Medical Research

Grant Abstracts 2019

Huntington Medical Research Institutes

Michael Harrington, Linda Petzold, Brian Stoltz
Pasadena, CA
$1,000,000
December 2019

An interdisciplinary team of investigators at the Huntington Medical Research Institutes, the University of California, Santa Barbara, and the California Institute of Technology proposes a new fundamental biological mechanism in which varying sodium levels in cerebrospinal fluid (CSF) or brain tissue alter local neuronal firing rates, resulting in fluctuation of brain performance.  Their initial studies of migraine pathophysiology revealed that CSF sodium regulation is a key factor in migraine: CSF sodium levels are higher near specific cranial nerves at the time that their excitability increases.  Moreover, based on animal and cell culture studies, the team predicts that fluctuating sodium levels are responsible for fluctuating brain performance in health and disease.  For example, altered sodium in the frontotemporal cortex may change executive and memory functions, while sodium fluctuations in the limbic system, amygdala, and prefrontal cortex may alter mood or cause anxiety or panic attacks.  To test their hypothesis, the investigators will measure sodium and ATPase activity in well-characterized individuals using multinuclear magnetic resonance imaging and will identify symptoms that match the changing biochemistry.  Furthermore, the team will develop new compounds to modulate the sodium/potassium ATPase at different sites to improve neurological functions.  Lastly, they will generate a physics-based model of the data to further our understanding of when, where and how specific episodic neurological functions arise.  Thus, modeling will establish the key rate-limiting steps in a complex brain network to predict failure of brain homeostasis.  Successful completion of this project will ascertain a new paradigm for health or brain pathology, whereby fluctuating neurological functions arise from fluctuating sodium levels.

Louisiana State University

Alyssa Johnson, Adam Bohnert
Baton Rouge, LA
$1,000,000
December 2019

Lysosomes are digestive organelles that govern cellular metabolism and homeostasis.  Despite their importance to animal health and disease, the current model of lysosome structure and function is quite simplistic: lysosomes are thought to exist mainly as discrete vesicles, each with similar degradative capacity.  Recently, two early career investigators at Louisiana State University discovered a new class of lysosomes that challenges this model.  In multiple species and cell types (including mammalian cells), the team has identified an interconnected, dynamic network of tubular lysosomes (TLs) that are exceptionally degradative.  Notably, these TL networks suppress age-related tissue degeneration, highlighting their biomedical relevance.  This study will utilize two genetically tractable model organisms, the nematode C. elegans and the fruit fly Drosophila melanogaster, to develop a comprehensive picture of this unique organelle.  Live-animal imaging will be used to track TL biogenesis and activity in different tissues throughout life and in response to metabolic stimuli.  In addition, the investigators will utilize fluorescent sensors to assess cargo turnover in TLs and they will perform unbiased screens to identify TL regulators.  These studies have the potential to redefine the landscape of a cell, while also hinting at natural disease-fighting mechanisms based on lysosomal plasticity.

Memorial Sloan-Kettering Cancer Center

Adrienne Boire, Christine Iacobuzio-Donahue, Dana Pe’er
New York, NY
$1,000,000
December 2019

Spread of cancer cells into the spinal fluid, or leptomeningeal metastasis (LM), is an increasingly common complication of cancer that results in rapid neurologic disability and death.  The molecular mechanisms that underlie cancer cell entry into this space remain poorly understood.  Preliminary data from both patient samples and mouse models suggest that certain cancer cells exploit the immune system to gain characteristics that enables them to live and grow in the spinal fluid, which is nutritionally sparse with limited oxygen, protein, glucose, lipids, and micronutrients essential for cell growth.  A team of three investigators at Memorial Sloan-Kettering Cancer Center plans to determine the mechanisms by which cancer cells become able to survive and grow within the spinal fluid environment.  The team hypothesizes that circulating cancer cells enter a structure called the choroid plexus.  Once in this structure, immune cells kill many cancer cells, but certain cells survive this selection, follow immune cells into the spinal fluid and live within this unfavorable environment.  To study these processes, the team proposes to subject patient spinal fluid samples and tissues to advanced analytical techniques to generate an LM “atlas” that describes molecular characteristics of cancer cells capable of living within the spinal fluid.  They will also employ their established mouse models of LM to further investigate the molecular characteristics of these populations of cancer cells.  This translational approach will improve understanding of the essential steps that govern cancer and immune cell entry into the spinal fluid and could provide new insights into therapeutic approaches for cancer metastasis.

