This $625,799 federal Project Grant award from the National Heart, Lung, and Blood Institute (CFDA 93.837 - Cardiovascular Diseases Research) aims to investigate the role of cellular senescence in the development of lung disease in individuals with Down syndrome (trisomy 21). The research will utilize developing human lung tissues, mesenchymal cells, and ex vivo explant models from fetal, neonatal, and pediatric samples to determine the impact of senescent cells and associated secretory...
The University of California, San Diego (UCSD) was awarded a $1,698,323 Project Grant from the National Institute on Aging (CFDA 93.866 Aging Research) to develop and validate a mouse model for Alzheimer's disease in Down syndrome (DS-AD). The goal is to create a genetically modified mouse that replicates key pathological features of DS-AD, including amyloid plaques, congophilic angiopathy, and neurofibrillary tangles. In the initial R61 phase, the researchers will demonstrate feasibility,...
This federal Project Grant award from the National Institutes of Health (NIH) Office of the Director under the Trans-NIH Research Support program (CFDA 93.310) provides $2,357,335 to study neuronal dysfunction in Down syndrome (DS) and its link to Alzheimer's disease (AD). The key products and services delivered under this award include: Utilizing induced pluripotent stem cell (iPSC)-derived cortical organoids and assembloids to examine the cellular, transcriptomic, and motility-related...
This Cooperative Agreement award, funded by the National Institutes of Health (NIH) Office of the Director under the Trans-NIH Research Support program (CFDA 93.310), will support a 5-year, longitudinal study entitled "Metabolic Health, Lifestyle, and Risk of Co-Occurring Health Conditions in Down Syndrome (MET-DS)". The study will enroll 200 participants aged 6-24 years with Down syndrome across 4 clinical sites to deeply characterize metabolic health, obesity, and lifestyle...
This $2,598,199 Cooperative Agreement, awarded by the National Institutes of Health (NIH) Office of the Director under the Trans-NIH Research Support program (CFDA 93.310), will support a multi-center, multi-disciplinary research project titled "Advancing the Lives & Health of Youth and Young Adults with Down Syndrome (ALLY-DS)." The project aims to establish a diverse cohort of individuals with Down syndrome for comprehensive longitudinal phenotyping, including multi-omics data...
This Project Grant award from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847), provides $225,000 to investigate the role of the protein α-synuclein in regulating the erythroid iron restriction response. The research aims to elucidate how α-synuclein and the neurotransmitter dopamine modulate erythropoiesis during iron deficiency, which can lead to iron deficiency anemia....
This Project Grant award from the National Institutes of Health (NIH) under the Trans-NIH Research Support program (CFDA 93.310) provides $1,257,163 to the Icahn School of Medicine at Mount Sinai to develop a humanized monoclonal antibody targeting follicle-stimulating hormone (FSH) as a potential treatment for Alzheimer's disease in individuals with Down syndrome. The 5-year project, beginning on Jul 1, 2025, will first measure FSH levels across the lifespan in mouse models of Down syndrome...
This Project Grant award of $195,041 from the National Institute on Aging (CFDA 93.866 - Aging Research) will support research to understand the role of cardiovascular disease in the development of Alzheimer's disease in individuals with Down syndrome. The University of Pittsburgh will lead this 2-year project, which will develop innovative statistical approaches combining Bayesian inference and machine learning to analyze comprehensive clinical, biospecimen, and imaging data from the...
The Trustees of the University of Pennsylvania received a $3.7 million Project Grant award from the Department of Health and Human Services National Institutes of Health Office of the Director to address co-occurring conditions in individuals with Down syndrome. Funded under the Trans-NIH Research Support program (CFDA 93.310), the three-year project will test whether reducing proteostatic stress with the FDA-approved small molecule 4-phenylbutyrate can ameliorate sleep deficits, metabolic...
This Project Grant award from the National Institute of Child Health and Human Development (NICHD) under the Child Health and Human Development Extramural Research program (CFDA 93.865) will fund research to investigate gastrointestinal dysfunction in Down syndrome. The $232,875 award to Virginia Commonwealth University will support a 2-year study to test the hypothesis that trisomy 21 in Down syndrome leads to altered voltage-gated calcium currents in smooth muscle of the distal colon,...
