Crnic Institute Grand Challenge Grants

Linda Crnic Institute logoThe Global Down Syndrome Foundation raises funds for the Linda Crnic Institute for Down Syndrome to underwrite critical research benefiting people with Down syndrome.  To date, we have provided $4.5 million in research grants to 29 investigators. Of the $4.5 million, the most important grants today are (1) the Crnic Grand Challenge Grants totaling over $2 million and (2) the Alzheimer’s disease-Down syndrome innovation grants co-funded with the Alzheimer’s Association.

The Crnic Grand Challenge Grants program was established in 2013 by Tom Blumenthal, Ph.D., executive director of the Crnic Institute. The grants are available to scientists from the University of Colorado system and were awarded to researchers from various disciplines at the University of Colorado at Boulder, and the University of Colorado School of Medicine at the Anschutz Medical Campus. Read the press release about the 2014 Grand Challenge Grants.

2014 Crnic Grand Challenge Grant Recipients

Thirty-three researchers from the University of Colorado at Boulder and the University of Colorado School of Medicine on the Anschutz Medical Campus applied for the 2014 Crnic Grand Challenge Grants. The proposals were reviewed by an elite group of scientists, including Tom Blumenthal, Katheleen Gardiner and Huntington Potter of the Linda Crnic Institute; Mark Johnston, chair of the CU School of Medicine Department of Biochemistry and Molecular Genetics; Lee Niswander of the CU School of Medicine Department of Pediatrics; and Leslie Leinwand and Min Han of the CU-Boulder Department of Molecular, Cellular and Developmental Biology.

2013 Crnic Grand Challenge Grants Recipients

Thirty-six grant proposals were reviewed by an elite group of scientists, and 14 exceptional research projects were selected. Each Linda Crnic Institute Grand Challenge Grant has the real potential to benefit people with Down syndrome. These grants will ensure that we create a true academic home for Down syndrome research in addition to funding research on a national and international basis.

Zhe Chen, PhDZhe Chen, PhD

2014 Grant Recipient
Research Assistant Professor of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder
Characterizing axon guidance phenotypes in Down syndrome models
People with Down syndrome have brain abnormalities causing cognitive deficits. These deficits may be due to failure of nerve cell axons to find their proper place in the brain. Several genes on human Chromosome 21 may play important roles in this process, and axon guidance errors may cause these cognitive deficits. It is currently unknown if trisomy 21 perturbs the function of these genes and consequently leads to axon guidance defects. Using mouse models for Down syndrome, this research group will characterize potential cellular and molecular abnormalities in axon guidance. Future results will determine if axon guidance errors contribute to the cognitive disability in Down syndrome, and thus provide a novel perspective in understanding the causes of cognitive deficits.

James DeGregoriJames DeGregori, Ph.D.

2014, 2013 Grant Recipient
Professor, Biochemistry and Molecular Genetics, Anschutz Medical Campus, UC Denver
Oncogenic adaptation, leukemogenesis and Down syndrome
Down syndrome is associated with a striking increase in leukemia, but decrease in many solid tumors. This research group will continue to test a novel idea linking impaired blood cell production and increased leukemia in individuals with Down syndrome. They suggest that defects in the ability of blood cells to replenish their numbers lead to selection for mutations in potential cancer causing genes that can overcome this defect. Using mouse models, they will ask whether particular cancer-causing events are specifically selected for within blood stem cells in Down syndrome. They will also determine how the extra Chromosome 21 impacts selection for these cancer-causing genes in other tissues, which could explain both increased leukemias as well as decreased solid tumor formation. In all, these studies could suggest a novel approach to limiting cancer: if we understand what leads to the cancer, we have a much better chance of finding cures.

Mark Dell’Acqua, PhD

2014 Grant Recipient
Professor of Pharmacology, University of Colorado School of Medicine
Amyloid Beta postsynaptic signaling through anchored calcineurin
In Alzheimer’s disease, overproduction of amyloid beta (Aβ) protein fragments from the amyloid precursor protein (APP) somehow interferes with the normal signaling functions of brain synapses, which causes dementia. The APP gene is on Chromosome 21, so people with Down syndrome have extra APP and Aβ in their brains, and many develop early-onset Alzheimer’s disease. Figuring out how Aβ interferes with synapes is key for understanding Alzheimer’s disease and could result in the identification of novel drug targets and therapies. Using an innovative genetically engineered mouse model, this research group will determine whether Aβ activates signaling that interferes with synapses through a protein called Calcineurin. This protein is anchored at synapses by a protein called AKAP150. They will investigate whether disruption of AKAP150 can prevent synapse dysfunction caused by the presence of Aβ.

