Causal Mapping of Enhancer-Gene Networks in Parkinson’s Disease via Single-Cell Perturb-Seq and AI

Study Rationale:                         

Most of our DNA does not contain genes but instead acts like a complex switchboard that controls when and where genes are turned on or off. In Parkinson's disease (PD), many genetic risk factors are located in these "switch" regions, but we don't understand how they cause brain cells to malfunction. This project will systematically test thousands of these DNA switches to create the first functional map of the genetic wiring that goes wrong in PD.

Hypothesis:

We believe that specific DNA "switches" (enhancers) become faulty in Parkinson's disease, activating harmful genetic programs in brain cells, and that by systematically turning them off, we can identify the critical switches that drive the disease.

Study Design:

We will use human induced stem cells to grow different types of brain cells in a dish. Using a technology called CRISPR, we will turn off thousands of different DNA "switches" in millions of these cells. We will then read the gene activity in each cell to see what happens when a specific switch is turned off. Finally, a powerful AI computer model will analyze this information to learn the rules and build a complete map of the brain's genetic wiring in PD.

Impact on Diagnosis/Treatment of Parkinson’s disease:                    

This project will create a detailed roadmap of the faulty genetic wiring that contributes to Parkinson's disease. This map can reveal the most critical switches and genes that drive the disease, identifying entirely new targets for drugs designed to slow or stop its progression.

Next Steps for Development:

If our study successfully identifies a critical "faulty switch," the next step would be to develop and test drugs that can specifically correct its function. These potential new therapies would then be validated in advanced disease models before any consideration for human clinical trials.