Establishment of human Embryonic Stem Cell Models to Study the Impact of Alzheimer's Disease Mutant Genes on Neuronal Functions

Funding Type: 
SEED Grant
Grant Number: 
RS1-00323
ICOC Funds Committed: 
$0
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
Alzheimer’s disease (AD) afflicts over 5 million Americans and is characterized by deposits of insoluble protein aggregates (amyloid plaques) and neurofibillary tangles as well as massive neuronal loss in regions affecting learning and memory. Currently, the best model for studying AD and testing novel therapies is a transgenic mouse that shows some, but not all, of the pathologies associated with AD. Mouse and human cells do not respond in the same ways to deleterious cell signals, so there is a great need for a model in which AD pathology can be studied in human cells. One difficulty in advancing AD research is that it is hard to obtain and examine live non-dividing (post-mitotic) neurons from AD patients. Even if such neurons are obtained, it is impossible to amplify them for reproduction of the obtained data or for sharing those neurons with other laboratories. As long as there is a possibility that different mechanisms may underlie different AD cases, it is considerably disadvantageous to investigate neurons from an individual AD patient with an unidentified cause. Our study will be conducted to overcome these difficulties. With recent progress in differentiating embryonic stem cells (ESC) into post-mitotic neurons, construction of ES cells expressing familial Alzheimer’s Disease (FAD) genes would allow for the creation of post-mitotic neurons bearing AD pathology. In this proposal, we have the advantage of having grown multiple HUES and some NIH-approved human ESC (hESC)lines and being able to express foreign genes at high levels in hESCs using lentiviral infection, as well as our expertise in the molecular and cell biology of AD. We propose to fully characterize these ES cell models in the context of AD pathologies such as A? generation and tau hyperphosphorylation, neuronal susceptibility to various neural toxicities, gene profiling, and neuronal differentiation. Three key genes/proteins known to be involved in AD pathogenesis are APP (?-amyloid (A?) precursor protein, from which A? is derived, PS1 (presenilin1) and tau. All the mutations in APP and PS1 are autosomal dominant leading to early onset of AD; mutations in tau (associated with familial frontotemporal dementia) favor the formation of neurofibrillary tangles (NFT). In addition to their well-defined functions in causing AD pathological lesions, these three genes/proteins have also been known to play key physiological roles including those in neurogenesis, neural development and synaptic functions. Defects in neuronal functions such as neurogenesis and neuronal differentiation have been found in AD brains in association with pathological abnormalities such as amyloid plaques (consisting of A?) and neurofibrillary tangles (NFT, consisting of hyperphosphorylated tau) as well as neuronal death in selected brain regions. The established hES cell models would be ideally important for drug screening which should eventually be instrumental for development of effective AD therapies.
Statement of Benefit to California: 
"DRAFT OF A DRAFT" California has a tradition of taking the lead in technology and medical breakthroughs, not only by invention and innovation, but also by following through with research, development, and commercialization of ideas. Californians have a tradition of encouraging an entrepreneurial spirit, making the state an attractive site to launch new and risky ventures. Our proposal takes advantage of California's greatest strengths: innovative scientific research and high tech expertise. We propose a collaboration that involves the best of cutting edge laboratory research with the kind of entrepreneurial spirit in computer technology that launched HP, Apple, Google, and Pixar. We propose to generate and analyze a large amount of information about stem cells, focusing first on the molecular signatures of these cells, and then adding information about their utility for scientific research and their efficacy in preclinical development and clinical trials. A partnership with experts in launching web-based databases will allow us to make these data accessible to scientists so that they can make intelligent choices about which of the hundreds of embryonic and somatic stem cell lines will be best for their needs. This will eliminate wasted resources by creating a shared information database, encourage collaboration, and immediately enable scientists from non-stem cell disciplines to plan and carry out their experiments in a sound scientific context. This project will be a unique opportunity for California to demonstrate the power of its large intellectual base, and will create a magnet for other researchers, inside and outside California, to contribute their own information and expertise, which will leverage the power of the California stem cell community to explore novel approaches. The proposed project will be a springboard to new commercial ventures, and attract investment in research and development. Ultimately, by encouraging sharing of information, the project will help maintain high standards of scientific research, and speed the development of clinical applications for stem cells that will benefit all Californians. ADD A SENTENCE ABOUT THE LARGER AGING POPULATION IN CA SO MORE AD - HUAXI TO ADD TO ABOVE
Progress Report: 
  • We study how chromatin, the complex of DNA and protein that makes up chromosomes, influences expression of genes to produce different tissues and organs in the process of development. Human embryonic stem cells provide a useful model system that allows us to address fundamental questions about role of chromatin modification and epigenetic mechanisms in cell fate decisions governing human development and disease.
  • With funding from CIRM we developed a human embryonic stem cell-derived in vitro model to study the formation and differentiation of human neural crest, a transient cell population that is ectodermal in origin, but undergoes a major gene expression reprogramming to acquire a remarkably broad differentiation potential and ability to migrate throughout the body to give rise to craniofacial bones and cartilages, peripheral nervous system, and cardiac structures.
  • We had shown that two distinct chromatin remodelers cooperate to promote the unique epigenetic plasticity and migration of the neural crest cells. Heterozygous mutations in gene encoding one of those remodelers, CHD7, result in a complex constellation of congenital anomalies called CHARGE syndrome, a sporadic, autosomal dominant disorder occurring in about 1:8000 life birth and characterized by malformations of the craniofacial structures, peripheral nervous system, ears, eyes and heart. Though our work we have elucidated for the first time the molecular mechanism underlying this relatively common, but poorly understood human syndrome, and identified novel candidates targets for genes mutated in this disease.

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