Developmental Disorders

Coding Dimension ID: 
290
Coding Dimension path name: 
Developmental Disorders

Alternative splicing during neural differentiation of human embryonic stem cells.

Funding Type: 
SEED Grant
Grant Number: 
RS1-00462
ICOC Funds Committed: 
$0
Disease Focus: 
Autism
Neurological Disorders
Developmental Disorders
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
Almost all genes in higher organisms are split into protein coding regions called exons, which are interrupted by non-coding regions called introns. Before a gene is translated into a functional protein, the non-coding introns must be removed and the coding exons joined together in a process called ‘splicing’. Splicing is a fundamental biological gene regulatory mechanism that operates in all higher organisms, both plants and animals. In humans (and other organisms) many genes can be spliced in several different ways such that some versions of the final product of the gene will include some coding exons but not others. This means that one gene can give rise to more than one protein. This process is called ‘alternative splicing’. Alternative splicing is also a fundamental biological gene regulatory mechanism that operates in all cells of all higher organisms. It is through alternative splicing that the human genome, containing ~30,000 genes, can produce greater than 150,000 proteins. Often, alternatively spliced variants of the same gene produce proteins with antagonistic functions, e.g. a protein that promotes the growth of cells may be produced from one spliced variant, while a protein that inhibits cell growth may be produced from another spliced variant of the same gene. These proteins with opposing functions are expressed in the same cell at the same time, but they are maintained in a delicate balance such that the cell grows just enough when necessary but can also stop growing before becoming cancerous. Human embryonic stem cells show evidence of a significant amount of alternative splicing of many genes that produce proteins that regulate cell growth and can direct the stem cells to adopt specific cell fates. Because splicing is one of the earliest steps in gene expression, alternative splicing may play a major role in controlling these types of cell fate decisions. Despite its importance in gene regulation, little is known about the role alternative splicing plays in stem cell growth or cell fate decisions. This is an enormous gap in the body of knowledge that is absolutely required before human embryonic stem cells can be used for therapeutic benefit. It is this gap that we will attempt to fill by investigating alternative splicing mechanisms in human embryonic stem cells. We will compare alternative splicing in several different human embryonic stem cell lines as they differentiate along neural pathways. During the course of these experiments we anticipate we will identify a number of new biomarkers of specific neural cell fates and may identify some gene products that direct the stem cell to adopt particular neural cell fates. We will test the role these gene products play in redirecting neural cell fates by manipulating the factors that regulate alternative splicing in human embryonic stem cells.
Statement of Benefit to California: 
This grant application describes experiments that are designed to investigate and provide insight into a fundamental biological gene regulatory mechanism called ‘alternative splicing’ that operates in all cells of all higher organisms including human embryonic stem cells. Alternative splicing is a key step in determining which proteins are expressed in specific cells at particular stages of all developmental pathways. Alternative splicing is so fundamentally important in regulating gene expression that if something goes awry with alternative splicing processes of growth control genes it can and does lead to many different types of cancer including primary malignant brain tumors such as astrocytomas. Almost nothing is currently known about the role alternative splicing plays in controlling growth or specifying cell fate decisions in human embryonic stem cells. This gap in the body of knowledge of a fundamentally important gene regulatory mechanism must be addressed before human embryonic stem cells can be used to realize their full therapeutic potential. For example, before one can utilize human embryonic stem cells that have been coaxed to differentiate into dopamine-producing neurons for the treatment of Parkinson’s disease or cholinergic neurons for the treatment of Alzheimer’s disease, one must be able to insure that the therapeutically introduced neurons do not inadvertently de-differentiate into precancerous astrocytic progenitor cells that may eventually give rise to an astrocytoma. Although the research described in this grant application does not address any specific human disease, a clear understanding of the role of alternative splicing in regulating gene expression during differentiation will be absolutely crucial before human embryonic stem cells can be utilized as a potential treatment for all human diseases. This understanding of basic gene regulatory mechanisms will be of enormous benefit to the State of California and any of its citizens suffering from diseases that may eventually be treated with human embryonic stem cells. It will provide a comparative global analysis of alternative splicing patterns in several different human embryonic stem cell lines and it will identify new biomarkers for distinguishing one neural cell fate from another. It may also provide insight into mechanisms of genesis of cancer stem cells and potentially new therapeutic targets for the treatment of some cancers.
Progress Report: 
  • Human stem cells, both embryonic and induced pluripotent stem cells, offer exciting opportunities for cell-based therapies in injured or diseased human brains or spinal cords. The clinical efficacy of grafted progenitor cells critically depends on their ability to migrate to the appropriate sites in the adult central nervous system without unwanted proliferation and tumor formation. However, little is known about the cellular behavior of human neural progenitor cells derived from human stem cells or how their proliferation and migration are coordinated. During this reporting period, we continued to study human neural progenitor cells derived from human stem cells, a cell culture system established during the prior reporting period. We focused on microRNAs, a class of small, noncoding RNAs of ~21–23 nucleotides that regulate gene expression at the posttranscriptional level. These small RNAs mostly destabilize target mRNAs or suppress their translation by binding to complementary sequences in the 3' untranslated regions (3'UTRs). Our results obtained during this reporting period indicate that some microRNAs have very interesting functions in human neural progenitors, both in in vitro cell culture system and when transplanted into mouse brains. These new findings may have important implications for stem cell based therapies for neurodegenerative diseases or brain/spinal cord injuries.

