Espinosa, Joaquin M PHD

– Overall. People with Down syndrome are strongly predisposed to develop a wide range of comorbidities that shorten their lifespan and decrease their quality of life, such as Alzheimer’s disease, congenital heart disease, leukemias, autoimmune disorders, and diverse neurological conditions. The proposed activities under this project seek to create a world-class resource for collaborative discovery, data sharing, data access, and integrative analysis that would enable novel investigations into all DS comorbidities across the lifespan and further integrating across datasets for related diseases occurring in the general population, thus paving the way for a precision medicine approach to DS. Furthermore, this resource and associated platforms will also have broader impacts by empowering physicians, educators, government officials, and advocates with the tools required to elicit evidence- based transformative action in the clinic, the classroom, the government, and society at large.

– Overall. People with Down syndrome are strongly predisposed to develop a wide range of comorbidities that shorten their lifespan and decrease their quality of life, such as Alzheimer’s disease, congenital heart disease, leukemias, autoimmune disorders, and diverse neurological conditions. The proposed activities under this project seek to create a world-class resource for collaborative discovery, data sharing, data access, and integrative analysis that would enable novel investigations into all DS comorbidities across the lifespan and further integrating across datasets for related diseases occurring in the general population, thus paving the way for a precision medicine approach to DS. Furthermore, this resource and associated platforms will also have broader impacts by empowering physicians, educators, government officials, and advocates with the tools required to elicit evidence- based transformative action in the clinic, the classroom, the government, and society at large.

People with Down syndrome, the genetic condition caused by trisomy 21, display a unique clinical profile across the lifespan, including much elevated rates of diverse co-occurring conditions. Research efforts investigating the mechanisms by which trisomy 21 causes the hallmarks of Down syndrome, as well as the factors that modify these effects, will accelerate discoveries to improve health outcomes in this population. This project aims to develop a network of Down syndrome research sites in the USA and Latin America to increase the racial, ethnic, and socio-cultural diversity of investigations of the population with Down syndrome.

People with Down syndrome display increased risk of developing diverse co-occurring conditions, but the mechanisms driving this unique clinical profile are yet to be defined. This project will develop a biobanking research infrastructure that could support a wide range of investigations by a multidisciplinary team of researchers through the collection of diverse biospecimens using harmonized protocols. These activities will greatly accelerate the pace of discoveries benefiting persons with Down syndrome.

PROJECT NARRATIVE – Overall People with Down syndrome are strongly predisposed to develop a wide range of co-occurring conditions that shorten their lifespan and decrease their quality of life, such as Alzheimer’s disease, congenital heart disease, autoimmune disorders, and diverse neurological conditions. The proposed activities under this project seek to further develop a world-class resource for collaborative discovery, data sharing, data access, and analysis that would enable novel investigations of DS across the lifespan, thus paving the way for a precision medicine approach to DS. Furthermore, this resource and associated platforms will also have broader impacts by empowering physicians, educators, government officials, and advocates with the tools required to elicit evidence- based transformative action in the clinic, the classroom, the government, and society at large.

Among the many co-occurring conditions that can affect individuals with Down syndrome, the neurological condition known as Down Syndrome Regression Disorder (DSRD) is undoubtedly one of the most detrimental, including symptoms such as catatonia, mutism, depersonalization, loss of ability to perform activities of daily living, hallucinations, delusions, and aggression. This project consists of a research-intensive clinical trial to compare the relative safety and efficacy of three alternative therapeutic approaches in DSRD, including two promising immune-modulatory medicines. Results from this project will produce much needed information about the etiology of DSRD and its response to diverse interventions.

Down syndrome (DS), the genetic condition caused by triplication of chromosome 21 (T21), is the most common chromosomal abnormality and a leading cause of intellectual and developmental disability. Although it is accepted that T21 causes genome-wide dysregulation of gene expression programs, little is known about how T21 affects gene expression across different tissues and organs, and how these effects contribute to the developmental and clinical hallmarks of DS. To address this knowledge gap, this proposal aims to generate a comprehensive atlas of tissue-specific gene expression changes caused by T21, matched to detailed metrics of organ development and architecture.

Individuals with Down syndrome, the genetic condition caused by trisomy 21, display widespread auditory dysfunction, with current estimates indicating that ~80% of this population may have one or more forms of hearing loss. However, the mechanisms by which trisomy 21 causes hearing loss are unknown. This project will fund a multi-disciplinary team of synergistic expertise that will employ a combination of human research and research in mouse models of Down syndrome to elucidate how trisomy 21 impairs auditory function.