Robin DowellRobin Dowell, Ph.D.

2014, 2013 Grant Recipient
Assistant Professor, Molecular, Cellular and Developmental Biology and BioFrontiers Institute, CU-Boulder
Allele specific transcriptional and post-transcriptional regulation in Down syndrome
This research group will experimentally determine which RNAs are dysregulated in individuals with Down syndrome. They will also determine which step of regulation is altered: transcription of the gene into RNA or stability of the RNA. Using novel techniques, and comparing their results to the genome sequence, they will identify the key regulators responding to trisomy 21. Ultimately, a detailed understanding of the impact of trisomy 21 on gene regulation is necessary to develop targeted molecular therapeutics.

Joaquin EspinosaJoaquin Espinosa, Ph.D.

2013 Grant Recipient
Associate Professor, Molecular, Cellular and Developmental Biology, CU-Boulder
A Genetic Screen For Synthetic Lethal Pathways With Trisomy 21
The Espinosa lab will scan the human genome in search of genes whose function is essential for the survival of cells with three copies of chromosome 21, yet dispensable for cells with only two copies. The identification of these genes will illuminate the molecular processes that allow the cells of individuals with Down syndrome to accommodate the burden of an additional chromosome. This knowledge may eventually enable the design of therapeutic strategies for these genes.

Fran HickeyFran Hickey, M.D.

2013 Grant Recipient
Anna and John J. Sie Center for Down Syndrome Medical Director
Professor, Pediatrics, Anschutz Medical Campus, UC Denver

The pharmacokinetics of morphine in post-operative cardiac patients with Down syndrome
This study will use blood samples from children with and without Down syndrome undergoing cardiac surgery. The study will provide information to improve the management of post-operative pain and sedation in children with Down syndrome, including those with congenital heart disease. Knowledge about the metabolism of morphine in these patients will guide dosing and help limit the risks and side-effects that these patients are exposed to in all clinical situations where pain control is needed.

Aaron Johnson, PhDAaron Johnson, PhD

2014 Grant Recipient
Assistant Professor of Biochemistry and Molecular Genetics, University of Colorado School of Medicine
Profiling Chromosome 21 inactivation by the Xist RNA
All chromosomes are composed of the genetic material (DNA) and many proteins that influence the expression of the DNA. This project will determine the protein composition of Chromosome 21 by re-building the interactions with this chromosome in the test tube. This research group will use this protein composition “signature” as a guide to study a recently developed RNA molecular therapy that can inactivate one of the three copies of Chromosome 21 in trisomic cells. This therapy has the potential to alleviate health complications for people with Down syndrome.

Kevin JonesKevin Jones, Ph.D.

2013 Grant Recipient
Associate Professor, Molecular, Cellular and Developmental Biology, CU-Boulder
BDNF augmentation as a therapeutic treatment for Down syndrome
There is evidence that reduced signaling between neurons mediated by growth factors, a class of signaling proteins that influence the health and function of cells, may be a significant contributor to the intellectual disability that occurs in Down syndrome. The Jones lab will test whether increasing the abundance of one specific growth factor can prevent Down syndrome pathology in a mouse model. They will screen for drugs that increase the abundance of this growth factor with the goal of developing therapeutic drugs for the treatment of Down syndrome.

Harald Junge, PhD

2014 Grant Recipient
Assistant Professor, Molecular, Cellular, and Developmental Biology, CU-Boulder
Optic development & Down syndrome
This research group is focusing on altered development of the eye in Down syndrome, specifically in the region where the optic nerve connects the eye to the brain. This is called the optic nerve head, and it is important for normal vision. Previous studies reported that many individuals with Down syndrome have optic nerve head abnormalities, yet little is known about the cause of these malformations. This group will use mouse models to study optic nerve head formation and function in Down syndrome to determine how the genetic alterations in Down syndrome lead to developmental defects in the eye. A better understanding of optic nerve head abnormalities should aid in the diagnosis and treatment of vision impairment in Down syndrome.

