Research Groups
Distinguished Prof. Natalie Ahn
Dr. Natalie Ahn’s work investigates new mechanisms underlying the regulation and function of cell signaling pathways that modulate transcription, epigenetics and cancer, by integrating biochemical and cellular strategies with biomolecular mass spectrometry and proteomics. Among many other contributions, she discovered key components of the mitogen-activated protein kinase (MAPK) pathway. In this context, David Vaisar, a CBB/SCR T32 graduate trainee in her lab is seeking to characterize conformation-selective inhibitors of MAPKs. These studies are poised to have a major impact in many aspects of Down syndrome associated conditions, where MAPKs, ERK1 and ERK2, -and their upstream regulators- are known to be overexpressed.
Prof. Mary Ann Allen
Ìý°Õ³ó±ð Allen lab is studing how the chromosome 21 gene RUNX1 affects embryonic hematopoietic development. In her postdoc, she found that RUNX1 has both a higher expression level and increased activity in Down syndrome lymphoblastoid cells. RUNX1 is required for proper blood development, leading to the hypothesis that RUNX1 overexpression may cause some of the blood phenotypes seen in Down Syndrome. In this regard, Dr. Allen has three critical goals: 1) determine how much of the blood phenotypes seen in Trisomy 21 is due to RUNX1. 2) evaluate how T21 cells respond when RUNX1 is activated (as happens in blood development), and 3) identify a novel small molecule inhibitor of RUNX1 via drug screening as a novel therapeutic strategy in Down syndrome.
Professor Halil Aydin
¶Ù°ù.Ìý’s research focuses on characterizing conserved pathways that regulate the morphological and functional plasticity of mitochondria in neurons and reveals how this enables the nervous system to function. His laboratory utilizes a multi-disciplinary approach that integrates structure determination by electron cryo-microscopy (cryoEM) with biochemistry, biophysics, and cell biology techniques to bridge detailed structural studies with a deeper knowledge of mitochondrial function to advance our understanding of how these cellular machines function normally, and how they are corrupted by disease.. In this regard, Hannah Arthur, a CBB/SCR T32 graduate trainee in his group is focused on the molecular determinants that regulate mitochondrial energy production pathways, a topic that is poised to elucidate the basis of numerous mitochondrial alterations frequently observed in Trisomy 21 cells.
Prof. Justin Brumbaugh
The Brumbaugh Lab is interested in understanding the function of the stem cells located in the gastrointestinal (GI) tract. The GI tract is a constant source of problems for individuals with Down syndrome. They have an increased incidence of Celiacs as well as frequent malformations of the intestines and anus. Furthermore, they have a marked predisposition to Hirschsprung's disease (no neurons in the large intestine). The GI tract must constantly cope with cell death and repair, and this process is likely altered in Down syndrome. The Brumbaugh lab collaborates with Peter Dempsy (¶¶Òõ¶ÌÊÓƵ Anschutz) to look at the GI tract in typical mice. The Brumbaugh lab will assess the molecular and physical alterations found in the small and large intestines and study the GI tract's chromatin state in multiple mouse models of Down syndrome.
Prof. Edward Chuong
Prof. Ed Chuong is a genome biologist studying how regulatory networks are established in evolution and disease. His lab employs cutting-edge computational and experimental techniques to investigate the origins and evolution of non-coding regulatory sequences. He leads a dynamic and transdisciplinary lab spanning genomics, epigenetics, evolution, immunity, and disease. In particular, he is addressing specific alternative splicing mechanisms that regulate Interferon (IFN) signaling and how to leverage them into translational applications for Down syndrome, where an exacerbated IFN signaling is the basis to several pathological conditions.
Prof. Robin Dowell
The has been exploring genomics questions in Down syndrome since 2015. While genomics is powerful, analysis of the resulting data is complicated because most bioinformatics software assumes a typical diploid genome. The Dowell lab has developed extensive infrastructure and novel algorithms to overcome this issue. Consequently, the Dowell lab also provides bioinformatics support for several Down syndrome colleagues across the Boulder campus. Additionally, the Dowell lab seeks to understand the widespread impact of Down syndrome on cell transcription and RNA degradation. Since many transcriptional regulators have tissue-specific functions, the Dowell lab employs a variety of cell types. The Dowell lab leverages novel machine learning algorithms and nascent transcription assays to understand dosage effects on transcription factor function and drug response.
