The ubiquitous anatomical position of the endothelium, as a quiescent population of several cell types, highlights its role as the initiator and coordinator of neovascularization occurring normally during development and wound (fracture) repair. In contrast, prominent pathological angiogenic events associated with ischemia and hypertrophy, including AIDS-associated Kaposi's sarcoma (KS), are characterized by invading, proliferating mesenchymal cells representing molecular factories delivering gene products involved in responding biological cascade mechanisms. Even though these angiopathic events involve a complementary interaction between inflammation and angiogenesis, the molecular basis for initiating and sustaining this response has eluded investigators. Mounting experimental evidence suggests that during AIDS-KS, the Tat protein, released from HIV-1 infected immune cells, may be a selective transcriptional activator of eukaryotic genes in target cells that function to initiate, sustain and perpetuate proliferative processes associated with tumorigenesis. The heparin binding growth factor (HBGF) family of polypeptides has gained general acceptance as initiators of angiogenesis and function as potent mitogens for mesoderm- derived cells in vitro. Extracellular presentation of HBGF in vivo functions as a hormonal inducer of complex neovascular organoid structure formation. It is the premise of this investigator that Tat transforms myofibroblasts into characteristic """"""""spindle cells"""""""" by transactivating expression and extracellular presentation of HBGF, which functions to sustain proliferative lesions associated with KS. This project will evaluate this proposed biological relationship between Tat and HBGF in Tat transgenic animals using a vascular implant model as a potential window to the pathology of angiogenesis. This model further permits the selective transplantation of myofibroblasts, transduced (retrovirally) with Tat, to experimentally perturb and modulate a localized, site-specific biological process. Northern and Western analysis of Tat-responsive events in cultured, transduced myofibroblasts will define specific DNA/antibody probes useful for in situ analyses or mRNA and protein expression both in Tat transgenics and transplanted cells. The recognition of defined gene expression events both in vitro and in vivo will allow a distinction of changes caused by pathological stimuli from those imposed by culture conditions. While the precise involvement of growth factors/cytokines are not known, the cumulative resources, reagents and techniques within this application may elucidate molecular mechanisms responding to Tat that underlie angiopathic events associated with KS. Fundamental mechanistic studies of Tat-induced processes will permit a more rational design of therapeutic intervention strategies.
| Walter, M A; Kurouglu, R; Caulfield, J B et al. (1993) Enhanced peripheral nerve regeneration by acidic fibroblast growth factor. Lymphokine Cytokine Res 12:135-41 |