University of California, Davis

Johannes Hell, Kit Lam, James Ames, Manuel Navedo
Davis, CA
$1,000,000
December 2019

The exact location of proteins inside a cell is critical for their function.  Antibodies are powerful tools for protein detection and have been developed against a multitude of proteins.  However, because of their size, defining the exact location of a protein is limited to 20 nanometers (10-9 m, nm) when most protein dimensions are in the range of 4-10 nm.  Thus, to accurately map the spatial relationships between individual proteins, new technology is required for their detection.  The first goal of this project is to develop groundbreaking technology for detection of protein targets with a resolution in the 1-5 nm range.  Investigators at the University of California, Davis will do so by combining a technology for screening peptides with dyes that fluoresce only if in contact with another protein.  Their approach would generate highly specific reagents for detection of a particular protein and could also address the – often underappreciated – issue of antibodies binding to proteins other than their intended targets.  The team will use this technology to develop peptides directed against key proteins at the synapse, the contact site of neurons.  They will focus on the AMPA-type glutamate receptor (AMPAR), which mediates most of the signal transmission between neurons in the brain.  Its exact localization within synapses determines the strength of the signal transmission, which in turn can be modified under physiological conditions such as learning and under pathological conditions such as drug addiction and post-traumatic stress disorder.  Identifying the exact location of AMPARs would advance our understanding of their function in health and disease.

University of Colorado at Boulder

Xiaoyun Ding, Jill Slansky, Todd Murray, Corey Philip Neu
Boulder, CO
$1,000,000
December 2019

Biomarkers, or biological markers, are measurable indicators of biological state or condition.  The measurement and characterization of mechanical biomarkers (mechanical properties) of cells, such as mass, compressibility, viscosity, stiffness and density, has been of great interest to biomedical researchers and could have profound impact in cellular biology, drug research, cancer and other diseases.  The cell mechanical properties are useful indicators of changes in cytoskeleton and nuclear organization.  They could serve as label-free biomarkers for determining cell states or properties such as metastatic potential, cell cycle stage, degree of differentiation, and leukocyte activation.  In this project, investigators at the University of Colorado aim to develop a newly conceptualized technology, termed acoustic activated flow cytometry, to simultaneously measure multiple mechanical biomarkers of individual cells at a high throughput of up to millions of cells per hour.  Surface acoustic wave (SAW), a kind of sound, is a mechanical wave that propagates at the interface of a solid and a liquid medium.  Its propagation is highly sensitive to the mechanical properties of the cells passing through the propagating pathway of SAW.  By measuring the SAW signal change when cells continuously flow through, the team would be able to collect the details of multiple mechanical properties of individual cells at a high rate.  The measurement of multi-dimensional mechanical biomarkers of individual cells in high throughput is beyond the capability of any current technology and could provide an entirely new foundation for both fundamental cell biology and clinical research.

Washington State University

James Krueger, Cheryl Dykstra-Aiello, Ilia Karatsoreos, Alexander Panchenko
Spokane, WA
$1,000,000
December 2019

In all humans, host cells and microbes live in a delicate symbiotic balance.  The gut microbiome affects cognition, emotion, sleep, circadian rhythms, and additional brain functions.  Yet, the causal brain mechanisms behind these effects are unknown.  A small literature, including past work by Washington State University (WSU) investigators, indicates that bacterial cell wall peptidoglycan (PG) is present in normal brain and changes with sleep loss.  These findings provide an intriguing new understanding of what it means to be human – bacteria participate in human neurobiology.  The WSU investigators posit that PGs regulate physiological brain functions including sleep and circadian rhythms.  They further expect that non-pathological alterations of sleep or circadian rhythms, e.g. acute sleep deprivation or simulated jetlag, induce dynamic changes in brain PG levels which, in turn, could induce changes in the expression of genes associated with sleep/wake cycles and circadian rhythms.  Using mouse models, the WSU investigators have demonstrated that the mRNA of a PG-binding peptide in the brain increases after acute sleep deprivation.  This peptide induces the expression of sleep regulatory cytokines involved in circadian rhythms.  In this project, the WSU team plans to measure the levels of PG and of the PG-binding peptide in the mouse brain under normal circadian rhythms and sleep-wake cycles.  They would determine how disrupting sleep or circadian rhythms drives changes in the levels of PG and PG-binding peptide along with other proteins related to circadian rhythms.  Lastly, using in vitro neuronal/glial co-cultures that simulate sleeplike states, the investigators would characterize the molecular mechanisms linking PG levels to cytokines and sleep.  Successful completion of this project would advance our understanding of the relationship among the microbiome, immune responses, sleep, and circadian rhythms.

