Over 7 million cases of dementia exist in the US (~3% of the population) and of these ~5% are frontotemporal dementia (FTD). It has been demonstrated recently that 5-10% of all FTD in the US are caused by mutations in the Progranulin (PGRN) gene. This is accompanied with a 50% reduction of PGRN level in patients'biological fluids. PGRN is a 593 amino-acid growth and survival factor. Cloning and sequencing of PGRN showed that it contains a 17 amino-acid signal peptide for secretion and seven and a half 6 kDa grn repeats with a unique tandem repeat double cysteinyl rich granulin (grn) motif. The 6 Kda Grns are generated by processing of PGRN by a proteolytic cleavage stimulated by elastase and blocked by secretory leucocyte protease inhibitor SLPI. Recent evidence suggests that both PGRN and grns may directly influence neurodegenerative diseases process, such as Alzheimer's disease, Parkinson's disease and certain types of FTD. It has been suggested that the balance of PGRN and grn levels is important for neuron protection/degradation as a result of inflammation. Accordingly, the measurement of PGRN and grn levels may shed light on the balance of normal versus disease related processes in the brain. Currently, relatively little is known about the function and expression of specific grns in the brain when compared to PGRN and about the possible mechanisms linking PGRN and grn to these diseases. Thus, it is critical to develop specific validated assay systems to advance the PGRN/grn field forward in the neurodegenerative disease. The principal investigator is a recognized expert in PGRN research particularly in cancer and has developed clinically validated high quality monoclonal antibodies and assays to measure PGRN in tissue and biological fluids in patients. Her PGRN assays and reagents are also used in collaborative studies with two centers of excellence in neurodegenerative disease. However, there are no reliable, sensitive and specific assays to measure grn molecules, thereby hampering understanding of the role of grns in neurodegenerative diseases. The principal investigator is requesting support in this RO3 application to develop a portfolio of monoclonal antibodies specific to grn. The approach will be to target the neo-cleavage sites of the seven different grns to develop mAbs suitable for sandwich ELISA assay for each of the 7 grns. Specifically, it is proposed to: 1) Develop high affinity mAbs specific to each of 7 grn molecule suitable for sandwich ELISA detection in biological samples: 2) Develop standardized laboratory assays for specifically detecting the 7 grns in biological fluids at concentrations of less than 100 pg/ml and without interference by PGRN. These studies will be important as the development of validated sandwich ELISA kits for each of the 7 grns, it will enable researchers to investigate the presence and the ratio of various grns and PGRN in CSF and other biological samples from patients with neurodegenerative diseases such as FTD. Providing tools that can detect measure and elucidate the role of these important biological products may also be useful in revealing the potential to use them as therapeutic targets or surrogate markers for disease or therapy monitoring.

Public Health Relevance

Over 7 million cases of dementia exist in the US (~3% of the population). Dementia is a loss of brain function affecting memory, thinking, language, judgment, and behavior. In recent years a genetic defect has been identified that causes a reduction in production of a protein called progranulin in the brain in some patients with dementia. This program will develop tools and methods to accurately measure levels of this protein and its related products (granulins) and in so doing may enable research to discover therapy to slow down or cure advancing dementia.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Research Grants (R03)
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Clinical Neuroscience and Neurodegeneration Study Section (CNN)
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Sutherland, Margaret L
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A and G Pharmaceutical, Inc.
United States
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