MicroRNAs in Human Stem Cell Differentiation and Mental Disorders

Funding Type: 
SEED Grant
Grant Number: 
RS1-00462
ICOC Funds Committed: 
$791 000
Disease Focus: 
Autism
Neurological Disorders
Developmental Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
Many mental disorders are closely associated with problems that occur during brain development in early life. For instance, by 2 years of age, autistic children have larger brains than normal kids, likely due to, at least in part, excess production of neurons and support cells, the building blocks of the nervous system. In autistic brains, how neurons grow various thread-like processes also shows some abnormalities. The cause of autism is complex and likely involves many genetic factors. These developmental defects are also associated with mental disorders caused by single-gene mutations, such as Rett syndrome and fragile X syndrome, the most common form of inherited mental retardation, whose clinical features overlap with autism. However, what causes the developmental defects in brains of children with different mental disorders is largely unknown. In recent years, an exciting new regulatory pathway was discovered that may well contribute to the etiology of mental disorders. The major player in this novel pathway is a class of tiny molecules 21
Statement of Benefit to California: 
California is the most populated state in the US and has a large number of patients suffering from various mental disorders. The proposed studies in this grant application will contribute to the mission of developing novel avenues through stem cell research for the diagnosis, prevention and treatment of mental disorders
Progress Report: 
  • Human stem cells, both embryonic and induced pluripotent stem cells, offer exciting opportunities for cell-based therapies in injured or diseased human brains or spinal cords. The clinical efficacy of grafted progenitor cells critically depends on their ability to migrate to the appropriate sites in the adult central nervous system without unwanted proliferation and tumor formation. However, little is known about the cellular behavior of human neural progenitor cells derived from human stem cells or how their proliferation and migration are coordinated. During this reporting period, we continued to study human neural progenitor cells derived from human stem cells, a cell culture system established during the prior reporting period. We focused on microRNAs, a class of small, noncoding RNAs of ~21–23 nucleotides that regulate gene expression at the posttranscriptional level. These small RNAs mostly destabilize target mRNAs or suppress their translation by binding to complementary sequences in the 3' untranslated regions (3'UTRs). Our results obtained during this reporting period indicate that some microRNAs have very interesting functions in human neural progenitors, both in in vitro cell culture system and when transplanted into mouse brains. These new findings may have important implications for stem cell based therapies for neurodegenerative diseases or brain/spinal cord injuries.

