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Previous Grantees


2018

James DeGregory & Jay Hesselbert  
Title

Causes and consequences of altered DNA repair in Down Syndrome

Abstract

DNA repair deficiency and alterations in mutation rates are associated with increases in cancer rates, stem cell deficiencies, neurological impairments, and progerias. Down Syndrome (DS) is associated with alterations in signaling, metabolism, redox status, and gene expression that could directly promote DNA damage and alter DNA repair capacity. We currently lack a solid understanding of how trisomy 21 affects DNA repair and mutation accumulation in tissues. We will determine somatic DNA repair capacity and mutational patterns in leukocytes and epithelial cells from individuals with and without Down Syndrome. A clear understanding of how trisomy contributes to the efficiencies of the various DNA repair pathways and to mutation spectra in tissues of individuals with DS is key to understanding how such alterations might contribute to DS phenotypes such as impaired stem cell function, premature aging, and altered disease susceptibility, including increased leukemia and decreased carcinoma rates.


Richard Reinhardt
Title

Mechanisms of reduced allergic susceptibility in Down syndrome

Abstract

Studies indicate that allergic sensitization occurs in only 7.6% of individuals with Down syndrome (DS) compared to 40.2% of non-DS individuals. Despite the striking difference in allergic sensitivity, few studies in mouse or humans have addressed allergic disease in DS, and the molecular mechanisms responsible for decreased allergic susceptibility in DS remain unknown. A gene on chromosome 21 in humans known to influence IL-4 and IL-13, key orchestrators of allergic inflammation, is Runx1. Runx1 inhibits the differentiation of T-helper 2 (Th2) cells, represses GATA3 (a key driver of IL-13), and binds to the IL-4 silencer in the il4 locus to prevent IL-4 production. Our central hypothesis is that increased gene dosage of Runx1 in DS results in impaired Th2 differentiation and decreased numbers of IL-4-producing follicular T cells after allergen exposure, which limits allergen-specific IgE and the development of allergic disease.

 
Edward Janoff
Title

Impact of Trisomy 21 on B cell Phenotype and Function in Adults

Abstract

The rapid increase in lifespan of people with Trisomy 21 (T21) has created a critical gap in our understanding of immunity in these adults. Their high rates of pneumonia and subsequent death may result from an impaired ability of B cells to generate antibodies of sufficient quantity, quality, and function to control respiratory pathogens. B cell defects among children with T21 show compromised class-switch memory responses and antibody subclass deficiencies (particularly IgM and IgG2) that may directly limit their ability to respond to generate both natural and vaccine-induced antibodies to pneumococcal polysaccharides.   We will characterize the B cell phenotype and activation ex vivo and with stimulation and associated regulatory factors to understand B cell defects that may persist or progress in the expanding population of adults with T21 in order to maintain health and prevent disease.

 

2017

Zhe Chen
Title

Characterizing axon myelination in Down syndrome models

Abstract

In Down syndrome (DS) individuals, some major nerves have been found to be reduced in size, which may underlie the cognitive and neurological deficits commonly associated with trisomy 21. Recent studies suggest that impairment of myelination may be a contributing factor to the loss of nerve structure and likely function in DS. Damage to myelin sheaths surrounding nerve fibers is the underlying cause of neuronal degeneration in demyelinating diseases such as multiple sclerosis. It is also implicated in many other neurodegenerative diseases including Alzheimer’s. In this proposal, we aim to determine if axon myelination is disrupted in DS mice. In addition, we will determine if certain external factors, such as cytokines and remyelinating agents, can influence the process of myelination in DS. Our study will provide a novel perspective in understanding the etiology of the disorder.


Santos Franco
Title

Defects in Neurogenesis and Neuronal Migration in DS Mouse Models: Elucidating the Developmental and Molecular Mechanisms

Abstract
Down syndrome is the most common genetic cause of intellectual disability, and all individuals with Down syndrome suffer from some level of cognitive delay and deficits in learning and memory. Although advances in early childhood care have led to significant improvements in the intellectual development of people with Down syndrome, the underlying neurodevelopmental causes of their brain dysfunction are still not known. In particular, there exist fundamental gaps in our knowledge of how the earliest cellular processes critical for embryonic brain development are affected in Down syndrome. In this application, we propose to test the hypothesis that embryonic defects in neurogenesis and neuronal migration lead to aberrant development of the cerebral cortex in Down syndrome mouse models. We expect these studies to contribute to the community of Down syndrome researchers by providing missing key information on the cellular defects that occur at the earliest stages of brain development.
 