The mission of the INCLUDE Data Coordinating Center is to accelerate research that benefits individuals with Down syndrome (DS) by facilitating access and analysis of data from cohort studies of people with DS. This award will fund the development of an immersive summer course in data sciences known as the Data Science for Developing Scholars in Down Syndrome Research (DS3), which will provide training in the basics of generation, identification and collection of high content multidimensional datasets; their management, analysis and visualization; as well as development of key professional skills required for the career advancement of trainees.

The respective biorepositories of the Children’s Hospital of Philadelphia and the Crnic Institute Human Trisome Project Biobank will partner with the INCLUDE Data Hub to support the proposed development of a centralized biorepository data resource to coordinate a single biospecimen data repository or a network of repositories curating and distributing tissue specimens, cell lines, and associated derived analytes such as DNA, RNA, metabolites or proteins relevant to Down syndrome research. Coordinating the linkages between samples, clinical data, and derived biosample characterization data and/files such that a federated framework of queryable samples are available as an integrated resource to the investigator community remains a fundamental challenge. This project will address this unmet need in the field.

This is a proposal to support the design of a pilot data portal for sharing and analysis of data from experimental models of Down syndrome, and to enhance the security ecosystem of the existing researcher portal known as the INCLUDE Data Hub. The activities supported by this award will enable the future creation of an Experimental Models Portal within the INCLUDE Data Hub, while also supporting full compliance with advanced security standards.

People with Down syndrome (DS) display profound immune dysregulation, which could have myriad negative impacts on their health, including the development of various immune and neurological disorders. Multiple lines of evidence indicate that hyperactivation of interferon (IFN) signaling drives immune dysregulation in DS. This proposal aims to expand activities in an ongoing clinical trial in adults with DS and immune skin conditions, using a pharmacological inhibitor of IFN signaling, which is expected to have multidimensional therapeutic benefits in this population.

This Supplement project aims to identify molecular markers of risk for autism spectrum disorder (ASD) in young children with Down syndrome (DS) to advance early screening procedures. We will leverage the ASD-related phenotyping data collected in project #R01HD110542 and collect blood samples concurrently with ASD assessment visits. The addition of biospecimen collection to parent project data collection could facilitate the discovery of molecular indicators of ASD in DS and advance early detection of DS+ASD. It could also identify potential mechanisms that contribute to the onset of DS+ASD and contribute to a new scientific foundation for early intervention and future treatments in this population.

This project will investigate the clinical and immunological characteristics of COVID19 in individuals with Down syndrome, who are at high risk of developing severe complications upon SARS-CoV-2 infection. The research activities in this proposal could enable tailored strategies for better prevention, diagnosis, and treatment of COVID19 in this vulnerable population.

One of the most common genetic alterations in cancer cells is the functional inactivation of the tumor suppressor protein p53. The goal of this research project is to decipher the molecular mechanisms regulating the genes acting downstream of p53, which may enable the design of novel therapeutic strategies.

This project will test the transformative hypothesis that Down syndrome, the genetic condition caused by an extra copy of chromosome 21, or trisomy 21, can be understood in large measure as an immune disorder. This project arises from the observation that people with Down syndrome display chronic immune dysregulation along with hyperactivity in a branch of the immune system known as the interferon response. This hypothesis will be tested through a synergistic combination of human and animal research, likely paving the road for the development of immune-based diagnostics and therapeutic strategies to serve this population.

– Overall. People with Down syndrome are strongly predisposed to develop a wide range of comorbidities that shorten their lifespan and decrease their quality of life, such as Alzheimer’s disease, congenital heart disease, leukemias, autoimmune disorders, and diverse neurological conditions. The proposed activities under this project seek to create a world-class resource for collaborative discovery, data sharing, data access, and integrative analysis that would enable novel investigations into all DS comorbidities across the lifespan and further integrating across datasets for related diseases occurring in the general population, thus paving the way for a precision medicine approach to DS. Furthermore, this resource and associated platforms will also have broader impacts by empowering physicians, educators, government officials, and advocates with the tools required to elicit evidence- based transformative action in the clinic, the classroom, the government, and society at large.

This project aims to identify early developmental, biomedical, and molecular indicators of risk for severe or profound intellectual disability in young children with Down syndrome (DS). Young children with DS will be assessed at three time points and cognitive outcomes will be analyzed in relation to behavioral, biomedical, and molecular risk factors. Results of this work will promote greater inclusivity in DS research and may facilitate innovations in both biomedical and behavioral intervention.