Neurological Disorders

Coding Dimension ID: 
303
Coding Dimension path name: 
Neurological Disorders
Grant Type: 
SEED Grant
Grant Number: 
RS1-00271
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$633 170
Disease Focus: 
Neurological Disorders
Parkinson's Disease
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

A promising approach to alleviating the symptoms of Parkinson’s disease is to transplant healthy dopaminergic neurons into the brains of these patients. Due to the large number of transplant neurons required for each patient and the difficulty in obtaining these neurons from human tissue, the most viable transplantation strategy will utilize not fetal dopaminergic neurons but dopaminergic neurons derived from human stem cell lines. While transplantation has been promising, it has had limited success, in part due to the ability of the new neurons to find their correct targets in the brain. This incorrect targeting may be due to the lack of appropriate growth and guidance cues as well as to inflammation in the brain that occurs in response to transplantation, or to a combination of the two. Cytokines released upon inflammation can affect the ability of the new neurons to connect, and thus ultimately will affect their biological function. In out laboratory we have had ongoing efforts to determine the which guidance molecules are required for proper targeting of dopaminergic neurons during normal development and we have identified necessary cues. We now plan to extend these studies to determine how these critical guidance cues affect human stem cell derived dopaminergic neurons, the cells that will be used in transplantation. In addition, we will examine how these guidance cues affect both normal and stem cell derived dopaminergic neurons under conditions that are similar to the diseased and transplanted brain, specifically when the brain is inflamed. Ultimately, an understanding of how the environment of the transplanted brain influences the ability of the healthy new neurons to connect to their correct targets will lead to genetic, and/or drug-based strategies for optimizing transplantation therapy.

Statement of Benefit to California: 

The goal of our work is to further optimize our ability to turn undifferentiated human stem cells into differentiated neurons that the brain can use as replacement for neurons damaged by disease. We focus onParkinson’s disease, a neurodegenerative disease that afflicts 4-6 million people worldwide in all geographical locations, but which is more common in rural farm communities compared to urban areas (Van Den Eeden et al., 2003), a criteria important for California’s large farming population. In Parkinson’s patients, a small, well-defined subset of neurons, the midbrain dopaminergic neurons have died, and one therapeutic strategy is to transplant healthy replacement neurons to the patient. Our work will further our understanding of the biology of these neurons in normal animals. This will allow us to refine the process of turning human ES cells onto biologically active dopaminergic neurons that can be used in transplantation therapy. Our work will be of benefit to all Parkinson’s patients including afflicted Californians. In addition to the direct benefit in improving PD therapies, discoveries from this work are also likely to generate substantial intellectual property and further boost clinical and biotechnical development efforts in California.

Grant Type: 
SEED Grant
Grant Number: 
RS1-00205
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$612 075
Disease Focus: 
Aging
Alzheimer's Disease
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

The goal of this proposal is to generate forebrain neurons from human embryonic stem cells. Our general strategy is to sequentially expose ES cells to signals that lead to differentiation along a neuronal lineage, and to select for cells that display characteristics of forebrain neurons. These cells would then be used in transplantation experiments to determine if they are able to make synaptic connections with host neurons. If successful these experiments would provide a therapeutic strategy for the treatment of Alzheimer’s disease and other disorders that are characterized by loss of forebrain neurons. Currently there is no effective treatments for Alzheimer’s disease, and with an aging baby-boomer population, the incidence of this disease is likely to increase sharply. One of the few promising avenues to treat Alzheimer’s is the possibility of cell replacement therapy in which the neurons lost could be replaced by transplanted neurons. Embryonic stem cells, which have the ability to differentiate into various cells of the body, could be a key component of such a therapy if we can successfully differentiate them into forebrain neurons.

Statement of Benefit to California: 

Alzheimer’s disease is a devastating sporadic neurological disorder that places all of us at risk. As the California population ages, there will be a significant increase in the incidence of Alzheimer’s disease, and the medical and financial cost on the state will be severe. There are currently no effective treatments for this disorder, and one of the few promises is the possibility of transplantation therapy to replace the neurons that are lost in the disease. Being able to generate forebrain neurons from human embryonic stem cells would provide a key tool in the fight against this disease. Needless to say, the development of an effective cell replacement therapy would not only be of immense medical significance as we care for our senior population, it will also greatly relieve the financial burden associated with the care of Alzheimer’s patients, which is often borne by the state.

