Research

Research

LRP - Hussaini LabASTROCYTOMA INVASIVE GROWTH

The research in my laboratory is centered on understanding the basic cellular mechanisms involved in astrocytoma invasive growth . The prognosis for patients with malignant astrocytomas tumors (brain tumors) is poor. The capacity of astrocytomas both to invade adjacent brain sites and to migrate to distant ones precludes curative surgical resection; and little progress has been made indesigning adjuvant therapies that significantly affect long-term patient survival. In order to formulate more novel therapeutic strategies, it is essential to have a better understanding of how the invasive growth of these tumors is controlled.

The primary interest of the laboratory isthe regulation of LRP (lowdensity lipoprotein receptor-related protein) expression and function in astrocytic tumor cells. LRP isan endocytic receptor involved in the trafficking of a variety ofprotein/protein complexes{including urokinase (uPA) and its receptor(uPAR), Lipoprotein metabolites, and activated alpha2-macroglobulin} that has patho- physiologic relevance in the central nervous system tumors. Alteration in LRP expression regulates the levels of modulators (uPA, uPAR and PAI-1) of migration/invasion aroundthe microenvironment of astrocytic tumors (Fundedby National Institute of Neurological Disorders and Stroke, NIH from 1997-2008).

The second project in my laboratory focuses on understanding differences in PKC-eta activation and expression between malignant vs. non-neoplastic astrocytes and on the role of PKC-eta in the control of cell proliferation and apop- tosis. The regulation of cell proliferation and apoptosis in malignant astrocytic tumors is undoubtedly complex; however, we are investigating how PKC-eta regulation of these processes may be exploited to provide an experimental system in which proliferative or apoptotic phenotype may be selectively induced and studied. We are also extrapolating some of our results in cultured cells to xenograft glioblastoma animal models in collaboration with Dr. Mark Shaffrey (Departmentof Neurological Surgery).

We hypothesize that pharmacological regulation of PKC-eta, in combination with drugs targeting cellular migration, maypresenta newtherapeutic paradigm for these aggressive brain tumors (Funded by National Cancer Institute, NIH from 2002-2007).

Techniques used in the Lab include, western and Northern blot analyses, immunocytochemistry, RT-PCR, thymidine incorporation, transwell invasion assay and zymography. The lab has recently silenced seven different proteins (LRP, uPA, PKCeta, PKCalpha, PKCbeta, PKCdelta and PKCzeta) using siRNA and cDNA antisense constructs.