City of Hope

Saswati Chatterjee
Duarte, CA
$1,000,000
June 2019

Gene editing is revolutionizing research from medicine to agriculture.  It is enabled by nuclease based platforms, such as CRISPR, which predominantly use error-prone non homologous-end-joining DNA repair, leading to unintended on-target mutations.  Repair of nuclease-induced double stranded DNA breaks via the highly precise homologous recombination (HR) pathway is rare.  Additionally, nuclease-based editing platforms carry the burden of promiscuous off-target cleavage, resulting in the potential for genome-wide mutagenesis.  Thus, significant challenges persist with current editing platforms.  Adeno-associated virus (AAV) based vectors have previously been shown to mediate genome editing without the requirement for exogenous nucleases.  However, genome editing efficiencies were too low to be useful.  Investigators at City of Hope recently reported that AAVHSC, a novel class of human stem cell (HSC)-derived AAV, mediate precise and efficient HR-based genome editing requiring no exogenous nucleases and no genomic scarring.  Genome editing is guided only by homology arms.  However, although this method is effective, little is known about the underlying processes by which any AAV, including AAVHSC, mediate gene editing.  In this project, the team will investigate the mechanisms by which AAVHSC executes this unique, efficient, HR-based editing.  Specifically, they will study the interactions between AAVHSC editing genomes and cellular DNA repair proteins and the role of the AAVHSC capsids in potentiating the efficiency of HR.  Additionally, they will investigate how AAVHSC mediates HR in non-dividing cells.  This study is expected to reveal novel cellular mechanisms that may be harnessed for a range of genomic applications including novel therapies.

Johns Hopkins University

Abdel Hamad, Thomas Donner, Chunfa Jie, Ruhong Zhou, Mario Suva
Baltimore, MD
$1,000,000
June 2019

More than 1% of the world’s population currently lives with an autoimmune disease.  In individuals affected by these conditions, immune cells fail to distinguish between self and foreign antigens, leading to immune attacks on the body itself, with often devastating consequences.  Intense efforts have been directed toward understanding the fundamental mechanisms underlying this abnormal immune response so that effective protective and therapeutic interventions can be developed for the nearly 100 known autoimmune diseases.  Yet critical gaps remain in our understanding of autoimmunity, including the identification of all cell types involved.  These deficiencies are reflected in the failures of recent clinical trials aimed at protecting those at risk of one of the most prevalent autoimmune diseases – type 1 diabetes (T1D).  The goal of this project is to test the hypothesis that a previously unknown immune cell type – the X cell – plays a central role in driving autoimmunity and holds the key to future treatments.  Investigators at Johns Hopkins University discovered X cells during their quest for rare pathogenic cells in T1D patients.  The team found that these cells are a hybrid between T and B cells, the two known distinct arms of the adaptive immune system.  The Johns Hopkins investigators, in collaboration with researchers from Des Moines, Columbia and Harvard Universities, aim to confirm the unique identity of X cells by characterizing the genes that are commonly and differentially expressed in X, B and T cells.  They will also investigate the role of X cells in the pathogenesis of T1D, challenging the current dogma that T and B cells are the sole adaptive immune cells driving autoimmunity.  It is expected that the information learned here would shed light on a possible wider role of X cells in other autoimmune diseases.

