Project Grant RF1AG079002
- 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...
- 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,...
- The National Institutes of Health (NIH) Office of the Director awarded a Project Grant of $1,896,457.00 under the Trans-NIH Research Support program (CFDA 93.310) to The General Hospital Corporation, doing business as Massachusetts General Hospital (MGH), for the project "BRAIN DEVELOPMENT IN DOWN SYNDROME DURING FETAL AND EARLY POSTNATAL AGES". The grant, awarded on Sep 18, 2024, aims to confirm earlier findings on brain abnormalities in Down syndrome (DS) using advanced...
- 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 federal 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), provides $429,000 to the Regents of the University of Michigan to conduct research on the molecular regulators of the GABAergic system in human neurons derived from control and trisomy 21 (Down syndrome) human embryonic stem cells. The primary goal is to discover the underlying mechanisms that cause...
- This $5.2 million project grant from the Department of Health and Human Services National Institutes of Health Office of the Director, under the Trans-NIH Research Support program, will fund research at the University of Colorado Denver to study neurovascular dysfunction in individuals with Down syndrome revealed by traumatic brain injury. Over three years, the collaborative multi-principal investigator team will establish how trisomy 21-related cellular defects and candidate genes exacerbate...
- This Project Grant award from the National Institute on Aging (CFDA 93.866 - Aging Research) provides $454,271 to Florida Atlantic University to investigate the role of amyloid precursor protein (APP) and cholesterol homeostasis in synaptic dysfunction and neurodegeneration related to Alzheimer's disease (AD). The research aims to use human neurons derived from induced pluripotent stem cells (hiNs) to systematically study how mutations affecting APP distribution, trafficking, and interaction...
- 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 Institutes of Health (NIH) Office of the Director under the Trans-NIH Research Support program (CFDA 93.310) provides $322,000.00 to Case Western Reserve University to perform the following: Analyze electroencephalographic (EEG) and plasma Alzheimer's disease (AD) biomarker data collected during a previous clinical trial studying the effects of the drug memantine on adolescents and young adults with Down syndrome. The analysis will examine the...
- Federal Project Grant Award Summary The National Institute of Neurological Disorders and Stroke (NINDS) awarded $395,009 to the University of California, Davis on August 1, 2025, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853). The two-year project, extending through July 31, 2027, supports foundational research to develop antisense oligonucleotide (ASO) therapy for ADNP syndrome (Helsmoortel-van der Aa syndrome), a severe...
THE ROLE OF APP IN NEUROGENESIS AND AD IN DOWN SYNDROME - DOWN SYNDROME (DS) IS A GENETIC DISORDER CAUSED BY THE TRIPLICATION OF CHROMOSOME 21. DS IS CHARACTERIZED BY DEFECTIVE BRAIN DEVELOPMENT, MANIFESTED BY INTELLECTUAL DISABILITY. THE MOLECULAR MECHANISMS CAUSING IT ARE NOT FULLY UNDERSTOOD. AMYLOID PRECURSOR PROTEIN (APP) RESIDES ON CHROMOSOME 21, THUS TRIPLICATED IN DS. APP PLAYS A ROLE IN DEVELOPMENTAL AND POST-NATAL NEUROGENESIS. HOWEVER, STUDIES EXAMINING THE ROLE OF APP OVERDOSE ON CORTICAL MALFORMATION IN DS ARE SCARCE. APPROXIMATELY FIFTY PERCENT OF PERSONS BORN WITH DS DEVELOP ALZHEIMER'S DISEASE (AD) BY SIXTY YEARS OF AGE. MUTATIONS IN APP CAUSE FAMILIAL AD. INCREASED DOSAGE OF APP IS PREDICTED TO RESULT IN ENHANCED ACCUMULATION OF APP CLEAVAGE PRODUCTS INCLUDING SS-AMYLOID (ASS). AGGREGATED ASS COMPRISES HALLMARK AMYLOID PLAQUES OBSERVED IN AD BRAINS. NOTABLY, PATIENTS WITH TRISOMY OF CHROMOSOME 21 LACKING THE APP LOCUS DO NOT DEVELOP AD. THUS, IT WOULD BE IMPORTANT TO DETERMINE WHETHER AN ADDITIONAL COPY OF APP IS ESSENTIAL OR NECESSARY FOR THE DEVELOPMENT OF AD IN DS. OUR PRELIMINARY STUDIES SHOW THAT SIGNALS CRITICAL FOR NEURAL STEM CELL PROLIFERATION, NEURONAL DIFFERENTIATION AND LAMINA SPECIFICATION ARE REDUCED IN DS ORGANOIDS. THIS PROJECT WILL TEST THE HYPOTHESIS THAT APP OVEREXPRESSION CAUSES OR CONTRIBUTES TO DEFICITS IN NEUROGENESIS AND ALZHEIMER'S PATHOLOGY IN DOWN SYNDROME. WE APPLIED CRISPR-CAS9 TECHNOLOGY TO ELIMINATE ONE COPY OF APP FROM DOWN SYNDROME-DERIVED IPSC [DSAPP]. USING BRAIN ORGANOIDS DEVELOPED FROM DSAPP, DS AND ISOGENIC IPSC, EXPERIMENTS IN AIM 1 WILL EXAMINE THE ROLE OF APP IN NEURAL STEM CELL PROLIFERATION AND NEURAL LINEAGE COMMITMENT IN DS, AIM 2 WILL ADDRESS THE ROLE OF APP IN NEURONAL DIFFERENTIATION AND CORTICAL ORGANIZATION, AND AIM 3 WILL EXAMINE WHETHER APP OVERDOSE IN DS IS ESSENTIAL OR NECESSARY FOR THE DEVELOPMENT OF AD PATHOLOGY. THESE EXPERIMENTS WILL ADDRESS CRITICAL GAPS IN UNDERSTANDING DS AND AD AND IDENTIFY NEW THERAPEUTIC TARGETS FOR THESE DISORDERS.
Mod # | Description | ReasonForModification | Federal Obligation | Date |
|---|---|---|---|---|
| Not listed | $0 | 1/27/26 | ||
| Not listed | $2.0m | 9/14/22 | ||
| Not listed | $2.0m | 9/14/22 |