Post-mitotic cells such as neurons must strictly regulate the pathway of apoptosis because these cells have limited regenerative potential and must survive for the lifetime of the organism. Understanding the molecular mechanisms of apoptosis, or programmed cell death, in neurons has enormous clinical significance due to the wide range of diseases which result from aberrant apoptotic regulation. For example, excessive activation of neuronal apoptosis is seen in neurodegenerative diseases and after stroke. On the other hand, evasion of cell death is a hallmark of cancer. In order to understand the pathogenesis of these diseases and to develop new therapeutics, it is crucial that we understand the molecular mechanisms of how neurons choose to live or die. The long-term objectives of this project are to further the understanding of changes that occur in the regulation of apoptosis in the maturing sympathetic nervous system. Consistent with their need for long-term survival, we find that sympathetic neurons utilize an increasing number of mechanisms to prevent unwanted activation of the apoptotic pathway as they mature. Using microarrays, I have identified changes in microRNA (miRNA) expression that correlate with changes in apoptotic restriction as sympathetic neurons mature. I hypothesize that these changes in miRNA expression have an important role in regulating the ability of these cells to survive cellular stresses.
The specific aims of this proposal are two-fold: 1) to determine how one miRNA, which is upregulated during neuronal maturation, is able to protect neurons from apoptotic stimuli, and 2) to determine if downregulation of the miRNA biogenesis machinery has a role in protecting mature neurons from apoptosis.
Neurons inappropriately die in many neurological diseases, leading to subsequent disability or death of patients. The experiments proposed in this grant will help explain how neurons are normally able to survive for an organism's lifetime and may shed light on how this process malfunctions when cells die. This information could lead to new therapies for preventing unwanted neuronal death seen in neurodegenerative disease or as a result of stroke.
|Kole, A J; Annis, R P; Deshmukh, M (2013) Mature neurons: equipped for survival. Cell Death Dis 4:e689|
|Kole, Adam J; Knight, Elizabeth R W; Deshmukh, Mohanish (2011) Activation of apoptosis by cytoplasmic microinjection of cytochrome c. J Vis Exp :|
|Kole, Adam J; Swahari, Vijay; Hammond, Scott M et al. (2011) miR-29b is activated during neuronal maturation and targets BH3-only genes to restrict apoptosis. Genes Dev 25:125-30|