Grant Type: 
SEED Grant
Grant Number: 
RS1-00413
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$625 617
Disease Focus: 
Cancer
Neurological Disorders
Skeletal/Smooth Muscle disorders
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

A variety of stem cells exist in humans throughout life and maintain their ability to divide and change into multiple cell types. Different types of adult derived stem cells occur throughout the body, and reside within specific tissues that serve as a reserve pool of cells that can replenish other cells lost due to aging, disease, trauma, chemotherapy or exposure to ionizing radiation. When conditions occur that lead to the depletion of these adult derived stem cells the recovery of normal tissue is impaired and a variety of complications result. For example, we have demonstrated that when neural stem cells are depleted after whole brain irradiation a subsequent deficit in cognition occurs, and that when muscle stem cells are depleted after leg irradiation an accelerated loss of muscle mass occurs. While an increase in stem cell numbers after depletion has been shown to lead to some functional recovery in the irradiated tissue, such recovery is usually very prolonged and generally suboptimal.Ionizing radiation is a physical agent that is effective at reducing the number of adult stem cells in nearly all tissues. Normally people are not exposed to doses of radiation that are cause for concern, however, many people are subjected to significant radiation exposures during the course of clinical radiotherapy. While radiotherapy is a front line treatment for many types of cancer, there are often unavoidable side effects associated with the irradiation of normal tissue that can be linked to the depletion of critical stem cell pools. In addition, many of these side effects pose particular threats to pediatric patients undergoing radiotherapy, since children contain more stem cells and suffer higher absolute losses of these cells after irradiation.Based on the foregoing, we will explore the potential utility and risks associated with using human embryonic stem cells (hESC) in the treatment of certain adverse effects associated with radiation-induced stem cell depletion. Our experiments will directly address whether hESCs can be used to replenish specific populations of stem cells in the brain and muscle depleted after irradiation in efforts to prevent subsequent declines in cognition and muscle mass respectively. In addition to using hESC to hasten the functional recovery of tissue after irradiation, we will also test whether implantation of such unique cells holds unforeseen risks for the development of cancer. Evidence suggests that certain types of stem cells may be prone to cancer, and since little is known regarding this issue with respect to hESC, we feel this critical issue must be addressed. Thus, we will investigate whether hESC implanted into animals develop into tumors over time. The studies proposed here comprise a first step in determining how useful hESCs will be in the treatment of humans exposed to ionizing radiation, as well as many other diseases where adult stem cell depletion might be a concern.

Statement of Benefit to California: 

Radiotherapy is a front line treatment used in California for many types of cancer, including brain, breast, prostate, bone and other cancer types presenting surgical complications. Treatment of these cancers through the use of radiation is however, often associated with side effects caused by the depletion of critical stem cell pools contained within non-cancerous normal tissue. While radiotherapy is clearly beneficial overall, many of these side effects have no viable treatment options. If we can demonstrate that human embryonic stem cells (hESC) hold promise as a safe therapeutic agent for the treatment of radiation-induced stem cell depletion, then cancer patients may have a new treatment for countering many of the debilitating side effects associated with radiotherapy. Once developed this new technology could position California to attract cancer patients throughout the United States, and the state would clearly benefit from the increased economic activity associated with a rise in patient numbers.

