Opportunities, barriers, and recommendations in down syndrome research
| dc.contributor.author | Hendrix, James A. | |
| dc.contributor.author | Lawrence, Jeanne B. | |
| dc.date | 2022-08-11T08:08:28.000 | |
| dc.date.accessioned | 2022-08-23T15:56:17Z | |
| dc.date.available | 2022-08-23T15:56:17Z | |
| dc.date.issued | 2021-04-15 | |
| dc.date.submitted | 2022-01-02 | |
| dc.identifier.citation | <p>Hendrix JA, Amon A, Abbeduto L, Agiovlasitis S, Alsaied T, Anderson HA, Bain LJ, Baumer N, Bhattacharyya A, Bogunovic D, Botteron KN, Capone G, Chandan P, Chase I, Chicoine B, Cieuta-Walti C, DeRuisseau LR, Durand S, Esbensen A, Fortea J, Giménez S, Granholm AC, Hahn LJ, Head E, Hillerstrom H, Jacola LM, Janicki MP, Jasien JM, Kamer AR, Kent RD, Khor B, Lawrence JB, Lemonnier C, Lewanda AF, Mobley W, Moore PE, Nelson LP, Oreskovic NM, Osorio RS, Patterson D, Rasmussen SA, Reeves RH, Roizen N, Santoro S, Sherman SL, Talib N, Tapia IE, Walsh KM, Warren SF, White AN, Wong GW, Yi JS. Opportunities, barriers, and recommendations in down syndrome research. Transl Sci Rare Dis. 2021;5(3-4):99-129. doi: 10.3233/trd-200090. Epub 2021 Apr 15. PMID: 34268067; PMCID: PMC8279178. <a href="https://doi.org/10.3233/trd-200090">Link to article on publisher's site</a></p> | |
| dc.identifier.issn | 2214-6490 (Print) | |
| dc.identifier.doi | 10.3233/trd-200090 | |
| dc.identifier.pmid | 34268067 | |
| dc.identifier.uri | http://hdl.handle.net/20.500.14038/29936 | |
| dc.description | <p>Full author list omitted for brevity. For the full list of authors, see article.</p> | |
| dc.description.abstract | BACKGROUND: Recent advances in medical care have increased life expectancy and improved the quality of life for people with Down syndrome (DS). These advances are the result of both pre-clinical and clinical research but much about DS is still poorly understood. In 2020, the NIH announced their plan to update their DS research plan and requested input from the scientific and advocacy community. OBJECTIVE: The National Down Syndrome Society (NDSS) and the LuMind IDSC Foundation worked together with scientific and medical experts to develop recommendations for the NIH research plan. METHODS: NDSS and LuMind IDSC assembled over 50 experts across multiple disciplines and organized them in eleven working groups focused on specific issues for people with DS. RESULTS: This review article summarizes the research gaps and recommendations that have the potential to improve the health and quality of life for people with DS within the next decade. CONCLUSIONS: This review highlights many of the scientific gaps that exist in DS research. Based on these gaps, a multidisciplinary group of DS experts has made recommendations to advance DS research. This paper may also aid policymakers and the DS community to build a comprehensive national DS research strategy. | |
| dc.language.iso | en_US | |
| dc.relation | <p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=34268067&dopt=Abstract">Link to Article in PubMed</a></p> | |
| dc.rights | © 2020 – The authors. Published by IOS Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC 4.0). | |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc/4.0/ | |
| dc.subject | Alzheimer’s disease | |
| dc.subject | Down syndrome | |
| dc.subject | autism spectrum disorder | |
| dc.subject | autoimmune disease | |
| dc.subject | cognitive development | |
| dc.subject | congenital heart disease | |
| dc.subject | intellectual disability | |
| dc.subject | leukemia | |
| dc.subject | muscle hypotonia | |
| dc.subject | obesity | |
| dc.subject | obstructive sleep apnea | |
| dc.subject | periodontitis | |
| dc.subject | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | |
| dc.subject | Nervous System Diseases | |
| dc.subject | Translational Medical Research | |
| dc.title | Opportunities, barriers, and recommendations in down syndrome research | |
| dc.type | Journal Article | |
| dc.source.journaltitle | Translational science of rare diseases | |
| dc.source.volume | 5 | |
| dc.source.issue | 3-4 | |
| dc.identifier.legacyfulltext | https://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3172&context=faculty_pubs&unstamped=1 | |
| dc.identifier.legacycoverpage | https://escholarship.umassmed.edu/faculty_pubs/2139 | |
| dc.identifier.contextkey | 27074130 | |
| refterms.dateFOA | 2022-08-23T15:56:17Z | |
| html.description.abstract | <p>BACKGROUND: Recent advances in medical care have increased life expectancy and improved the quality of life for people with Down syndrome (DS). These advances are the result of both pre-clinical and clinical research but much about DS is still poorly understood. In 2020, the NIH announced their plan to update their DS research plan and requested input from the scientific and advocacy community.</p> <p>OBJECTIVE: The National Down Syndrome Society (NDSS) and the LuMind IDSC Foundation worked together with scientific and medical experts to develop recommendations for the NIH research plan.</p> <p>METHODS: NDSS and LuMind IDSC assembled over 50 experts across multiple disciplines and organized them in eleven working groups focused on specific issues for people with DS.</p> <p>RESULTS: This review article summarizes the research gaps and recommendations that have the potential to improve the health and quality of life for people with DS within the next decade.</p> <p>CONCLUSIONS: This review highlights many of the scientific gaps that exist in DS research. Based on these gaps, a multidisciplinary group of DS experts has made recommendations to advance DS research. This paper may also aid policymakers and the DS community to build a comprehensive national DS research strategy.</p> | |
| dc.identifier.submissionpath | faculty_pubs/2139 | |
| dc.contributor.department | Lawrence Lab | |
| dc.contributor.department | Department of Neurology | |
| dc.source.pages | 99-129 |
Files in this item
This item appears in the following Collection(s)
Except where otherwise noted, this item's license is described as © 2020 – The authors. Published by IOS Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC 4.0).
