Research Bio
During development of the nervous system, as many as half of all neurons generated are ultimately eliminated by a process known as programmed cell death. Much of this cell death occurs as newly differentiated neurons compete for limiting amounts of survival-promoting 'neurotrophic' factors. Though counterintuitive, the selective death of neurons at specific times during development is critical for sculpting a properly wired nervous system. While programmed cell death is essential for normal development, too much or too little cell death later in life is a confounding factor in diseases ranging from Alzheimer's disease and stroke to brain cancer. Research in the Freeman laboratory is aimed at characterizing the mechanisms that regulate cell death in the mammalian nervous system. More specifically, we aim to identify and understand the critical cell signaling events that, if left unchecked, commit a neuron to die.
Our basic approach involves comparing gene expression and protein function in neurons before and after exposure to a death-inducing stimulus. For example, to study programmed cell death during development, we use a model in which neurons are deprived of the neurotrophic factor nerve growth factor. Using this model, we have discovered new roles during cell death for two proline-modifying enzymes, the prolyl hydroxylase EGLN3 and the peptidyl-prolyl isomerase PIN1. Using techniques and approaches from cell and molecular biology, genetics, and biochemistry, we are (1) determining the effects of knocking out these proteins on cell death during development and disease, (2) identifying their biochemical targets and substrates, and (3) characterizing the pathways that regulate their function in dying neurons.
A second interest of the laboratory concerns the mechanisms by which oxygen availability regulates the survival of developing neurons. Prenatal or perinatal hypoxia and hypoxia-ischemia are important causes of neonatal brain injury and abnormal brain development. To better understand these processes, we are investigating the regulation and function of the hypoxia-inducible factor (HIF) family of transcription factors in neurons exposed to different oxygen tensions. Ultimately, our research efforts are driven by the prospect that the mechanisms we uncover may ultimately contribute to the development of new therapies for cell death-related diseases and disorders of the nervous system.
2012 May
Fernandes KA, Harder JM, Fornarola LB, Freeman RS, Clark AF, Pang IH, John SW, Libby RT. "JNK2 and JNK3 are major regulators of axonal injury-induced retinal ganglion cell death." Neurobiology of disease. 2012 May; 46(2):393-401. Epub 2012 Feb 14. |
2011
Guo H, Barrett TM, Zhong Z, Fernandez JA, Griffin JH, Freeman RS, Zlokovic BV. "Protein S blocks the extrinsic apoptotic cascade in tissue plasminogen activator/N-methyl D-aspartate-treated neurons via Tyro3-Akt-FKHRL1 signaling pathway." Molecular neurodegeneration. 2011 6:13. Epub 2011 Feb 03. |
2010 Nov 17
Zhong Z, Wang Y, Guo H, Sagare A, Fernández JA, Bell RD, Barrett TM, Griffin JH, Freeman RS, Zlokovic BV. "Protein S protects neurons from excitotoxic injury by activating the TAM receptor Tyro3-phosphatidylinositol 3-kinase-Akt pathway through its sex hormone-binding globulin-like region." The Journal of neuroscience : the official journal of the Society for Neuroscience. 2010 Nov 17; 30(46):15521-34. |
2009 May
Lomb DJ, Desouza LA, Franklin JL, Freeman RS. "Prolyl hydroxylase inhibitors depend on extracellular glucose and hypoxia-inducible factor (HIF)-2alpha to inhibit cell death caused by nerve growth factor (NGF) deprivation: evidence that HIF-2alpha has a role in NGF-promoted survival of sympathetic neurons." Molecular pharmacology. 2009 May; 75(5):1198-209. Epub 2009 Feb 09. |
2009 Apr 23
Guo Y, Schoell MC, Freeman RS. "The von Hippel-Lindau protein sensitizes renal carcinoma cells to apoptotic stimuli through stabilization of BIM(EL)." Oncogene. 2009 Apr 23; 28(16):1864-74. Epub 2009 Mar 23. |
