Exosome RNA Exosome RNA Research & Industry News
This Funding Opportunity Announcement (FOA) invites innovative research focused on understanding the role of exosome biogenesis and secretion in modulating and propagation of early pathogenesis in sporadic and late-onset Alzheimer’s disease (AD). Specifically, this FOA encourages collaborative approaches designed to identify and characterize the regulation of molecular machines that are responsible for exosome biogenesis and the secretion of exosomal cargo molecules in AD.
Alzheimer’s disease (AD) is a progressive, degenerative disorder of the brain and is the most common form of dementia of the elderly. AD is the sixth leading cause of death in the United States. Prominent behavioral manifestations of AD include memory impairments and decline in other cognitive domains. Currently, at least five million Americans at age 65 and older suffer from AD, and it is projected that the number of new cases of AD will double by 2025. AD is clearly becoming a national health crisis affecting Americans across all regions of the country, and the total annual payments of health care for people with AD are projected to be more than $1 trillion in 2050. In response to this looming public health crisis, the National Alzheimer’s Project Act (NAPA) was signed into law in 2011. The primary research goal of the NAPA is to prevent the onset of and develop effective treatments for AD by 2025. As part of the strategic planning process to implement NAPA, NIH AD Research Summits were held in 2012 and 2015 and identified research priorities and strategies needed to accelerate basic research and the development of effective therapies. A FY2017 Alzheimer’s disease bypass budget with milestones was published in 2015 to establish research and funding priorities in response to the NAPA and the AD Research Summits (https://www.nia.nih.gov/alzheimers/bypass-budget-FY 2017). This funding opportunity announcement was developed in response to the recommendations of the AD Research Summits to support interdisciplinary research to understand the heterogeneity and multifactorial etiology of AD.
Exosomes are extra-cellular microvesicles that are hypothesized to alter the cellular phenotype of target cells and play an essential role in the growth and survival of various neuronal cells in the central nervous system. Exosomes are ~40–100 nm vesicles of endocytic origin that are constitutively released by cells into the extracellular environment as a result of multivesicular endosomes fusing with the plasma membrane. Originally thought of as “garbage” vesicles that aid the removal of excess plasma membrane receptors or other cellular components, exosomes have now been shown to have a role in intercellular communication, and they are highly enriched in biological fluids such as plasma.
Exosomes are abundant in biological fluids and have emerged as carriers of potential biomarkers including tau, APP, Aß, RNAs and bioreactive lipids. As a consequence, there is much excitement about the possibility of developing exosome-based “liquid biopsies” to monitor the progression of various neurodegenerative diseases, including AD and Parkinson’s disease. Recently, several studies also demonstrated that the blockage of exosome biogenesis is able to abolish the propagation of tau-related pathologies in mice, suggesting exosomes might play a pivotal role in cell-cell communication and the initiation of early AD pathogenesis.
Despite a positive correlation between the abundance of secreted exosomes and AD-related biomarkers, the factors and stimuli that regulate exosome biogenesis and secretion are not completely understood. To address the role of exosomes in initiation and propagation of AD-related pathologies, this FOA invites applications designed to identify and characterize the regulation of molecular machines that are responsible for the recruitment of exosomal cargo proteins and exosome biogenesis in AD.
Areas of research interest include but are not limited to:
- Identification of key molecular machines or chemical modifications that are required for the recruitment and secretion of exosomal cargo molecules.
- Functional annotation of cellular and biochemical pathways that are specifically associated with the exosomal cargo molecules’ selection, packaging and secretion, including the role of glial and non-neuronal cells in spreading of pathological aggregates in AD.
- Identification of potential ligands and receptors involved in modulating the uptake and propagation of exosomal cargo molecules on the recipient cells.
- Processing and function of exosomal cargo molecules in recipient cells, including initiation of AD pathological processes.
- Use of bioinformatics and “omics” approaches to define the minimal requirements for the classification and reporting of exosomal marker molecules as potential biomarkers for AD and other age-related degenerative diseases.
- Development and implementation of novel or existing methodologies and high throughput systems to rapidly enrich exosomes from various biological fluids.
- Development of new in vitro and in vivo models to address the role of exosomes in propagation of early AD pathologies.
Criteria for non-responsive applications:
Applications that propose only to establish a database of exosome cargo molecules from various tissues or biological fluids without any mechanistic or functional validation will be considered non-responsive and will not be reviewed.