Matthew KennedyMatthew Kennedy, Ph.D.

2013 Grant Recipient
Associate Professor, Pharmacology, Anschutz Medical Campus, UC Denver
Mechanisms of beta-amyloid synapse elimination
Certain features of Down syndrome brain pathology closely resemble Alzheimer’s disease. One of the hallmarks of Down syndrome and Alzheimer’s is the loss of neuronal contacts, or synapses, in the brain. Loss of synapses leads to cognitive symptoms associated with these conditions and is thought to be a result of increased production of a toxic peptide called beta-amyloid. The Kennedy lab will investigate how beta-amyloid causes synapse loss in hope of finding targets for future therapies.

Christopher LinkChristopher Link, Ph.D.

2014, 2013 Grant Recipient
Associate Professor, Integrative Physiology, CU-Boulder
Transcriptome analysis in iPSC-derived and directly reprogrammed neurons from Down syndrome cells
Down syndrome results from an extra copy of Chromosome 21, and it is believed that the resulting extra copies of genes of this chromosome lead to Down syndrome traits. Presumably the extra copies of Chromosome 21 genes results in the higher expression of these genes. It is this increased expression of a subset of genes that results in specific Down syndrome traits, such as intellectual disability. However, it has been difficult to directly test this assumption, or identify the critical genes, due to the experimental inaccessibility of human tissue, particularly the brain. Newly developed technology now enables researchers to convert human skin cells into neurons and to mimic aspects of human brain development in a cell culture dish. This research group will use these technologies to generate neurons from individuals with Down syndrome, and measure expression of all the genes from every chromosome. One idea they will test is that overexpression of one specific gene on Chromosome 21 may alter the function of a set of proteins involved in neurotransmission. Support for this idea would identify specific proteins as candidate drug targets to alleviate brain deficits found in individuals with Down syndrome, such as epilepsy and intellectual disability.

Steven Maier, PhDSteven Marier, PhD

2014 Grant Recipient
Distinguished Professor of Psychology and Neuroscience, University of Colorado, Boulder
The roles of activated microglia and brain interleukin-1 in Down syndrome
The brain contains immune cells, called microglia, which produce neuroinflammation when they are activated. This inflammation can cause learning and memory deficits. The proposed research will examine these cells in brain regions in mice that express the same genetic anomaly as occurs in Down syndrome. If microglia in these mice are indeed activated and inflammatory, then further experiments can determine whether the deficits in learning and memory can be reduced by inhibiting microglia activation. This would suggest that the cognitive alterations associated with Down syndrome are not produced by damage to brain cells per se, but by inflammation in the brain.

Bradley Olwin, PhD

2014 Grant Recipient
Professor of Molecular, Cellular and Developmental Biology, University of Colorado Boulder
Mechanisms of muscle dysfunction in Down syndrome
Muscle dysfunction is one particularly understudied area of Down syndrome pathology. Muscle weakness and low muscle tone affects mobility, limiting ability to complete daily tasks, and diminishing quality of life, increasing health care costs and leading to morbidity. The mechanisms that underlie muscle weakness in Down syndrome are essentially unknown. Adult stem cells in a mouse model of Down syndrome are impaired and likely contribute to premature aging. Muscle stem cells are required for proper skeletal muscle development, maintenance of muscle tissue, and regeneration following injuries. Loss of muscle stem cell function during aging and in neuromuscular diseases, contributes to a progressive loss of muscle function that appears similar to that observed in Down syndrome. This research group will determine if muscle stem cell abnormalities exist in Down syndrome mouse models and whether these abnormalities contribute to pathological loss of muscle strength.

Anne-Laure Perraud, PhD

2014 Grant Recipient
Associate Professor of Immunology, University of Colorado Denver, National Jewish Health
The role of the TRPM2 ion channel and calcium signaling in innate immune functions in Down syndrome
Impairments of the immune system represent a significant burden on the well being and health of people with Down syndrome. This research group will investigate the biological function in immune cells of a protein that transports calcium ions across cell membranes. This protein is made by a gene on Chromosome 21. Calcium ions play a crucial role in mediating immune activation and enhancing inflammation. The central idea is that elevated levels of this protein in Down syndrome contributes to inflammation by promoting activation of immune cells, and might therefore be instrumental in creating conditions leading to tissue damage. This will be tested in animal models and in samples from people with Down syndrome. This research will shed important light on an understudied aspect of Down syndrome biology, ion channels, which represent a large group of potential therapeutic targets.