Center of Excellence for Stem Cell Genomics

Funding Type: 
Genomics Centers of Excellence Awards (R)
Grant Number: 
GC1R-06673-C
ICOC Funds Committed: 
$40 000 000
Disease Focus: 
Brain Cancer
Cancer
Developmental Disorders
Cancer
Toxicity
Public Abstract: 
The Center of Excellence in Stem Cell Genomics will bring together investigators from seven major California research institutions to bridge two fields – genomics and pluripotent stem cell research. The projects will combine the strengths of the center team members, each of whom is a leader in one or both fields. The program directors have significant prior experience managing large-scale federally-funded genomics research programs, and have published many high impact papers on human stem cell genomics. The lead investigators for the center-initiated projects are expert in genomics, hESC and iPSC derivation and differentiation, and bioinformatics. They will be joined by leaders in stem cell biology, cancer, epigenetics and computational systems analysis. Projects 1-3 will use multi-level genomics approaches to study stem cell derivation and differentiation in heart, tumors and the nervous system, with implications for understanding disease processes in cancer, diabetes, and cardiac and mental health. Project 4 will develop novel tools for computational systems and network analysis of stem cell genome function. A state-of-the-art data management program is also proposed. This research program will lead the way toward development of the safe use of stem cells in regenerative medicine. Finally, Center resources will be made available to researchers throughout the State of California through a peer-reviewed collaborative research program.
Statement of Benefit to California: 
Our Center of Excellence for Stem Cell Genomics will help California maintain its position at the cutting edge of Stem Cell research and greatly benefit California in many ways. First, diseases such as cardiovascular disease, cancer, neurological diseases, etc., pose a great financial burden to the State. Using advanced genomic technologies we will learn how stem cells change with growth and differentiation in culture and can best be handled for their safe use for therapy in humans. Second, through the collaborative research program, the center will provide genomics services to investigators throughout the State who are studying stem cells with a goal of understanding and treating specific diseases, thereby advancing treatments. Third, it will employ a large number of “high tech” individuals, thereby bringing high quality jobs to the state. Fourth, since many investigators in this center have experience in founding successful biotech companies it is likely to “spin off” new companies in this rapidly growing high tech field. Fifth, we believe that the iPS and information resources generated by this project will have significant value to science and industry and be valuable for the development of new therapies. Overall, the center activities will create a game-changing network effect for the state, propelling technology development, biological discovery and disease treatment in the field.

Center of Excellence for Stem Cell Genomics

Funding Type: 
Genomics Centers of Excellence Awards (R)
Grant Number: 
GC1R-06673-A
ICOC Funds Committed: 
$40 000 000
Disease Focus: 
Brain Cancer
Cancer
Developmental Disorders
Heart Disease
Cancer
Genetic Disorder
Stem Cell Use: 
iPS Cell
Embryonic Stem Cell
Adult Stem Cell
Cancer Stem Cell
Cell Line Generation: 
iPS Cell
Public Abstract: 
The Center of Excellence in Stem Cell Genomics will bring together investigators from seven major California research institutions to bridge two fields – genomics and pluripotent stem cell research. The projects will combine the strengths of the center team members, each of whom is a leader in one or both fields. The program directors have significant prior experience managing large-scale federally-funded genomics research programs, and have published many high impact papers on human stem cell genomics. The lead investigators for the center-initiated projects are expert in genomics, hESC and iPSC derivation and differentiation, and bioinformatics. They will be joined by leaders in stem cell biology, cancer, epigenetics and computational systems analysis. Projects 1-3 will use multi-level genomics approaches to study stem cell derivation and differentiation in heart, tumors and the nervous system, with implications for understanding disease processes in cancer, diabetes, and cardiac and mental health. Project 4 will develop novel tools for computational systems and network analysis of stem cell genome function. A state-of-the-art data management program is also proposed. This research program will lead the way toward development of the safe use of stem cells in regenerative medicine. Finally, Center resources will be made available to researchers throughout the State of California through a peer-reviewed collaborative research program.
Statement of Benefit to California: 
Our Center of Excellence for Stem Cell Genomics will help California maintain its position at the cutting edge of Stem Cell research and greatly benefit California in many ways. First, diseases such as cardiovascular disease, cancer, neurological diseases, etc., pose a great financial burden to the State. Using advanced genomic technologies we will learn how stem cells change with growth and differentiation in culture and can best be handled for their safe use for therapy in humans. Second, through the collaborative research program, the center will provide genomics services to investigators throughout the State who are studying stem cells with a goal of understanding and treating specific diseases, thereby advancing treatments. Third, it will employ a large number of “high tech” individuals, thereby bringing high quality jobs to the state. Fourth, since many investigators in this center have experience in founding successful biotech companies it is likely to “spin off” new companies in this rapidly growing high tech field. Fifth, we believe that the iPS and information resources generated by this project will have significant value to science and industry and be valuable for the development of new therapies. Overall, the center activities will create a game-changing network effect for the state, propelling technology development, biological discovery and disease treatment in the field.

