Modern molecular medicine encompasses the utilization of molecular and cell biology techniques to the study of human disease in order to produce a new understanding of the molecular basis of biology and diseases. Implementation of this new understanding will create the basis for novel diagnostics and therapeutics as well as new prevention and intervention strategies in many public health problems. Molecular level understanding of diseases will have to rely on molecular probes to recognize the molecules of interest. Out of the many potential molecular probes, a new class of designer nucleic acid molecules (called aptamers) holds great potential in elucidating molecular mechanisms of diseases and in being used for the molecular recognition in bioanalysis of many important biomolecules. Aptamers have their own advantages in low molecular weight, easy and reproducible synthesis, easy to use and fast tissue penetration. They can be selected for single proteins and even small molecules such as amino acids. Recently, we have developed a novel cell based aptamer selection (Cell-SELEX) technique to generate a group of aptamers for the specific recognition of individual cells without prior knowledge of the potential biomarkers for the cells. The subtraction selection process is simple, straightforward and reproducible. The aptamers can bind to target cells with Kd in the nM to pM range. These newly selected molecular probes will provide us unique opportunities in disease early diagnosis, targeted drug therapy and biomarker discovery. To this end, we will pursue the selection of aptamers for small cell lung cancer, leukemia cells and other cells such as Pancreatic Beta cells and liver cancer cells, each of which currently possesses great challenges to conventional means of detection, biomarker development, and targeted therapy. Once the aptamers for these cell lines have been selected, each aptamer will be enabled by the bioanalytical tools (biosensors, molecular imaging and molecular engineering) well developed in our labs before applied to different aims in medical research. We will concentrate on four potential applications in exploring the wide utility of the aptamers directly selected from cells: cancer early diagnosis with small cell lung cancer, targeted therapy with aptamer conjugated drugs, biomarker discovery and molecular profiling. Once completed this proposal will not only show that cell based aptamer selection can be widely applicable to various types of cells to generate effective molecular probes for specific recognition, but we will be able to convincingly demonstrate the advantages of using cell based aptamers for medical and technical difficulties that current methodologies fail to adequately address
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