Karl PfenningerKarl Pfenninger, M.D.

2014, 2013 Grant Recipient
Professor, Pediatrics, Anschutz Medical Campus, UC Denver
Developmental effects of APP overexpression in Down syndrome
The gene for the amyloid precursor protein (APP) is present on Chromosome 21. Although it is known primarily for its role in Alzheimer’s disease, it may also be important for causing cognitive deficits in Down syndrome since it is produced in abnormally large amounts in the brains of individuals with Down syndrome, even early in development. This research group’s preliminary studies suggest that extra APP does indeed cause abnormalities in the nervous system at an early age in a mouse model. Their results suggest that early intervention with therapies to reduce APP levels could help to ameliorate cognitive deficits in Down syndrome.

Tamim ShaikhTamim H. Shaikh, Ph.D.

2014, 2013 Grant Recipient
Associate Professor, Pediatrics, Anschutz Medical Campus, UC Denver
Genetic Modifiers of Autism Spectrum Disorders in Patients with Down Syndrome.
Many children with Down syndrome are also diagnosed with autism spectrum disorders. Do genetic factors play an important role in the increased incidence of autism in individuals with Down syndrome? In order to identify these genetic factors, this research group will analyze the genomes of children with only Down syndrome and those with both conditions using cutting edge genome analysis tools. This will allow them to determine if differences in specific genes contribute to the prevalence of autism in association with Down syndrome. The identification of these genes will provide potential targets for therapeutic intervention to help alleviate social and behavioral impairments associated with autism in individuals with Down syndrome.

Richard SpritzRichard Spritz, M.D.

2013 Grant RecipientProfessor, Human Medical Genetics, Anschutz Medical Campus, UC Denver
Genetic Analysis of Autoimmunity in Down syndrome
More than half of patients with Down syndrome develop one or more autoimmune diseases – autoimmune thyroid disease, celiac disease, vitiligo, type 1 diabetes and rheumatoid arthritis. The Spritz lab has discovered a gene on chromosome 21 called UBASH3A that contributes to these diseases in non-Down syndrome patients. The lab will determine whether UBASH3A causes the very high risk of autoimmune diseases in Down syndrome. If it does, their findings will enable easy testing to identify the subgroup of Down syndrome individuals at highest risk and who would benefit from intensive clinical surveillance and early treatment.

Ding XueDing Xue, Ph.D.

2013 Grant Recipient
Professor, Molecular, Cellular and Developmental Biology, CU-Boulder
Presenilin and Ubiquilin and their roles in Down Syndrome treatments
Down syndrome patients are at high risk of developing Alzheimer’s disease. Mutations in two genes, presenilin and ubiquilin have been shown to cause apoptosis, a major form of neurodegeneration in Alzheimer’s. The Xue lab will use C. elegans as a model to study the mechanisms and signaling pathways of presenilin and ubiquilin and to identify treatments that can ameliorate the effects of Down syndrome and Alzheimer’s.

Michael YeagerMichael Yeager, Ph.D.

2013 Grant Recipient
Assistant Professor, Pediatric Critical Care, Anschutz Medical Campus, UC Denver
Depressed AIRE Expression Causes Immune Cell Dysfunction & Autoimmunity in Down syndrome
Immune system disturbances experienced by individuals with Down syndrome account for an enormous disease burden ranging from quality-of-life issues (hair loss), to more serious health issues (thyroid disease) and life-threatening issues (leukemia, respiratory tract infections). The Yeager lab will shed light on why the immune system does this. Their goal is to drive the development of newer therapies to help individuals with Down syndrome in their immune health care, from improved self-image to longer, more productive and happier lives.

Rui YiRui Yi, Ph.D.