The CIRM Human Pluripotent Stem Cell Biorepository – A Resource for Safe Storage and Distribution of High Quality iPSCs

Funding Type: 
hPSC Repository
Grant Number: 
IR1-06600
ICOC Funds Committed: 
$9 999 834
Disease Focus: 
Developmental Disorders
Heart Disease
Infectious Disease
Alzheimer's Disease
Neurological Disorders
Autism
Respiratory Disorders
Vision Loss
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Critical to the long term success of the CIRM iPSC Initiative of generating and ensuring the availability of high quality disease-specific human IPSC lines is the establishment and successful operation of a biorepository with proven methods for quality control, safe storage and capabilities for worldwide distribution of high quality, highly-characterized iPSCs. Specifically the biorepository will be responsible for receipt, expansion, quality characterization, safe storage and distribution of human pluripotent stem cells generated by the CIRM stem cell initiative. This biobanking resource will ensure the availability of the highest quality hiPSC resources for researchers to use in disease modeling, target discovery and drug discovery and development for prevalent, genetically complex diseases.
Statement of Benefit to California: 
The generation of induced pluripotent stem cells (iPSCs) from patients and subsequently, the ability to differentiate these iPSCs into disease-relevant cell types holds great promise in facilitating the “disease-in-a-dish” approach for studying our understanding of the pathological mechanisms of human disease. iPSCs have already proven to be a useful model for several monogenic diseases such as Parkinson’s, Fragile X Syndrome, Schizophrenia, Spinal Muscular Atrophy, and inherited metabolic diseases such as 1-antitrypsin deficiency, familial hypercholesterolemia, and glycogen storage disease. In addition, the differentiated cells obtained from iPSCs represent a renewable, disease-relevant cell model for high-throughput drug screening and toxicology/safety assessment which will ultimately lead to the successful development of new therapeutic agents. iPSCs also hold great hope for advancing the use of live cells as therapies for correcting the physiological manifestations caused by disease or injury.

Generation and characterization of high-quality, footprint-free human induced pluripotent stem cell lines from 3,000 donors to investigate multigenic diseases

Funding Type: 
hiPSC Derivation
Grant Number: 
ID1-06557
ICOC Funds Committed: 
$16 000 000
Disease Focus: 
Developmental Disorders
Genetic Disorder
Heart Disease
Infectious Disease
Alzheimer's Disease
Neurological Disorders
Autism
Respiratory Disorders
Vision Loss
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Induced pluripotent stem cells (iPSCs) have the potential to differentiate to nearly any cells of the body, thereby providing a new paradigm for studying normal and aberrant biological networks in nearly all stages of development. Donor-specific iPSCs and differentiated cells made from them can be used for basic and applied research, for developing better disease models, and for regenerative medicine involving novel cell therapies and tissue engineering platforms. When iPSCs are derived from a disease-carrying donor; the iPSC-derived differentiated cells may show the same disease phenotype as the donor, producing a very valuable cell type as a disease model. To facilitate wider access to large numbers of iPSCs in order to develop cures for polygenic diseases, we will use a an episomal reprogramming system to produce 3 well-characterized iPSC lines from each of 3,000 selected donors. These donors may express traits related to Alzheimer’s disease, autism spectrum disorders, autoimmune diseases, cardiovascular diseases, cerebral palsy, diabetes, or respiratory diseases. The footprint-free iPSCs will be derived from donor peripheral blood or skin biopsies. iPSCs made by this method have been thoroughly tested, routinely grown at large scale, and differentiated to produce cardiomyocytes, neurons, hepatocytes, and endothelial cells. The 9,000 iPSC lines developed in this proposal will be made widely available to stem cell researchers studying these often intractable diseases.
Statement of Benefit to California: 
Induced pluripotent stem cells (iPSCs) offer great promise to the large number of Californians suffering from often intractable polygenic diseases such as Alzheimer’s disease, autism spectrum disorders, autoimmune and cardiovascular diseases, diabetes, and respiratory disease. iPSCs can be generated from numerous adult tissues, including blood or skin, in 4–5 weeks and then differentiated to almost any desired terminal cell type. When iPSCs are derived from a disease-carrying donor, the iPSC-derived differentiated cells may show the same disease phenotype as the donor. In these cases, the cells will be useful for understanding disease biology and for screening drug candidates, and California researchers will benefit from access to a large, genetically diverse iPSC bank. The goal of this project is to reprogram 3,000 tissue samples from patients who have been diagnosed with various complex diseases and from healthy controls. These tissue samples will be used to generate fully characterized, high-quality iPSC lines that will be banked and made readily available to researchers for basic and clinical research. These efforts will ultimately lead to better medicines and/or cellular therapies to treat afflicted Californians. As iPSC research progresses to commercial development and clinical applications, more and more California patients will benefit and a substantial number of new jobs will be created in the state.

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