Prof. Virginia Lea Ferguson
Trisomy 21 is associated with skeletal consequences of low bone mass and bone strength, which lead to increased fracture risk. Bones in humans and mice with trisomy 21 show evidence of low bone turnover despite profound hypogonadism (altered follicle-stimulating hormone, FSH, and luteinizing hormone). The Ferguson lab has recently collaborated with Raj Kumar at Anschutz, an expert in FSH-induced bone decrements with aging and menopause, to elucidate how elevating FSH levels influence bone fragility independent of estrogen. Similarly, they can evaluate how gonadal hormones and other factors expressed in bone and serum from trisomy 21 mouse models correlate with bone strength and fracture toughness. For this project, the Ferguson lab will use mechanical testing for strength assessment, microCT (computed tomography) to evaluate bone volume and architecture, and materials assessment assays to evaluate bone tissue chemistry and material properties in multiple Down syndrome mouse models. They will then collaborate with the Allen lab to determine the molecular changes that correlate with the bone phenotypes. The overall goal is to determine the genes that lead to impaired skeletal outcomes in Trisomy 21.
Prof. Charles Hoeffer
The Hoeffer lab will continue their research into the cognitive effects of Down syndrome on brain function and sleep. Specifically, they have preliminary data that the Dp16 mice (one mouse model of Down syndrome) have sleep abnormalities (like DS individuals) corrected in part by deleting one of three copies of RCAN1, restoring the dosage of the gene to disomic levels. Since the hippocampus regulates several aspects of sleep architecture, they will be evaluating the molecular impacts of RCAN1 level correction in the Dp16 hippocampus. The Hoeffer lab will do more sleep analysis of mutants that change RCAN1 levels and target pathways known to be regulated by RCAN1 in Down syndrome. Additionally, they will also use RNA-sequencing of the hippocampus to determine the effect of these changes and identify pathways perturbed in Down syndrome that may control sleep and circadian function in Down syndrome.
Prof. Loren Hough
Dr. Loren Hough studies the biophysics of disordered proteins and develops innovative methodology to investigate previously uncharacterized protein domains. Disordered domains perform many important cellular functions in homeostasis and in stress due to their ability to form molecular condensates. In this regard, he recently obtained a collaborative AB Nexus Grant with Dr. Chad Pearson (Linda Crnic Institute) to investigate how the self-assembly of the chromosome 21-encoded protein Pericentrin regulates intracellular trafficking during cilia formation and signaling.
Prof. Christopher D. Link
Dr. Link's lab is focused on elucidating changes in gene expression that underly specific Down Syndrome traits, such as intellectual disability. They have undertaken an extensive transcriptome analysis of paired trisomic vs. disomic induced pluripotent stem cells (iPSCs) and cortical neuronal cultures derived from them. Their data and similar recent studies led them to propose that chromosome 21 trisomy may prevent stem cells from attaining full pluripotency, contributing to several neurodegerative alterations found in T21 individuals. They will continue these research lines with the final goal of better understanding the mechanisms that drive an accelerated mental deterioration in DS.
Distinguished Prof. Karolin Luger
Dr. has devoted her career to uncovering how DNA is organized and packed into nucleosomes and higher order chromatin structures from a quantitative, mechanistic, and structural perspective, providing the basis for understanding gene regulation and epigenetics in health and disease. In this regard, Sashi Weerawarana, a CBB/SCR T32 graduate trainee in her group is focused on the molecular determinants that regulate mitochondrial DNA architecture and function, a field that has remained largely unexplored and that directly relates to the extensive mitochondrial alterations frequently observed in Trisomy 21 cells.