IRON METABOLISM IN TS65DN MICE, A MODEL OF DOWN SYNDROME - PROJECT SUMMARY/ABSTRACT DOWN SYNDROME (DS) IS A DEVELOPMENTAL DISABILITY THAT TYPICALLY RESULTS FROM THE TRIPLICATION OF CHROMOSOME 21 WITH AN OCCURRENCE OF 1 IN 700 LIVE BIRTHS. CHROMOSOME 21 TRIPLICATION MAY ALTER NORMAL GENE EXPRESSION AND LEAD TO INTELLECTUAL DISABILITY, EARLY ONSET ALZHEIMER'S DISEASE, CONGENITAL HEART DISEASE, HEMATOLOGIC DISORDERS, AMONG OTHER CONDITIONS. DYSREGULATION OF IRON HOMEOSTATIC MECHANISMS MAY BE AN UNDERLYING FACTOR IN CLINICAL OUTCOMES ASSOCIATED WITH DS. IRON IS A TRACE ELEMENT WELL-KNOWN FOR ITS INVOLVEMENT WITH PHYSIOLOGICAL PROCESSES THAT INCLUDE OXYGEN TRANSPORT, INFLAMMATORY RESPONSE, ENERGY METABOLISM, AND DNA SYNTHESIS. IRON HOMEOSTATIC DYSREGULATION IN DS COULD LEAD TO COMPROMISED PLASMA IRON LEVELS AND TISSUE IRON ACCUMULATION THAT CATALYZES THE PRODUCTION OF REACTIVE OXYGEN RADICAL SPECIES (ROS). DESPITE REPORTS OF IRON STATUS PARAMETERS IN DS THERE IS A LACK OF CLEAR AND COMPREHENSIVE UNDERSTANDING OF IRON HOMEOSTATIC REGULATION AMONG THIS POPULATION OF INDIVIDUALS. THE TS65DN MOUSE IS AN ESTABLISHED MODEL OF DS THAT MAY HOLD CONSIDERABLE VALUE TO STUDY MECHANISTIC FACTORS THAT REGULATE IRON HOMEOSTASIS IN DS. THE OBJECTIVE OF THIS PROJECT IS TO DELINEATE SEX AND AGE-RELATED ALTERATIONS IN IRON HOMEOSTATIC REGULATION OVER THE ADULT LIFESPAN OF TS65DN MICE AND TO ASSOCIATE CHANGES IN IRON REGULATION WITH TISSUE IRON LEVELS AND OXIDATIVE STRESS. IN THESE STUDIES, TISSUES (BRAIN, LIVER, AND PLASMA) FROM TS65DN MICE AND WILD-TYPE (WT) COLONY CONTROLS AT 3, 12, AND 18 MONTHS OF AGE WILL BE STUDIED TO ADDRESS TWO INTEGRATED SPECIFIC AIMS: 1) DEPICT THE IRON HOMEOSTATIC PHENOTYPE OF TS65DN MICE ACROSS THE ADULT LIFESPAN, AND 2) DETERMINE THE IMPACT OF HYPOXIA EXPOSURE (10% INSPIRED O2) ON SYSTEMIC AND TISSUE IRON HOMEOSTASIS, HEMATOLOGIC PROFILE, AND TISSUE OXIDATIVE STRESS IN TS65DN MICE. THE FIRST AIM OF THIS PROPOSAL WILL ESTABLISH THE UTILITY OF THE TS65DN MOUSE MODEL TO STUDY IRON STATUS AND IRON HOMEOSTATIC REGULATION IN DS. IT IS HYPOTHESIZED THAT TS65DN MICE WILL SHOW GREATER INFLAMMATION THAT WILL PROMOTE AN IRON REGULATION RESPONSE LEADING TO LOWER PLASMA COMPARTMENT IRON AND ELEVATED IRON IN THE STORAGE COMPARTMENT. ELEVATED TISSUE IRON IN TS65DN MICE IS POSTULATED TO ASSOCIATE WITH GREATER OXIDATIVE INJURY. THE SECOND AIM WILL EMPLOY HYPOXIA EXPOSURE TO ALTER IRON HOMEOSTATIC REGULATION OF TS65DN AND WT MICE TO TEST THE HYPOTHESIS THAT HYPOXIA INDUCED IRON DISTRIBUTION SHIFTS FROM STORAGE TO THE PLASMA COMPARTMENT WILL REDUCE TS65DN TISSUE IRON TOXICITY AND IMPROVE THE HEMATOLOGIC PROFILE. FURTHERMORE, IT IS HYPOTHESIZED THAT MALE MICE WILL DISPLAY GREATER IRON STATUS AND OXIDATIVE STRESS THAN FEMALES, WITH TS65DN SHOWING GREATER LEVELS THAN WT CONTROLS. AS IRON METABOLISM DYSREGULATION AND TISSUE IRON ACCUMULATION CAN BECOME MORE PROMINENT WITH AGING, UNDERSTANDING IRON METABOLISM IN DS IS OF UTMOST IMPORTANCE AS LIFE EXPECTANCY OF THIS POPULATION HAS DRAMATICALLY IMPROVED OVER THE PAST SEVERAL DECADES.