McLean Hospital 115 Mill Street Belmont, MA 02478
Kwang-Soo Kim, PhD, has over 25 years of experience investigating molecular and developmental neurobiology of the midbrain dopamine neuronal system in health and disease, focusing on elucidating the mechanisms underlying development and maintenance of dopamine neurons. His recent research focuses on identification and validation of potential molecular targets for novel neuroprotective and mechanism-based therapeutics for Parkinson’s disease (PD) and other neurodegenerative diseases. Promising compounds are being generated by medicinal chemistry and tested in preclinical models.
Dr. Kim’s lab also investigates personalized cell therapy of PD and is optimizing reprogramming and differentiation methods. His lab has pioneered the generation of safe iPS cells by direct delivery of reprogrammed proteins and demonstrated that these protein-based iPS cells can efficiently generate functional dopamine neurons and improve motor deficits in animal models of PD. Dr. Kim is the recipient of several awards, including two NARSAD Independent Research Awards and the NIH Director’s RO1 Award.
Dr. Kim’s Molecular Neurobiology Laboratory, founded in 1998, studies the biology of brain cells that rely on the brain chemical dopamine to communicate. Major brain disorders such as Parkinson’s disease, ADHD, and schizophrenia are related to abnormalities affecting these cells.
Parkinson’s, Alzheimer’s, and autoimmune diseases involve damage to specific cell types. Dr. Kim and his group work to identify the defective components from these cells—like the protein Nurr1, which is critical for dopamine neurons and inflammation—in order to understand and reverse the damage. This transcription factor appears to be key to the loss of A9 subtype dopamine neurons of the substantia nigra in Parkinson’s disease (PD). Nurr1 represents a potential drug target for associated human disorders, so the lab is exploring promising drug candidates targeting Nurr1 that could potentially slow down PD progression in a mechanism-based and neuroprotective manner.
In addition, Dr. Kim’s lab pioneered the development of safe, patient-specific stem cells using a new technique—a highly promising breakthrough for treating and studying human diseases. Cell replacement therapies require clinically safe stem cells that can be used to generate many (possibly all) types of cells. Most iPS cells have been derived through the use of viral vectors and are not ideal for the study and potential treatment of human diseases. The lab pioneered the generation of safe human iPS cells via the direct delivery of reprogramming proteins. More recently, they identified novel mechanisms underlying the reprogramming process through metabolic control and devised more efficient and safer reprogramming methods. The new iPS cells generated using novel methods may represent biomedically- and clinically-ideal cells, providing potential platforms for studying human disease mechanisms and achieving the long-term goal of personalized cell-replacement therapy.
Dr. Kim’s current research into molecular mechanisms underlying the development and maintenance of the midbrain dopamine neuronal system focuses on identifying and validating potential molecular targets of novel mechanism-based and neuroprotective therapeutics for PD and other neurodegenerative and neuropsychiatric disorders. The lab aims to understand the molecular mechanisms underlying the development and maintenance of dopamine neurons in healthy and diseased brains, including key regulators, transcription factors, and signaling molecules, along with their interactions. These findings should translate into preclinical and clinical applications.
This approach is based on detailed mechanistic studies of the relationship between critical extrinsic signals and intrinsic transcription factors. These studies furthered their understanding of important genetic networks and their functional roles in orchestrating the development and maintenance of dopamine neurons. These investigations yielded useful guidelines for generating functional dopamine neurons from stem cells.
The lab’s research into putative involvement of inflammation pathways in neurodegeneration and other conditions such as autism includes studies focusing on the interaction between the immune system and the brain, with the goal of identifying key regulators of neuroinflammation. Surprisingly, recent studies from many laboratories including their own identified Nurr1 as a key modulator of (neuro)inflammation functioning as a transcriptional repressor for neurotoxic cytokine production. Remarkably, the lab found that small molecules enhancing Nurr1’s function can robustly suppress neuroinflammation and expression of proinflammatory genes in immune cells. Thus, the lab’s approach may hold great promise for potential treatment of (neuro)inflammation-related human diseases both in and outside the central nervous system.
Lee M-O,Moon SH, Jeong H-C, Yi J-Y, Lee T-H, Shim SH, Rhee Y-H, Lee S-H, Oh S-J, Lee M-Y, Han M-J, Cho YS, Chung H-M, Kim K-S, Cha H-J. Inhibition of pluripotent stem cell-derived teratoma formation by small molecules. Proceedings of the National Academy of Sciences of the United States of America 2013;110(35):E3281-90.
Park H, Kim D, Kim C-H, Mills R, Chang M-Y, Iskow RC, Ko S, Moon J-I, Choi HW, Yoo PSM, Do J, Han M-J, Lee EG, Jung JK, Zhang C, Lanza R, Kim KS. Increased genomic integrity of an improved protein-based iPS cell method compared to current viral-induced strategies. Stem Cells Translational Medicine 2014;3:599-609.
Kim C, Han B-S, Moon J, Kim D-J, Shin J, Rajan S, Nguyen QT, Sohn M, Kim W-G, Han M, Jeong I, Kim K-S, Lee E-H, Tu Y, Naffin-Olivos JL, Park C-H, Ringe D, Yoon HS, Petsko GA, Kim KS. Agonists for nuclear receptor Nurr1 enhance its dual functions and improve behavioral deficits in animal models of Parkinson’s disease. Proceedings of the National Academy of Sciences of the United States of America 2015;112(28):8756-61.
Belmont campus - Mailman Research Center, Room 216