Grant Type: 
SEED Grant
Grant Number: 
RS1-00462
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$791 000
Disease Focus: 
Autism
Developmental Disorders
Neurological Disorders
Human 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

Grant Type: 
SEED Grant
Grant Number: 
RS1-00377
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$619 223
Disease Focus: 
Neurological Disorders
Spinal Cord Injury
Human Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Our understanding of the effect of immunosuppressive agents on stem cell proliferation and differentiation in the central nervous system is limited. Indeed, even the necessity for long-term immunosuppression to promote the survival of stem cells grafted into the “immunoprivileged” central nervous system (CNS) is unknown. Grafting multipotent stem cells into the injured CNS often results in a failure of the cells to survive. If the cells survive, often they differentiate into astrocytes, a cell-type not considered beneficial. We recently grafted human stem cells (hCNS-SC) into spinal injured mice and observed behavioral improvements coupled with differentiation of these human cells into neurons and oligodendrocytes. We also observed mouse-human synapse formation and remyelination. The mice we used lacked a functional immune system, enabling us to grafting human cells into the mice without the use of immunosuppressants. When these same cells were grafted into spinal injured rats with a normal immune system, we had to immunosuppress the animals. Exposure of these human stem cells to immunosuppressive drugs resulted poor cell survival. The cells that did survive predominantly differentiated into astrocytes. Did the immunosuppressive drugs we used alter the ability of the human stem cells to differentiate into useful cells?

All cell-based therapeutic approaches are dependent upon either immunosuppression in an otherwise normal animal or testing for proof of principal in an immunodeficient animal model. This has quite significant implications for animal experiments or human trials, where continuous immunosuppression is required to obtain successful graft survival. No one knows if there are direct effects of immunosuppressant drugs on neural stem cells.

Stem cells may also respond differently to immunosuppression depending on their “ontogenetic” age (embryonic vs. fetal vs. adult). There is a common perception that “young” ES cells will have greater potential than “older” stem cells. Stem cells isolated at different ontogenetic stages might respond differently to immunosuppression.

We predict that the immunosuppressive drugs will exert direct effects on stem cell proliferation, gene expression, and fate determination, both in cell culture and when grafted into animals with spinal cord injury. We will also test if “ontogenetic” age alters the responsiveness of stem cells.

Statement of Benefit to California: 

The California Institute for Regenerative Medicine (CIRM) recognizes that the field of stem cell biology is in its infancy. CIRM has requested a broad range of research to fill in key gaps in our understanding of basic stem cell biology and the possible use of these cells as therapeutics. Grants are to be judged on impact (extent the proposed research addresses an important problem; significantly moves the field forward scientifically; moves the research closer to therapy; and changes the thinking or experimental practice in the field), quality (is proposed research planned carefully to give a meaningful result; are possible difficulties are acknowledge; does the timetable allows for achieving significant research) and innovation (to what extent the research approach is original, breaks new ground, and brings novel ideas to bear on an important problem).

We believe that the projects proposed here target several of the areas CIRM cites as beneficial to the State of California. This proposal addresses the critical area of immunosuppression and stem cell survival in animal transplantation models. Future therapies using human stem cells will have to surmount the possible rejection by the host of cells derived from another source. If traditional immunosuppressive drugs are to be used, we will need to understand whether these drugs have a direct effect on stem cell proliferation and fate determination (or differentiation). Furthermore, these projects will allow for a direct comparison of stem cells from different ontogenetic stages and the ability to improve functional outcome after spinal cord injury. Thus we may gain insight into whether embryonic derived stem cells are more useful than adult derived stem cells as a therapeutic tool.

Grant Type: 
SEED Grant
Grant Number: 
RS1-00215
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$564 309
Disease Focus: 
Neurological Disorders
Parkinson's Disease
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

In this application, we propose to identify small molecule compounds that can stimulate human embryonic stem cells to become dopamine-producing neurons. These neurons degenerate in Parkinson’s disease, and currently have very limited availability, thus hindering the cell replacement therapy for treating Parkinson’s disease.

Our proposed research, if successful, will lead to the identification of small molecule compounds that can not only stimulate cultured human embryonic stem cells to become DA neurons, but may also stimulate endogenous brain stem cells to regenerate, since the small molecule compounds can be made readily available to the brain due to their ability to cross the blood-brain barrier. In addition, these small molecule compounds may serve as important research tools, which can tell us the fundamental biology of the human embryonic stem cells.

