Donghe Yang, PhD

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Investigator Bio:

Dr. Donghe Yang is a postdoctoral fellow in Dr. Lorenz Studer’s laboratory at Memorial Sloan Kettering Cancer Center in New York. His research focuses on leveraging cutting-edge genetic, human pluripotent stem cell (hPSC), and single-cell sequencing technologies to understand, model, and potentially treat neurodegenerative disorders such as Parkinson’s disease (PD). Dr. Yang received his PhD in 2022 from the University of Toronto in Canada under the mentorship of Dr. Gordon Keller. His PhD research focused on mapping evolutionarily conserved embryonic cardiac programs using hPSCs and single-cell transcriptomics. His work has garnered multiple awards, peer-reviewed articles, and patents.  

Currently, Dr. Yang’s postdoctoral research aims to dissect the development of midbrain dopaminergic neuron (mDA) subtypes, with a particular focus on generating the A9 mDA subtype, which is responsible for motor control and most susceptible to degeneration in PD patients. This work aims to understand the molecular drivers underlying mDA subtype development, provide the first comprehensive single-cell multi-omics roadmap of mDA subtype development, and establish robust methods for generating these neurons. This will pave the way for generating A9 mDA neurons to model PD in vitro and developing novel cell replacement therapies to cure PD. 

Objective:

Our aim is to identify and manipulate the key processes that lead to the development of A9 mDA neurons, enabling us to generate this specific neuron subtype from hPSCs. 

Background:

The mDA neuron system is essential for movement control and behavior, consisting of various neuronal subtypes. In PD, the A9 subtype is particularly susceptible to degeneration. The loss of A9 mDA neurons and their connections to the dorsolateral striatum leads to the typical motor deficits seen in PD. Although significant progress has been made in generating clinically suitable mDA neurons from hPSCs, current cell replacement therapies use heterogeneous and insufficiently characterized cell populations. Methods to selectively derive the A9 mDA subtype remain elusive but are crucial for advancing next-generation cell replacement therapies and accurate human PD models. This study will investigate the genetic and biochemical changes during mDA neuron subtype development.

Methods/Design:

The proposed study involves using single-cell transcriptomic and epigenetic analyses to examine the molecular profiles of mDA neuron populations generated from hPSCs. Additionally, we will employ CRISPR/Cas9 genetic screening to identify factors influencing the specification and development of mDA neuron subtypes. To assess the functional properties of these neurons, we will conduct electrophysiological and biochemical assays. Finally, we will evaluate the therapeutic efficacy of A9-enriched neuron grafts by transplanting them into rat models of PD and observing their effects on motor function. This comprehensive approach aims to advance our understanding of A9 mDA neuron development and contribute to improved strategies for treating PD.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:

The proposed study addresses a significant gap in the ability to generate A9 mDA neurons from hPSCs, which is critical for developing precise models and therapies for PD. Currently, the lack of robust methods to generate specific mDA subtypes impedes progress in treating PD with cell-replacement therapies. The findings from this study will enable PD-related research that was previously not possible. We will be able to examine the effectiveness of A9-like cells in PD models in restoring motor functions, serving as a proof of principle for future clinical studies. Additionally, this work sets the stage for exploring why A9 neurons are particularly susceptible to PD, potentially leading to new insights into understanding and preventing PD development, as well as developing therapeutic strategies for affected individuals.