# Systematic study of extracellular vesicles and their integrative analysis with Parkinson's organoids MAP

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $738,375

## Abstract

PROJECT SUMMARY AND ABSTRACT
Parkinson's disease (PD) is the most common neurological disease associated with movement abnormality. It has been 25
years since the first genetic cause of PD was identified, and yet there is still no effective treatment for the disease. One of
the hinders we think is the lack of models that assess early PD pathogenesis and therapy responses in its real
neurophysiological environment. This provides a significant bottleneck in our ability to make progress in this disease.
Two lines of recent evidence motivate us to study PD pathogenesis in a real neurophysiological environment: (1) Human
neuroimaging data and animal models both showed that synaptic disruption proceeds neuronal death, making the case
that PD is a synaptopathy. (2) Many novel, regulatory, non-coding RNAs show linkage to PD pathogenesis. For instance,
we found over 20,000 enhancer RNAs (or eRNAs) candidates in dopamine neurons of human post-mortem brains (Dong et
al. Nature Neuroscience, 2018). They significantly co-localized with PD risk variants. The other class of novel RNAs is
circular RNAs (circRNAs), which are predominantly enriched in the brain, highly specific to the synapse, and ultra-stable
(e.g., 10x longer half-life than linear RNAs). We identified >11,000 circRNAs actively expressed in the dopamine neurons,
many of which are significantly associated with PD pathology (Dong et al. in submission). More importantly, circRNAs can
form a regulatory network with lncRNAs and miRNAs, and can be wrapped into extracellular vesicles (EV), penetrating
blood-brain barriers. Based on these, we hypothesize that regulatory RNAs incl. circRNAs, eRNAs, miRNAs, lncRNAs
can be detected in EV and might play a role in the synaptic dysfunction in PD pathogenesis.
To test this hypothesis, we need a model to recapitulate the dynamic physiological microenvironment of PD pathogenesis.
In this study, we will combine our expertise in brain organoids, PD biology, exosome analysis, single-cell omics,
bioinformatics, and biomedical engineering to develop a new 3D brain organoids microphysiological analysis platform
(MAP) to recapitulate the dopamine neurons' interconnectivity and study molecular neurodegeneration
systematically. We will (1) first develop PD organoids and profile the transcriptome (incl. circRNAs, miRNAs, mRNAs,
lncRNAs, etc.) of secreted EV and single-cell transcriptome of brain organoids, to identify PD-associated RNAs, then (2)
map the pathophysiological dynamics of PD organoids in a novel, high-throughput, mini-brain-on-chip platform, and last
will (3) integrate the EV-organoid temporal multi-dimensional data to infer the PD-associated RNAs and their regulatory
dynamics during the PD pathogenesis.
Recent breakthroughs in RNA therapeutics have led to multiple first-in-human trials and clinical approval (e.g., Moderna,
Alnylam, and Ionis pharmaceuticals). circRNAs have many advantages over linear RNAs, making them potentially better
suited for translation...

## Key facts

- **NIH application ID:** 10345089
- **Project number:** 1R01NS124916-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Xianjun Dong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $738,375
- **Award type:** 1
- **Project period:** 2022-04-15 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10345089

## Citation

> US National Institutes of Health, RePORTER application 10345089, Systematic study of extracellular vesicles and their integrative analysis with Parkinson's organoids MAP (1R01NS124916-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10345089. Licensed CC0.

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