Professor Emeritus of Biological Sciences
PhD, 1982 Rice University
Stem cell biology and therapies for neurodegeneration and brain tumors
Research descriptionOur overall goals are to study the derivation of neural stem cells from mouse embryonic stem cells and regulation of the vertebrate neural stem cell (NSC) niche, and to develop stem cell therapies to treat neurodegenerative diseases.
We have developed a novel NSC culture system, starting with mouse embryonic stem (ES) cells. This system displays elements of a NSC niche in the absence of exogenously applied mitogens or complex physical scaffolding. Mouse ES cells are neuralized with retinoic acid and plated on a coated glass surface at high density. Six to eight days after plating complex, multi-cellular structures consisting of heterogeneous cell types develop spontaneously. Neural stem and progenitor cell proliferation and differentiation continue within these structures. The identity of cellular and molecular components within the cultures was documented using RT-PCR, immunocytochemistry and neurosphere forming assays. We have shown that embryonic stem cells can be induced to form structures that exhibit key properties of a developing neural stem cell niche. We believe this system can serve as a useful model for studies of neurogenesis and regulation of stem cell activity in the NSC niche as well as for applications in stem cell transplantation.
In a second study, we focus on a class of hereditary diseases called the neuronal ceroid-lipofuscinoses (NCLs; often grouped together under the name Batten Disease). The NCLs are a group of autosomal, recessively inherited, progressive neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigment in various tissues, including the retina and CNS. Children with NCLs are normal at birth but undergo progressive brain and retinal atrophy, and patients with early onset forms of NCL seldom survive past their teenage years. Of the genes responsible for NCLs, Cln1, Cln2, Cln3, Cln5, Cln6 and Cln8 have been cloned and characterized to some extent.
We are working on two mouse models of NCLs that exhibit degeneration of the neural retina, brain and spinal cord, one with a mutation in Cln1 and one with a mutation in Cln8. We are testing whether transplanted stem cells will (1) become integrated into the degenerating nervous system as differentiated neurons and glia, (2) remain integrated within the retina indefinitely and (3) secrete normal forms of the Cln proteins and in the case of Cln1, transfer the normal protein to neighboring mutant cells or secrete growth factors that produce neurotrophic effects on host cells. This approach provides a potential "cure" for host cells and may prevent neurodegeneration. At present there are no effective therapies for any of the NCLs. Our research will provide important new information about the use of stem cells in potential treatments for the NCLs. Our hope is that NCLs and other neurodegenerative diseases will become treatable using a combination of gene and stem cell therapies.
In a third project, we are developing stem cell therapies for brain tumors. The above studies are performed in collaborations with Dr. Martin Katz (Department of Ophthalmology, MU), Dr. Joel Maruniak (Division Biological Sciences, MU), and Drs. Scott Litofsky and Douglas Miller (Dept. of Pahtology & Anatomical Sci., MU).
Tracy CJ, Sanders DN, Bryan JN, Jensen CA, Castaner LJ, Kirk MD, Katz ML. (2016) Intravitreal implantation of genetically modified autologous bone marrow-derived stem cells for treating retinal disorders. Advances in Experimental Medicine and Biology, 85: 571-577.
Lee EJ, Rath P, Liu J, Ryu D, Pei L, Noonepalle SK, Shull AY, Feng Q, Litofsky NS, Miller DC et al. (2015) Identification of global DNA methylation signatures in glioblastoma-derived cancer stem cells. Journal of Genetics and Genomics, 42(7):355-371.
Tullis GE, Spears K, Kirk MD. (2014) Immunological barriers to stem cell therapy in the central nervous system. Stem Cells International. Vol. 2014, Article ID 507905, 12 pages, doi:10.1155/2014/507905
Zhao M, Whyte JJ, Hopkins GM, Kirk MD, Prather RS. (2014) Methylated DNA immunoprecipitation and high-throughput sequencing (MeDIP-seq) by using low amounts of genomic DNA. Cellular Reprogramming. 16(3): 175-184
Dunham C, Kirk MD. (2013) Neuralized mouse embryonic stem cells develop neural rosette-like structures in response to retinoic acid and produce teratomas in the brains of syngeneic mice. Advances in Life Sciences. 6(4): 1-14.
Honors & Awards
Selected honors and awards
Excellence in Advising Award 2014
Program Director, NSF, Biology Directorate, Division of Integrative Organismal Systems, Neural Systems Cluster 2009
AAAS Science and Technology Policy Fellow, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Office of Science Policy and Communications 2008
Purple Chalk Award for Excellence in Teaching 2000
Outstanding Greek Faculty Teaching Award 1997