Licit and illicit drug use places a large burden on the nation's health care systems and
the economy, costing more than $500 billion annually. Addiction is a chronic brain
disease that leads to a compulsive desire for drugs despite significantly harmful
consequences, including direct effects on health as well as detriments to society,
including disintegration of families, child abuse, loss of employment, and a broad array
of crimes. Reprogramming of human somatic cells to alter cellular identity has enormous
potential for neurological disease modeling, high-throughput drug screening, cell therapy,
and personalized medicine. However, several challenges remain before patient-specific
cells produced by reprogramming can provide reliable insights into neurological disease
mechanisms (e.g., Drug abuse/ addiction, other neurological disorders) or be efficiently
applied to drug discovery and transplantation therapy. Using our innovative patented
technology to develop Artificial 3D Microenvironment Niche and screen for
reprogramming small molecules (US Patent # 9045737), we have developed a
preliminary small molecule cocktail that efficiently (up to 50% of starting cell numbers,
mostly Glutamatergic Neurons) and directly converts human fibroblasts into neurons,
bypassing the neural progenitor stage (Chemically induced Neurons, hCiN). In this
Phase I proposal, we attempt to demonstrate the feasibility of this methodology by
optimizing our preliminary hCiN cocktails while investigating hCiN functionally with
molecular, cellular, electrophysiological assays and in a mouse brain transplantation
model.