Statement of Benefit to California: 

The proposed research will potentially lead to a cure for the devastating neurodegenerative, movement disorder, Parkinson’s disease. The proposed research will potentially provide important research tools to better understand hESCs. Such improved understanding of hESCs may lead to better treatments for a variety of diseases, in which a stem-cell based therapy could make a difference.

Grant Type: 
SEED Grant
Grant Number: 
RS1-00170
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$500 000
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurological disease that leads to the degeneration of motor neurons in the brain and in the spinal cord. There are currently 20,000 ALS patients in the United States, and 5,000 new patients are diagnosed every year. Unfortunately no cure has been found for ALS. The only medication approved by the FDA to treat ALS can only slow the disease’s progression and prolong life by a few months in some patients. Thus it is critical to explore other therapeutic strategies for the treatment of ALS such as cell replacement strategy.

Because of the ability to generate many different cell types, human embryonic stem cells (hESCs) may potentially serve as a renewable source of cells for replacing the damaged cells in diseases. However, transplanting ESCs directly may cause tumor growth in patients. To support cell transplants, it is important to develop methods to differentiate hESCs into the specific cell types affected by the disease. In this application, we propose to develop an effective method to differentiate hESCs into corticospinal motor neurons (CSMNs), the neurons in the cerebral cortex that degenerate in ALS. We will test whether these CSMNs generated from hESCs in culture conditions can form proper connections to the spinal cord when transplanted into mouse brains.

To direct hESCs to become the CSMNs, it is critical to establish a reliable method to identify human CSMNs. Recent progress in developmental neuroscience have identified genes that are specifically expressed in the CSMNs in mice. However no information is available for identifying human CSMNs. We hypothesize that CSMN genes in mice will be reliable markers for human CSMNs. To test this hypothesis we will investigate whether mouse CSMN markers are specifically expressed in the human CSMNs.

The therapeutic application of hESCs to replace damaged CSMNs in ALS depends on the ability to direct hESCs to develop into CSMNs. Currently a reliable condition to direct hESCs to differentiate into CSMNs has not been established. We will attempt to differentiate hESCs into CSMNs based on the knowledge gained from studying the development of nervous system. We will achieve this goal in two steps: first we will culture hESCs in a condition to make them become progenitors cells of the most anterior region of the brain; then we will culture these progenitors to become neurons of the cerebral cortex, particularly the CSMNs. We will study the identities of these neurons using the CSMN markers that we have proposed to identify.

To apply the cell replacement strategy to treat ALS, it will be critical to test if human CSMNs generated from cultured hESCs can form proper connections in an animal model. We will transplant the CSMNs developed from hESCs into the brains of mice and test whether they can form connections to the spinal cord.

When carried out, the proposed research will directly benefit cell replacement therapy for ALS.

Statement of Benefit to California: 

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurological disease that leads to the degeneration of motor neurons in the brain and in the spinal cord. There are currently 20,000 ALS patients in the United States, and 5,000 new patients are diagnosed every year. Unfortunately no cure has been found for ALS. The only medication approved by the FDA to treat ALS can only slow the disease’s progression and prolong life by a few months in some patients. Thus it is critical to explore other therapeutic strategies for the treatment of ALS such as cell replacement strategy.

Because of the ability to generate many different types of cells, human embryonic stem cells (hESCs) may potentially serve as a renewable source of cells for replacing the damaged cells in diseases. However, transplanting ESCs directly may cause tumor growth in patients. To support cell transplants, it is important to develop methods to differentiate hESCs into the specific cell types affected by the disease. In this application, we propose to develop an effective method to differentiate hESCs into corticospinal motor neurons (CSMNs), the neurons in the cerebral cortex that degenerate in ALS. We will test whether these CSMNs generated from hESCs in culture conditions can form proper connections to the spinal cord when transplanted into mouse brains.

Everyday, 15 people die from ALS. For patients diagnozied with ALS, time is running out very fast. It is critical to explore novel therapeutic strategies for this rapidly progressive and fatal disease. The research proposed in this application may provide the basis for a novel cell replacement therapy for ALS, thus it will greatly benefit the State of California and everyone in the State.