Prof. Susanna Molas
The is focused on understanding the neural circuits that regulate behaviors in models of novelty/familiarity, addiction, autism and Down syndrome. They use state-of-the-art technologies to manipulate and measure the neural function of murine models and assess the outcomes on different behavioral tasks. She is particularly interested on clarifying how Trisomy 21 alters the neural connections that lead to increased predispotition to anxiety, depression and other neurodevelopmental conditions associated with DS.Â
Prof. Brad Olwin
The Olwin lab identified deficiencies in skeletal muscle stem cells (MuSCs) of the Ts65Dn mouse model of Down syndrome, preventing adequate maintenance and repair of skeletal muscle. He plans to use newer T21 mouse models and human biopsies to identify mechanisms underlying muscle dysfunction in DS. Additionally, Dr. Olwin's lab has also successfully derived muscle progenitor cells from human iPSCs. They will apply this technology to derive iPSCs from individuals with Down syndrome and determine if the down syndrome satellite cell defects they identified in mice are also present in human DS-iPSC-derived muscle progenitors. Finally, Dr. Olwin will employ single-cell sequencing and single nuclear sequencing to identify differences in Down syndrome muscle progenitor cells compared to isogenic controls. Data from these experiments will provide the framework for screening compounds to correct MuSCs.
Prof. Amy Palmer
 is interested in the mechanisms by which the essential micronutrient Zn2+ influences cell proliferation and how these processes are affected in trisomy 21, where Zn2+ deficiency is frequent. Maria Lo, PhD, a postdoctoral associate in her lab received a Sie Fellowship from the Crnic Institute and the Anna and John J. Sie Foundation to investigate the potential links between Zn2+ metabolism, neural function and Down syndrome.Â
Distinguished Prof. Roy Parker
Dr. Roy Parker’s group has been studying a link between the loss of white matter, protein production and stress responses in cells derived from individuals with Down Syndrome.To this end, Stephanie Moon, PhD, received a postdoctoral Sie Fellowship from the Crnic Institute and the Anna and John J. Sie Foundation. This group will continue studying the neurodevelopmental effects of stress on DS models and the relations between RNA-protein condensates and Trisomy 21.
Prof. Jingshi Shen
Dr. Jingshi Shen was a recipient of the 2017 Crnic Institute Grand Challenge Grants to study whether trisomy 21 causes dysregulation of cytotoxic lymphocyte-mediated cell killing. His lab will continue to elucidate the implications and alterations of relevant vesicle-mediated transport mechanisms, such as the release of cytotoxic cargo, in Down syndrome immune responses.
Prof. Sabrina Leigh Spencer
The overarching goal of the Spencer Lab is to decipher how mammalian cells make the choice between proliferation (cell-cycle progression) and quiescence (cell-cycle exit). On this quest, the group has developed cutting-edge cell biology methods, including fluorescent biosensors, multi-day time-lapse microscopy, and automated single-cell tracking. They also pioneered the automated pairing of live-cell microscopy with subsequent fixed-cell staining, allowing to match each cell’s current molecular state with its history. Correct execution of the proliferation-quiescence decision is important in many biological settings, from developmental processes to adult tissue homeostasis, and dysregulation of this decision appears to take place in cells with Trisomy 21. The lab is particularly interested in the role of the chromosome 21-encoded kinase DYRK1A as a modulator of Cyclin D degradation.
Prof. Dylan Taatjes
Mediator, a large protein complex associated with RNA polymerase II, is a driver of cellular responses to Interferon (IFN). The Taatjes lab has been investigating the regulation of Mediator function for years, and Mediator inhibitors are already being tested clinically in cancer treatment. In collaboration with the Dowell lab, they have an R01 grant that aims to understand if inhibition of a specific Mediator function can alter the response to IFN in blood cells. Additionally, Dr. Taatjes plans to explore Mediator function in Down syndrome iPSC cells. Mediator is required to reprogram transcription during cellular differentiation, and, intriguingly, Down syndrome is characterized by a lag in stem cell differentiation. The Taatjes lab has a long-term interest on how interferon over-activation could affect pluripotent cell phenotypes associated with Trisomy 21.