Secondary Research / Clinical / Teaching Interests
Keyword: HIV associated dementia and neuroprotection

Details:  Role of IGF-I, and Tumor Necrosis Factor a (TNFa) in HIV associated dementia. In a substantial number of AIDS patients HIV infection results in a serious neurological disorder of the central nervous system, HIV–associated dementia (HAD). Currently, there is no specific treatment for HAD, mainly because of an incomplete understanding of how HIV infection causes neuronal injury and apoptosis. The predominant pathogenesis of HAD is believed to involve activation of macrophages and microglia and their subsequent release of toxins that lead to neuronal and astrocytic dysfunction. Activation of the insulin-like growth factor I receptor (IGF-IR) represents a strong neuro-protective mechanism against a wide variety of insults. A unique aspect of this protection comes from recent discoveries showing that three independent anti-apoptotic pathways can be initiated from the activated receptor: (i) PI3-kinase mediated activation of Akt; (ii) IRS-1 recruitment to the tyrosine 950 of the IGF-IR ß-subunit; and (iii) Raf translocation to the mitochondrial compartment. We are presently testing our working hypothesis that neurotoxic effects of TNFa can be counteracted by the reactivation of the IGF-I system in the affected neurons. The protective mechanisms involve activation of multiple antiapoptotic signals from the IGF-IR, and a switch from pro-apoptotic (recruitment of procaspase 8) to anti-apoptotic (translocation of NFkB to the nucleus). Therefore, our future task in this project is to determine molecular pathways involved in the cross-talk between IGF-I and TNFa receptors in the cells of the Central Nervous System.