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Robbins Lab Research

Research Areas

The Robbins laboratory is developing novel approaches to treat autoimmune (type 1 diabetes, rheumatoid arthritis), inflammatory (inflammatory bowel disease, delayed type hypersensitivity) and age-related degenerative diseases using biologics and small  molecules. The therapeutic approaches being developed include: 

1) AAV mediated gene transfer of anti-inflammatory or immunosuppressive agents.  Here we are using AAV-mediated gene transfer to endogenous islets of NOD mice (see figure below) to prevent onset of type I diabetes. We also are using AAV-mediated gene transfer to joints to treat rheumatoid and osteoarthritis. We previously performed a gene therapy trial for rheumatoid arthritis using synovial fibroblasts genetically modified to expressing IL-1Ra as outlined below. A clinical study using AAV-mediated gene transfer of IL-1Ra for treatment of osteoarthritis will be initiated in 2014.

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2) Development of peptide and small molecule inhibitors of the transcription factor of NF-κB for treating inflammatory and degenerative diseases.  We have developed a fusion peptide containing a protein transduction domain fused to a peptide (NBD) able to disrupt the kinase (IKK) important for inducing the activity of NF-κB. This peptide is highly therapeutic in mouse models of autoimmune, inflammatory and degenerative diseases including aging. We currently are developing small molecule mimetics of the NBD peptide for clinical use. Also, as shown below, we are examining the upregulation of NF-κB transcriptional activity with aging using a transgenic mouse carrying a NF-κB dependent promoter-eGFP reporter.  Using this reporter mouse model, we have demonstrated that NF-κB is activated in a stochastic manner with aging.

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3) Development of novel osteogenic peptides. We have demonstrated that certain isoforms of the intracellular Lim Mineralization Protein (LMP) is highly osteogenic following gene transfer.  We are currently mapping the osteogenic domain(s) of LMP in order to develop peptides able to induce osteogenesis following protein transduction mediated delivery.  As shown below, gene transfer of LMP to muscle results in efficient ectopic bone formation.

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4) Aging of adult stem cells.  We have demonstrated previously that function and number of adult stem cell populations decline with aging.  Interestingly, injection of functional adult stem cells into a mouse model of accelerated aging extended lifespan and healthspan through an apparent endocrine/paracrine mechanisms (see figure below).  We currently are examining approaches to improve the function of aged stem cells as well as identify the therapeutic factors secreted by functional stem cells.

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5) Therapeutic applications of microvesicles (exosomes).  Exosomes are a type of secreted membrane vesicles produced by a large variety of cell types. They are characterized by an endocytic origin, formed by the reverse budding of the multivesicularbodies and have a size of around 30-100 nM in diameter (see figure below). Their protein content largely reflects those of the parental cells and is enriched in certain molecules including proteins and miRNA.  We have demonstrated that dendritic cell-derived exosomes can be highly immunosuppressive, able to reverse established autoimmune disease.  We currently are examining the mechanism of immunosuppression of antigen-presenting cell derived as well as tumor-derived exosomes.  Similarly, we are examining the possible role of exosomes in regulating aging.  

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6) Identification of pathways important for cellular senescence.   Cellular senescence has been linked to both aging and cancer.  We have demonstrated that inhibition of certain pathways or factors (mTOR, NF-κB, ROS) can prevent or reverse senescence (see figure below).  We currently are developing approaches to screen for drugs that can reverse DNA damage-induced cellular senescence. The drugs identified as reversing senescence will then be tested for ability to extend lifespan and healthspan in a mouse model of accelerated aging.

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