Medical Student Research Fellowship for Summer 2006

Mentor: Kevin P. Rosenblatt, M.D., Ph.D.
Department: Pathology, Division of Translational Pathology
Room number: Office NB6.428, Lab NB6.112
Mail Code: 9072
Phone number: O: 214-648-4125, L: 214-648-1177
E-mail: Kevin.Rosenblatt@UTSouthwestern.edu
Project title: Testing an age suppressing hormone (Klotho) for neuroprotection in a mouse model of Parkinson's disease

Human subjects IRB approved project number (where applicable):

Animal subjects IRB approved project number (where applicable): 1092-05-01-1

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects)
Animal-based, basic research

Brief Description of Project:
Our collaborator, Dr. Kuro-o, has discovered a gene named klotho that is involved in the suppression of aging. Mice with a mutated klotho gene develop aging-like symptoms and suffer from multiple age-related disorders that are observed in humans, including shortened life span, arteriosclerosis, osteoporosis, etc. Recently, we have demonstrated that overexpressing Klotho in mice significantly extends their life span. Additionally, we found that the Klotho protein functions as a circulating hormone that binds to a cell-surface receptor and represses the intracellular signaling of insulin and insulin-like growth factor 1 (IGF1), which is an evolutionarily conserved mechanism for extending life span. Analysis of human klotho gene polymorphisms further suggests the association between Klotho and multiple age-related human diseases, including Alzheimer's disease, arteriosclerosis, and osteoporosis, and human longevity. Finally, we have found that the Klotho protein provides protection against oxidative stress at the cellular and whole animal level in mice that overexpress the protein. The Klotho protein activates FoxO forkhead transcription factors that are negatively regulated by insulin/IGF1 signaling, leading to the induced expression of manganese superoxide dismutase (MnSOD2). This enzyme drives the removal of reactive oxygen species (ROS), conferring a resistance to oxidative stress: mice overexpressing Klotho survive normally lethal quantities of injected paraquat, an herbicide that generates the potent ROS superoxide. Paraquat injection can induce a Parkinson's disease (PD) phenotype in animals, and superoxide dismutase activation can protect against paraquat in these animals. A more specific toxin for DA loss in rodents is the neurotoxin MPTP, which also works through ROS-based mechanisms. The goal of this project is to determine whether klotho can protect the midbrain dopamine neurons from neurodegeneration in the MPTP mouse. A positive finding will suggest insight into the development of novel drug targets for PD.

Previous Research Activities or Publications with Medical Students:
Katherine Smith, MSTP student, Clinical proteomics to diagnose Parkinson's disease in animal models

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