Texas A&M University

Michael Golding, Tracy Clement, Ivan Ivanov
College Station, TX
$900,000
June 2019

Clinical studies report that 75% of fetal alcohol spectrum disorder (FASD) children have biological fathers who were either heavy drinkers or chronic alcoholics.  However, the role of male alcohol use in the development of fetal alcohol syndrome birth defects remains unexplored.  This is largely due to the misconception that sperm do not transmit heritable information beyond the genetic code.  Using a mouse model, investigators at Texas A&M University have linked preconception male alcohol use to fetal growth restriction, placental dysfunction, and long-term deficits in the metabolic health of the adult offspring.  These phenotypes are similar to those reported in children with FASD and reveal male alcohol use to be an unrecognized contributing factor in the development of alcohol-induced growth defects.  Using state-of-the-art sequencing technologies, this project aims to define the epigenetic mechanisms by which alcohol-induced errors in developmental programming transmit to the offspring and determine how long these environmentally induced effects persist after the males stop drinking.  Subsequently, the investigators will examine why the offspring of alcohol-exposed males become growth restricted.  This proposal challenges the prevailing paradigm, which exclusively focuses on maternal alcohol exposures and examines a novel hypothesis that considers paternal contributions to FASD birth defects.  This study will be among the first to explore the role of sperm-inherited alterations in epigenetic programming in the development of a pediatric disorder and will develop biomarkers of exposure that will offer the opportunity to significantly enhance the health of future pregnancies.

Tulane University

James McLachlan, John McLachlan, Franck Mauvais-Jarvis
New Orleans, LA
$1,000,000
June 2019

Across the animal kingdom, it is well-known that males and females exhibit different immune responses with females responding more robustly in nearly all cases.  The reasons for this difference are not entirely understood.  For females, this disparity may be beneficial in combatting infections, but can also be detrimental due to a greater incidence of many autoimmune diseases.  A team of Tulane University investigators serendipitously discovered that males and females appear to have evolved the ability to trigger immunity differently in traditional (lymphoid) and non-traditional (non-lymphoid) organs throughout the body.  To help decipher these responses, the team proposes to investigate how immune cells in these organs are differentially activated by a variety of challenges and how hormones and sex chromosomes regulate the unique differences of immune cells in these distinctive tissues.  A better understanding of the contribution of lymphoid and non-lymphoid organs to alterations in immunity between sexes will provide a greater awareness of how these immune systems have evolved and will allow for improved precision when treating men and women for various diseases.

Vanderbilt University Medical Center

Kasey Vickers, MacRae Linton, Ryan Allen, Quanhu Sheng
Nashville, TN
$1,000,000
June 2019

As the leading cause of death worldwide, cardiovascular disease (CVD) affects one in three people.  For decades, plasma cholesterol levels have been considered the leading risk factor for CVD, with low density lipoprotein-cholesterol (LDL-C) as the primary prevention target.  But cholesterol is only part of the equation, as millions of individuals with clinically normal cholesterol levels, managed by statins, still have risk for CVD.  This residual risk is likely conferred by vascular inflammation, which prompts a crucial question: what are the pro inflammatory stimuli that drive the development of atherosclerosis?  Cholesterol is the best known cargo carried by circulating lipoproteins; however, researchers at Vanderbilt University Medical Center discovered that lipoproteins also transport small non-coding RNAs (sRNAs).  Strikingly, the majority of sRNAs on lipoproteins are not human, but microbial, and originate from the host microbiome, diet or other environmental exposure to micro-organisms.  The biological function of microbial sRNAs on lipoproteins is completely unknown.  Could sRNAs be the previously unidentified inflammatory stimuli of atherosclerosis?  Vanderbilt University Medical Center Investigators hypothesize that this previously unmeasurable cargo trafficked on LDL particles engages pro-inflammatory gene regulatory networks to drive atherosclerosis and other metabolic diseases with underlying inflammation.  To test this hypothesis, the researchers will determine how lipoproteins acquire microbial sRNAs, define the biological relevance of microbial sRNAs on lipoproteins, and determine the underlying mechanisms of lipoprotein-mediated cross-kingdom gene regulation.  The discoveries could redefine and disrupt long-held paradigms linking dyslipidemia and inflammation and establish a new field of study for lipoprotein function and extracellular RNA applicable to many chronic diseases.

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