2014, 2013 Grant Recipient
Assistant Professor, Molecular, Cellular and Developmental Biology, CU-Boulder
Identification and functional analysis of dosage imbalanced genes in Down syndrome
Down syndrome is caused by the presence of an extra copy of Chromosome 21. This research group will use a new RNA sequencing tool to directly measure the rate of protein synthesis for every human gene. They will identify genes expressed at abnormal levels in stem cells from people with Down syndrome and neurons derived from these cells. To decipher their function in Down syndrome, they will harness the power of a brand new technology that allows precise genome editing to remove one copy of the dosage imbalanced genes in Down syndrome cells. These studies will provide important insights for the underlying mechanism of Down syndrome and pave the way for therapeutic development.

The total members of the Down Syndrome Supergroup, which meets monthly to discuss science related to Down syndrome, are (by lab):

Vivek Balasubramaniam, M.D., Associate Professor
Sharon Ryan, B.S., Professional Research Assistant

James DeGregori, Ph.D., Professor
Alex Liggett, M.S., Graduate Student
Jen Salstrom, M.D., Ph.D., Pediatric Oncology Fellow

Robin Dowell, Ph.D., Assistant Professor
Mary Allen, Ph.D. Postdoctoral Fellow
Justin Freeman, Professional Research Assistant
Amber Sorenson, Graduate Student

Joaquin Espinosa, Ph.D., Associate Professor
Eliana Gomez, Research Associate

Francis Hickey, M.D., Professor and Sie Center Medical Director
Ben Goot, M.D., Fellow, Co-Principal Investigator

Kevin Jones, Ph.D., Associate Professor
Nick Galati, Graduate Student

Mathew Kennedy, Ph.D., Associate Professor
Brian Hiester, Ph.D., Postdoctoral Fellow

Chris Link, Ph.D., Associate Professor
Joe Cabral
Patrick Gonzales
Chris Roberts
Gretchen Stein, Ph.D., Senior Research Associate, Co-Principal Investigator

Karl Pfenninger, M.D., Professor
Malene Ambjorn, Ph.D., Postdoctoral Fellow
Glenn Simon, Ph.D., Postdoctoral Fellow
Lucas Sosa, M.D., Ph.D., Research Fellow

Tamim Shaikh, Ph.D., Associate Professor
James Yu, Ph.D., Postdoctoral Fellow

Richard Spritz, M.D., Professor

Ding Xue, Ph.D., Professor
Akihisa Nakagawa, Ph.D., Postdoctoral Fellow
Riley Skeen-Gaar, Undergraduate student

Michael Yeager, Ph.D., Assistant Professor
Kelley Colvin – Principal Scientist, M.S., Professional Research Assistant

Rui Yi, Ph.D., Assistant Professor
Jaimee Hoefert, Graduate student

Huntington Potter, Ph.D., Professor & Director, Alzheimer’s Disease Programs
Steven Bennett, Ph.D., Postdoctoral Fellow
Tim Boyd, Ph.D., Research Associate
Julbert Caneus, M.S., Graduate Student
Joseph Daniels, M.P.H., Professional Research Associate
Michelle Norden, A.A., Professional Research Associate
Athena Wang, Ph.D., Postdoctoral Fellow

Katheleen Gardiner, Ph.D., Research Professor
Md. Mahiuddin Ahmed, Ph.D., Research Associate
Aaron Block, B.S., Professional Research Assistant
Ranjitha Dhanasekaran, Ph.D., Postdoctoral Fellow

Tom Blumenthal, Ph.D., Executive Director, Linda Crnic Institute for Down Syndrome
Donald Evans, Ph.D., Research Associate
Robert Levin, Fellow and Director, Center for the Integrative Study of Work in Living Systems
Neil Markham, B.S., Senior Professional Research Assistant

Kristin Artinger, Ph.D., Assistant Professor
Karim Bahmed, Ph.D., Postdoctoral Fellow
Chelsea Corser-Jensen, B.S., Graduate Student
Christina Coughlan, Ph.D., Instructor
Mark Dell’Acqua, Ph.D., Associate Professor
Csaba Galambos, M.D., Ph.D., Associate Professor
Patricia Heyn, Ph.D., Assistant Professor
Verity Johnson, Graduate Student
Karen Moulton, M.D., Assistant Professor
Diego Restrepo, Ph.D., Professor
Zhongping Tan, Ph.D., Assistant Professor
Michael Wempe, Ph.D., Associate Research Professor

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