Related items
Showing items related by title, author, creator and subject.
-
Role of WFS1 in Regulating Endoplasmic Reticulum Stress Signaling: A DissertationThe endoplasmic reticulum (ER) is a multi-functional cellular compartment that functions in protein folding, lipid biosynthesis, and calcium homeostasis. Perturbations to ER function lead to the dysregulation of ER homeostasis, causing the accumulation of unfolded and misfolded proteins in the cell. This is a state of ER stress. ER stress elicits a cytoprotective, adaptive signaling cascade to mitigate stress, the Unfolded Protein Response (UPR). As long as the UPR can moderate stress, cells can produce the proper amount of proteins and maintain a state of homeostasis. If the UPR, however, is dysfunctional and fails to achieve this, cells will undergo apoptosis. Diabetes mellitus is a group of metabolic disorders characterized by persistent high blood glucose levels. The pathogenesis of this disease involves pancreatic β-cell dysfunction: an abnormality in the primary function of the β-cell, insulin production and secretion. Activation of the UPR is critical to pancreatic β-cell survival, where a disruption in ER stress signaling can lead to cell death and consequently diabetes. There are several models of ER stress leading to diabetes. Wolcott-Rallison syndrome, for example, occurs when there is a mutation in the gene encoding one of the master regulators of the UPR, PKR-like ER kinase (PERK). In this dissertation, we show that Wolfram Syndrome 1 (WFS1), an ER transmembrane protein, is a component of the UPR and is a downstream target of two of the master regulators of the UPR, Inositol Requiring 1 (IRE1) and PERK. WFS1 mutations lead to Wolfram syndrome, a non-autoimmune form of type 1 diabetes accompanied by optical atrophy and other neurological disorders. It has been shown that patients develop diabetes due to the selective loss of their pancreatic β-cells. Here we define the underlying molecular mechanism of β-cell loss in Wolfram syndrome, and link this cell loss to ER stress and a dysfunction in a component of the UPR, WFS1. We show that WFS1 expression is localized to the β-cell of the pancreas, it is upregulated during insulin secretion and ER stress, and its inactivation leads to chronic ER stress and apoptosis. This dissertation also reveals the previously unknown function of WFS1 in the UPR. Positive regulation of the UPR has been extensively studied, however, the precise mechanisms of negative regulation of this signaling pathway have not. Here we report that WFS1 regulates a key transcription factor of the UPR, activating transcription factor 6 (ATF6), through the ubiquitin-proteasome pathway. WFS1 expression decreases expression levels of ATF6 target genes and represses ATF6-mediated activation of the ER stress response (ERSE) promoter. WFS1 recruits and stabilizes an E3 ubiquitin ligase, HMG-CoA reductase degradation protein 1 (HRD1), on the ER membrane. The WFS1-HRD1 complex recruits ATF6 to the proteasome and enhances its ubiquitination and proteasome-mediated degradation, leading to suppression of the UPR under non-stress conditions. In response to ER stress, ATF6 is released from WFS1 and activates the UPR to mitigate ER stress. This body of work reveals a novel role for WFS1 in the UPR, and a novel mechanism for regulating ER stress signaling. These findings also indicate that hyperactivation of the UPR can lead to cellular dysfunction and death. This supports the notion that tight regulation of ER stress signaling is crucial to cell survival. This unanticipated role of WFS1 for a feedback loop of the UPR is relevant to diseases caused by chronic hyperactivation of ER stress signaling network such as pancreatic β-cell death in diabetes and neurodegeneration.
-
COVID-19: Pathophysiology and implications for cystic fibrosis, diabetes and cystic fibrosis-related diabetesThe novel SARS-CoV-2 coronavirus (COVID-19) has become a global health crisis since its initial outbreak in Wuhan, China in December 2019. On January 30, 2020, the WHO recognized the COVID-19 outbreak as a Public Health Emergency, and on March 11, 2020, it was declared a pandemic. Although all age groups have been affected, patients with cystic fibrosis (CF) and patients with type 1 or type 2 diabetes have been categorized as highly vulnerable to SARS-CoV-2 infection. Thus far, studies have found that the incidence of SARS-CoV-2 in the CF population is lower than the general population. We review the underlying protective mechanisms which may reduce inflammation and lung damage in CF patients, thus decreasing their risk of severe COVID-19. While the effect of SARS-CoV-2 in those with diabetes related to CF is unknown, other forms of diabetes have been associated with more severe disease. To further understand the potential impact of SARS-CoV-2 in cystic fibrosis-related diabetes, we provide a comprehensive overview of the potential factors contributing to COVID-19 severity in other forms of diabetes, including direct viral effect on the pancreas and indirect effects related to hyperglycemia and immune dysregulation.
-
Gaucher disease in the COVID-19 pandemic environment: The good, the bad and the unknownEarly in the course of the novel coronavirus disease 2019 (COVID-19) pandemic, the rare disease community anticipated that patients with lysosomal and other metabolic disorders would be at increased risk for poor disease outcomes and mortality from the SARS-CoV-2 virus.