Csaba Galambos
Title

Overexpression of anti-angiogenic genes impairs lung development in Dp16 mic

Abstract
Lung hypoplasia with pulmonary hypertension (PHT) has been recognized as a significant contributor to the quality of life of subjects with Down syndrome (DS). However, the molecular events leading to lung disorders are unknown. We have been testing our overriding hypothesis that altered angiogenic signals drive DS lung disorder. We have shown that interruption of angiogenic signals leads to lung hypoplasia/PHT in neonatal lung disorders, fetal and neonatal DS lungs show defective lung and vascular growth, and DS fetal lungs overexpress angiogenic genes. We have established that DS mouse model Dp16 that has triplicated gene for angiogenic factor Rcan1 develops lung hypoplasia, identical to that of DS.  Using this model our proposal aims to investigate angiogenic genes and their pathways with a special focus on VEGF/Rcan1/calcineurin/NFAT pathway, their relationship to severity of lung hypoplasia/PHT to design future interventions, drug discovery and biomarker studies to attenuate and prevent lung disorders in DS.

Elena Hsieh
Title

Understanding the Hyperactive Interferon Response in Trisomy 21 at the Single-Cell Level

Abstract

Individuals with Down syndrome, also known as trisomy 21 (T21), suffer from various co-morbidities including cognitive impairment, heart disease, recurrent infections, autoimmune complications, and malignancy.  Despite much research, the genetic mechanisms that link T21 to specific disease traits are poorly understood. Recently, Sullivan et al., 2016 identified a consistent interferon-stimulated transcriptional response in cells affected by T21.  While gene expression analysis showed that all cells with T21 had a hyperactivated interferon response, the specific genes stimulated by interferon (IFN) signaling varied by cell type. How this variability in IFN-dependent and cell type-specific responses relate to the clinical variability observed in T21 patients remains unknown.  Our objective is to elucidate at the single-cell level via mass cytometry, the relationship between aberrant IFN-dependent cellular signaling/cytokine pathways, and specific T21 co-morbidities associated with immune dysfunction. Our central hypothesis is that cell type-specific IFN-dependent signaling/cytokine signatures will correlate with specific immune dysfunction co-morbidities.


Laurel Lenz
Title

Mechanisms responsible for increased type I IFN responses in Trisomy 21

Abstract

Down Syndrome (DS) is associated with Trisomy 21 (T21). Genes for both type I interferon (IFN) receptor subunits (IFNAR1 and 2) are carried on chromosome 21 and overexpressed in T21 cells. This leads to constitutive expression of IFNs and IFN-stimulated genes (ISGs) that likely contributes to the cognitive impairments and altered susceptibility to infections in individuals with DS. How increased IFNAR expression causes constitutive production of IFNs and ISGs is unclear. We will investigate mechanisms for this towards identifying novel therapies to prevent hyper-production of IFNs in DS. Surface expression and signal transduction by IFNAR1 and/or IFNAR2 are regulated post-transcriptionally. We thus hypothesize that over-expression of IFNAR1 and/or 2 triggers constitutive IFN responses because it overloads regulatory mechanisms that are not increased by T21. We will test this hypothesis and determine if boosting negative regulators such as prolidase dampens IFN production in the context of T21.


Ken Maclean
Title

Endoplasmic reticulum stress, impaired proteostasis, autophagy and lysosomal dysfunction: Towards the rational design of novel treatments for age-related cognitive decline in Down syndrome

Abstract

Our hypothesis is that trisomy 21 results in a toxic synergy between increased transcriptional/translational burden and failure to clear misfolded proteins resulting in ER stress and failure to induce autophagy combined with impaired mitochondrial function/renewal and decreased cell viability. Our model identifies multiple stages for targeted intervention in DS. And we will test a range of novel treatments for DS by investigating the following specific aims. 1. Investigate ER stress/UPR activation in multiple brain regions and non-neural tissues of DP16 mice, perform a metabolomic and targeted lipidomic analysis of DP16 mouse hippocampus/cortex. Investigate ER stress/UPR activation and impaired proteostasis in patient-derived fibroblasts trisomic for chromosomes 8 and 18. 2. Investigate the ability of cystathionine, salubrinal, rapamycin and BDNF to ameliorate ER stress in DS. 3: Investigate autophagic function in DS cells and evaluate the impact of proteostasis network dysfunction on mitochondrial dynamics and the cellular proteome.

 
Niklaus Mueller
Title

Malformation of the Ocular Lens in Down Syndrome Visual Impairment

Abstract

Visual impairment is increased in individuals with Down syndrome (DS). Some of these impairments are associated with the ocular lens, like cataracts, hyperopia, myopia, and astigmatism. These visual impairments are a result of changes in the lens refractive properties which focus light on the retina. Lens refractive properties are driven by crystallins that make up the majority of lens protein. The most abundant lens crystallin, ?A-crystallin, is encoded by CRYAA on chromosome 21 that is triplicated in DS. Mutations to ?A-crystallin result in cataract indicating its importance in lens function. Moreover, the DP17 mouse model of DS has three copies of cryaa, homologous to CRYAA, and has a lens phenotype. We propose to characterize lenses from donors with DS to determine if a similar phenotype is found in humans. Additionally, we will use lens extracts from cataract patients and DP17 mice to determine changes in crystallin protein composition between groups.


