Project Summary
Disease modeling with patient-derived induced pluripotent stem cells (iPSCs) enables researchers to observe
the embryonic development, maturation, and aging of any cell type from the patient’s body in a laboratory petri
dish. This novel and powerful technology therefore enables researchers to closely observe the development of
age-related, late onset diseases that affect specific cells in the patient by replaying the molecular events that
occur inside the cells prior to and during the disease. With this knowledge in hand, researchers can then
design therapies based on the molecular dysfunctions implicated in causing the disease. A highly active area
of disease modeling research using iPSC technology is in Amyotrophic Lateral Sclerosis (ALS), a devastating
neurodegenerative disorder characterized by the death of motor neurons, typically occurring in late adulthood,
for which there is no cure and patients face an average of three years of life remaining. However, a major
challenge currently facing this field is that the motor neurons grown from iPSCs in the petri dish are molecularly
more similar to immature embryonic cells rather than to mature and aged adult cells. Since ALS causes the
death of adult rather than embryonic motor neurons, a necessary goal is to generate mature and aged motor
neurons to study in the dish. By integrating comparative genomic, transcriptomic, and proteomic approaches
proposed in this application, we aim to identify the molecular roadblocks regulating the path to the mature
motor neuron state. First, we will employ a comparative medicine approach between mouse and human cells
to find common and distinct genes and expression networks regulating motor neuron development, maturation,
aging, and ALS-induced degeneration. This comparison serves to capture essential maturation and aging
pathways in the mouse that can hypothetically be enacted and accelerated in human cells. Second, we will
employ a single cell RNA-sequencing and proteomic approach to deeply and sensitively detect populations of
mature motor neurons vulnerable to ALS. Lastly, we will integrate our data to predict and experimentally
validate regulatory factors controlling key gene expression networks in iPSC-derived motor neurons. By
understanding the cellular systems controlling the maturation and aging processes, we can then develop
strategies to accelerate motor neuron maturation and aging in the dish, and thereby faithfully reproduce the
late onset molecular events leading to the degeneration of motor neurons in ALS.