NY
$1,000,000
June 2017

In moving towards the goal of personalized medicine, investigators at Stony Brook University in collaboration with researchers at Massachusetts General Hospital/Harvard Medical School approach brain network connectivity, assessed by functional magnetic resonance imaging (fMRI) and associated cognitive function, as a dynamic emergent phenomenon.  They plan to integrate human neuroimaging data (7-Tesla fMRI and positron emission tomography, the latter to measure nutrient consumption by brain cells) with multi-scale biomimetic modeling, to test hypotheses with respect to how energy constraints (from diet to mitochondria) affect neural efficiency with age.  The interdisciplinary team of researchers will also experimentally investigate the use of exogenous ketones, a fuel source that is alternative to glucose, as a way to ameliorate age-related effects.  Based upon single subject-specific parameters, models will predict how networks self-organize in response to changes in energy supply and demand, then will be compared against human network trajectories.  Using an iterative approach, in which human data provide feedback, informing the models, which then make predictions that are tested against the next individual’s data, models will eventually converge in predicting human network trajectories based upon individually variable parameters.  In addition to generating fundamental understanding of how nutrition of brain neurons affects cognitive capacity and aging in humans, the project could provide a critical first step towards personalized neurology.  This would be accomplished by simulating—for a single individual—the potential consequences of different dietary interventions in protecting the aging brain.

University of Delaware

Jennifer Biddle, Adam Marsh, Thomas Hanson
Newark, DE
$1,000,000
June 2017

It is well known that DNA alone does not determine the destiny of mammalian cells and organisms and that environments exert significant influence through epigenetic “above the genome” mechanisms.  What is not known is how the environment can shape the destiny of a microbe.  All organisms need to control which genes they express and send specific signals to coordinate metabolism and growth.  While humans and larger eukaryotes are known to have epigenetic components to this regulation, a new and exciting area of interdisciplinary research has emerged as researchers discovered that microbes may also use DNA methylation as an epigenetic control.  A team of investigators at the University of Delaware proposes to investigate the relationship between DNA methylation, gene regulation and energy stress in model and environmental microbial systems at genomic scales by building on their current platform development efforts.  Their hypothesis is that microbes do employ functional epigenetic signals, and that this mode of regulation is important under energy stress or in low-energy environments.  Through a better understanding of microbial gene control, the team expects to better understand how microbes impact the environment and human health.

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