Brian O'Connor 
Title

Examining Chromatin Regulation of Adaptive Immune Dysfunction in Down Syndrome

Abstract

Although Trisomy 21 is defined as a genetic disorder, the molecular pathways responsible for generating the multiple pathologies associated with the disease are not well characterized. The disease course of Trisomy 21 (T21) and severity of symptoms vary greatly among affected individuals, which includes varying immune system disorders. Thus, despite the genetic nature of the disease ontogeny, the complex pathophysiology implicates molecular mechanisms that can modulate developmental cell fate programming, such as epigenetic regulation. It is compelling to hypothesize that the immune dysfunction and variable phenotypes observed with T21 fundamentally derive from the mutability of epigenetic signatures that define unique individuals in coordination with genetic code implementation. However, targeted analysis of chromatin dynamics within specific immune cells of T21 affected individuals remains undone. The goal of this proposal is to begin to examine the chromatin programming changes specific to T21 that regulate key biological pathways in the immune system.


William Old

Title

DYRK1A inhibitor mediated rescue of Down syndrome phenotypes in cerebral organoids

Abstract

Our efforts over the next year are aimed at elucidating the molecular and cellular mechanisms that underlie the growth defect and harmine-rescue phenotypes in Down syndrome cerebral organoids, an emerging model system of human cortical development. To increase statistical power and extrapolate to broader DS populations, we will generate cerebral organoids from several T21 individuals with euploid controls. Life expectancy of people with Down syndrome is steadily increasing (2), creating an urgent need to develop new personalized therapies targeting DS-related Alzheimer’s disease and to improve the quality of life for people with DS. Our goal is to leverage our new Down syndrome specific model system to close a major gap in our understanding of how DYRK1A contributes to how the the brain develops in Down syndrome, and quicken the pace at which these discoveries can be made.


Chad Pearson
Title

Ciliary trafficking defects and cerebellar hypoplasia in Down syndrome

Abstract

Down syndrome (DS) pathologies overlap with a spectrum of disorders known as ciliopathies, caused by abnormalities of cellular appendages called cilia. Both DS and ciliopathy syndromes exhibit defects in Sonic hedgehog (Shh) signaling that requires cilia. During our first funding cycle from the Linda Crnic Institute, we discovered that cilia are less frequent and shorter in DS. This is important because ciliary frequency and length dictate the efficiency of Shh signaling. Ciliary formation, length and function requires that structural and regulatory components traffic to, from and within the cilium. Three ciliary transport mechanisms (vesicular trafficking, satellite trafficking and IFT) are essential for normal cilia formation and function. Preliminary evidence suggests such trafficking is disrupted in DS. Moreover, in DS and when ciliary trafficking is disrupted the cerebellum is underdeveloped. We will establish whether disrupted ciliary trafficking and function is the underlying mechanism that drives cerebellar hypoplasia in DS.


Kelly Sullivan
Title

The role of IFN signaling in Down syndrome pathology in vivo.

Abstract

Individuals with Down syndrome (DS) experience a unique disease spectrum in which they are predisposed to certain conditions such as autoimmune disorders and Alzheimer’s Disease, but protected from others such as solid tumors. We recently discovered that trisomy 21, the cause of DS, results in constitutive activation of interferon (IFN) signaling in myriad cell types. We hypothesize that altered IFN signaling contributes to the unique disease spectrum of individuals with DS and represents a target for therapeutic intervention. In this proposal, we propose to test the effects of genetic or pharmacological blockade of IFN signaling on disease-associated molecular and behavioral phenotypes of the Dp16 mouse model of DS.

 
Michael Yeager

Title

Interferon and Interleukin-10 Mediated Immune Suppression in Down Syndrome Maintains a Post-Viral Like State of Susceptibility to Severe Pneumonia

Abstract

Down Syndrome (DS) is the most common chromosomal abnormality among live-born infants. DS is associated with increased rates and severity of respiratory infection, accounting for more deaths in DS than any other condition. There is an urgent need to understand how trisomy 21 contributes to respiratory infectious disease. Recently, persons with DS were shown to consistently activate the interferon response. Following major epidemics of influenza (“la grippe” in 1803 and the 1918 Spanish flu pandemic), enhanced susceptibility to bacterial pneumonia caused the overwhelming majority of deaths. Our preliminary data of high levels of interferons and interleukin-10 in DS mirrors the post-influenza dysregulated cytokine response. Our hypothesis is that the constitutive activation state of interferon signaling in the DS lung drives IL-10 signaling and immune suppression. This state phenocopies the increased susceptibility and severity of S. pneumoniae pneumonia that is observed in non-DS individuals after a course of viral infection.