Disease Type

Cancer researchers are focusing their efforts on identifying central pathways that trigger or enhance the invasiveness of tumor cells. One such target is EMMPRIN (Extracellular Matrix Metalloproteinase Inducer). It has been shown that EMMPRIN expression is linked to various cell signaling pathways that lead to an increase in tumor cell vascularization. Researchers are focusing efforts on elucidating the role of EMMPRIN in a number of disorders including cancer, arthritis, tissue repair and numerous inflammation-dependent diseases. DESCRIPTION/DETAILS Basigin is a member of the immunoglobulin superfamily thatis also known as EMMPRIN. Human basigin is expressed as two differentiallyspliced isoforms encoded by a single gene found on chromosome, renamedrespectively as basigin-1 and basigin-2. Attempts to demonstrate specifichemophilic on separate cells, or between soluble forms of recombinant basiginusing surface Plasmon resonance have not been successful, suggesting thatbasigin-2 cannot function as a receptor for itself. In order to identify possible receptors for soluble basiginligand, an affinity purification approach was employed. This approach resulted inthe labeling of several potential interacting proteins, and MALDI MS/MSsequencing of one of these proteins identified a novel isoform of human basigin(basigin-3).

Immunoprecipitation studies using cell fractions revealed thatrBSG interacts with basigin-2 at the cell membrane, and subsequently interactswith the basigin-3 isoform within the cell. Small-interfering RNA (siRNA)knockdown of basigin-2 protein reduced, but did not eliminate, rBSG-mediatedERK activation in HESCs, suggesting that additional cell surface receptors forsoluble basigin may exist. Taken together, these results support the hypothesisthat basigin-2 can function as a receptor for soluble basigin and demonstratethat the hemophilic interactions between basigin proteins are not dependentupon glycosylation of the basigin ligand. It has also been shown that soluble EMMPRIN binds tomembrane-bound EMMPRIN and the bound complex is internalized presenting apotential means to deliver therapeutic compounds to the cell in a highlytargeted manner. A therapeutic scheme isproposed that aims to design EMMPRIN-conjugates designed to deliver cancertherapeutics in a targeted fashion.

Applications

Conjugation oftherapeutics to EMMPRIN increases specificity and targets cancers cells cancer (skin, bladder,breast); other inflammatory diseases (arthritis, endometriosis); Upregulationof inflammatory response.

Benefits

It is possible to design therapeutic agents directed toward human basigin. Possible therapeutic scheme to block tumor progressionor inflammation.

This invention allows the engineering of semi-synthetic lantibiotics to a much larger extent than using typically practiced in vivo methods. The method is the first in vitro reconstruction lantibiotic photosynthesis and introduces non-proteinogenic amino acids.

Lantibiotics are peptide-based compounds produced by bacteria that live on lactic acid. They are used as natural antibiotic food preservatives as an alternative to chemical reagents and have been used for half a century without any significant signs of lantibiotic-resistant bacteria popping up.

Researchers at the University of Illinois have isolated and purified the LctM enzyme, responsible for synthesis of lacticin 481. This approach, the first in vitro reconstruction of lantibiotic biosynthesis, allows for lantibiotic engineering and opens the door to possible generations of new lantibiotics with greatly increased yields and improved activities.

Applications 

• Food preservation
• Industrial enzyme production
• Bioengineering of novel lantibiotics

Benefits

• Greater Production Flexibility: In vitro methodology allows for lacticin 481 production using semi-synthetic substrates.
• Avoids Complications of In Vivo Production: In vitro methods avoid product cytotoxicity, degradation and bypasses many of the In vivo regualtory complications.
• Better Resistance Profile: Lantibiotics have been used for half a century in more than 40 countries without any significant signs of lantibiotic-resistant bacteria appearing.
• More Possibilities: The method works well with combinatorial techniques, increasing the number of substrates that can be used in production of lacticin 481. In addition, isolation of the LctM enzyme allows for more efficient synthesis with greater structural and functional tolerance of the biosynthetic pathway. 

Phosphonic and phosphinic acids are bioreactive compounds that have been used as antibiotics, antifungal agents, antimalarial drugs, and herbicides. Rhizocticins are naturally occurring phosphonates produced by Bacillus subtilus that have antifungal properties and interfere with the biosynthesis of the amino acid threonine. By varying the N-terminal amino acid group in the rhizocticin compound, it is possible to alter its biological activity. In particular, oligopeptides that are created by varying this amino acid could potentially allow enhanced capability for controlling selectivity for targeting particular organisms. As a result, compounds are less toxic to the host species and hold more promise for creating therapeutics. Despite the potential for making these types of compounds, organic synthesis has never been achieved due largely in part to the fact that the biosynthetic pathway has not been well understood. University of Illinois scientists have now identified the gene cluster responsible for biosynthesis of rhizocticin in B. subtilis, making biosynthesis of rhizocticin compounds possible.

Details

Original attempts to isolate and identify this unquie cluster failed, however, the genome of a specific strain of B. subtilis was sequenced and open reading frame locations were determined and annotated. Upon comparison with a non-rhizocticin-producing strain of B. subtilis, the rhizocticin biosynthetic gene cluster was able to be identified and isolated. There are more than 10 genes in the B. subtilis rhizocticin cluster. The biosynthetic pathway was proposed using sequence homology (similarity) for each of the genes. One particular gene in the cluster was identified by the inventors as being unique to this biosynthetic pathway. The cluster responsible for rhizocticin was verified by successfully inserting it into a non-producing strain of B. subtilis.

Applications

• Pharmaceutical industry: Synthesis of biologically active compounds and analogs of rhizocticin.
• Production of novel oligopeptides with therapeutic properties
• Agricultural industry: Herbicide

Benefits

The identification of specific gene cluster for biosynthesis of rhizocticin allows:

• Specific synthesis of compounds;
• Control of biological activity of compounds; and
• Control of compound toxicity in mammals

Researchers from the University of Illinois have developed a new synthetic tissue microenvironment that may give cancer researchers the next-best look at tumor growth and behavior. The 3D patterned vasculature tumor microenvironment is created by changing the flow rates of fluid channels and the structures are made of alginate that was mixed with breast cancer cells in the outer layer and macrophages on the inner layer. The 3D vascularization, a network of capillaries that carry drugs and other materials are created can go from straight, to snakelike, to any shape, that offers modelling for metastasis, because the vessel architecture can be tuned on the fly. 

The technology accurately predicted the clinically measured EC50 of three drugs: Gefitinib, zoledronic acid, and RAC inhibitor. This quick process to create synthetic tumor microenvironments lends to tremendous potential such as model systems for high-throughput screening for drug efficacy, as well as flowable and vascularized lab-on-a-fiber platforms. Finally, biopsied cancer cells lends to personalized cancer treatments with this device that could realistically and quickly recreate microenvironments found across biology.