The long term goals of this research are to define and characterize molecular mechanisms by which mutations in proteins cause neurodegenerative disease and to identify pharmacological agents that ameliorate disease symptoms stemming from the accumulation of unfolded protein intermediates in neural cells. The accumulation of unfolded proteins in intracellular compartments is thought to underlie pathogenesis for a number of neurodegenerative diseases, including ALS, Parkinson, Huntington and Alzheimer diseases. More recently, the unfolded protein response has also been implicated in the pathophysiology of metabolic syndrome (diabetes/obesity/insulin resistance/cardiovascular disease), which significantly increases the impact of our work because unfolded diseases may be relevant to more than 6% of Americans. Two key components of our research have been the availability of well-defined mouse models for genetic manipulation, such as gene ablation or the introduction of heterologous transgenes, and the willingness of patients with unfolded protein disease to be involved in clinical studies. In this application, we will continue our work with patients to measure several clinical metrics from MRI and correlate these with disease severity. In addition, we will generate a novel mouse model on unfolded protein disease that will allow us to extend our understanding of the pathophysiology of unfolded protein disease.
Specific Aim#1 : we will develop a novel in vivo mouse model in which the unfolded protein response can be followed in real time, in individual cells, in vivo. This model will allow us to identify novel gene targets of UPR-induced transcription factors. Currently, several targets have been identified from in vitro cells in culture;however, we find that the data from in vivo experiments often contradict in vitro studies. Our paradigm will enable us to characterize the temporal sequence of events that generate the pathophysiology of neurodegeneration associated with protein trafficking defects in oligodendrocytes.

Public Health Relevance

Wayne State University is Michigan's only urban research university, located in Detroit-one of the economically hardest hit cities in the country. Detroit's current city deficit is approaching $300 million. The traditional source of jobs in the region, the U.S. automotive industry, is in significant decline, having reached a 50 year low in per-capita auto sales in February 2009. In addition, the recent closing of the Pfizer plant in Ann Arbor has left thousands of highly trained scientists without jobs. Michigan's jobless rate jumped to 11.6% in January the highest level in the nation (average unemployment in the US is 8.5%). Wayne State University is a key supporter of this blighted region. Currently Wayne State University is Detroit's 6th largest employer and generates $1 billion in economic activity annually in Southeastern Michigan. NIH ARRA funding of this project will allow for: a) full time retention of a research assistant b) full time employment of a second research assistant who has been volunteering in the laboratory c) recruitment of a research assistant d) recruitment of a postdoctoral fellow As such, this proposal fulfills the retention and job creation stipulations of the stimulus package. It is estimated that, in fiscal year 2007, each dollar of NIH funding generated more than twice as much in state economic output.* Thus, the proposed work stands to stimulate the beleaguered Michigan economy by approximately $1 million over the next two years, offering an alternative source of employment from the automotive industry for local residents and re-positioning those employed to take part in the growing knowledge-based economy. Foundation FU. In Your Own Backyard: How NIH Funding Helps Your State's Economy New York: Families USA: June 2208 Alexander Gow, PhD, P.I. 2.4 calendar month effort - has 15 years of experience in making and characterizing transgenic and knockout mice. He is also experienced with molecular and cellular techniques. He will oversee every aspect of the project. He will supervise the research assistants and postdoctoral fellow and perform confocal microscopy as necessary to characterize transgene expression in the transgenic and knockout mice. Chad Beasley, BS, Research Assistant, 2.4 calendar month effort - Mr Beasley has 5 years experience working with transgenic mice and 1 year with colonies in the PIs laboratory. He will perform genotyping and breeding for this project with assistance the TBN research assistant and oversea day-to-day operations of the colonies and breeding strategies. Alina Iovleva, BS, Research assistant, 6 calendar month effort - Ms Iovleva is a junior research assistant in the lab who has recently graduated. She has been working in the laboratory for the last 12 months as a volunteer to gain lab experience. She will perform Southern blotting to characterize the genetics of the transgenic and knockin mice and collect tissue for northern and western blotting to characterize expression of the heterologous genes. She will assist the postdoc in general laboratory work. TBN, BS, 12 calendar month effort -will have general molecular biology experience. Will be mentored by the PI and Mr Beasley to genotype mice and carry out day-to-day activities of the mouse colony in genotyping and breeding / backcrossing strategies. TBN, PhD, 12 calendar month effort - junior postdoctoral fellow with experience in molecular biology and transgenic mouse projects. Will work with Ms Iovleva in characterizing the Cre transgenic mice

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS043783-06A2
Application #
7467469
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Sutherland, Margaret L
Project Start
2009-07-16
Project End
2011-06-30
Budget Start
2009-07-16
Budget End
2010-06-30
Support Year
6
Fiscal Year
2009
Total Cost
$380,000
Indirect Cost
Name
Wayne State University
Department
Genetics
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
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