Grant Type: 
Basic Biology II
Grant Number: 
RB2-01628
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 458 000
Disease Focus: 
Neurological Disorders
Human Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Closed
Public Abstract: 

Pluripotent stem cells have a remarkable potential to develop into virtually any cell type of the body, making them a powerful tool for the study or direct treatment of human disease. Recent demonstration that induced pluripotent stem (iPS) cells may be derived from differentiated adult cells offers unprecedented opportunities for basic biology research, regenerative medicine, disease modeling, drug discovery and toxicology. For example, using patient-derived iPS cells, one can model diseases in vitro and screen for drugs in ways never before possible, enabling the identification of promising new therapeutic candidates earlier in the drug discovery process. In addition, iPS cell derivatives represent an ideal source for autologous cell replacement therapies, as they would not be rejected upon transplantation back into the patient.

While it is clear that iPS cells hold great promise for finding therapies for diseases, there are significant hurdles that need to be overcome before full clinical potential is realized. The mechanism of iPS cell derivation is largely elusive, and the process used to generate them is very inefficient and needs to be improved in significant ways. Currently, iPS cells are generated by forced expression of four molecular factors using genome-integrating viruses. This may lead to mutations and altered differentiation potential of iPS cells, as well as tumorogenesis if transplanted back into the patient. The inefficient and stochastic nature of the reprogramming process indicates that additional, as yet unidentified mechanisms may exist and contribute to iPS cell generation. Finally, increasing the efficiency of current iPS cell derivation protocols will increase the ability to generate large panels of patient-specific iPS cell lines.

We propose to use a human cell-based assay to identify small molecules that can enhance the efficiency of iPS cell generation. Our strategy will allow us to identify small molecules that target events essential for derivation of iPS cells, as well as those that replace one or more of the four virally-delivered factors. We will use the identified small molecules to discover regulatory pathways and molecular targets involved in induction of pluripotency, gaining valuable insight into the mechanism of cellular reprogramming. Application of these small molecules themselves, as well as novel approaches derived from mechanism of action studies, will help overcome issues associated with viral integration and has the potential to transform personalized cell-replacement therapies as well as accelerate drug discovery based on iPS cell-derived disease models.

Statement of Benefit to California: 

California’s health care system faces significant challenges as millions of children and adults suffer from a host of incurable illnesses. It is expected that health care costs will continue to rise as California’s citizenry ages and requires treatments for age-related, chronic metabolic, cardiovascular, and neurodegenerative disorders. Both the measureable economic impact on California’s health care system and the incalculable emotional suffering of affected individuals, their families and communities, make it an imperative to develop novel therapeutic treatments to address these mounting medical and economic societal challenges.

Recognizing the potential utility of novel stem cell technologies to address California’s unmet medical needs, California voters approved Proposition 71 which created the California Institute for Regenerative Medicine (CIRM), an agency that administers funds to support stem cell research that has the greatest potential for development of novel regenerative medical treatments and cures. The CIRM Basic Biology Awards II program is intended to fund studies that will lay the foundation for future stem cell-based translational and clinical advances. In keeping with this mission, our proposed research program aims to discover new methods for producing human induced pluripotent stem cells (iPS cells) on an industrial scale and in an efficient manner; and to develop a better understanding of the mechanisms underlying cellular reprogramming. As such, our research program will help accelerate the realization of the full potential of iPS cells in cell-based regenerative medicine therapies and drug discovery.

Our proposed research program will benefit the State of California and its citizens in several ways. Firstly, our research program will lay the foundation for future stem cell-based clinical and translational advances to treat and manage one of California’s most pressing unmet medical needs. Secondly, execution of our research program will create new jobs in the academic, biotechnology and pharmaceutical sectors throughout California. Funding from CIRM will be expanded with additional funding from the applicant to augment achievement of the aims of this project. CIRM funding will leverage other sources of investment in this project to help ensure California’s continued future as a world leader in biomedical innovation and translational medicine for the benefit of human health. Lastly, our proposed research program will stimulate California’s economy by creating new enabling tools and technologies that can be broadly adopted across the life science industry, thus promoting development across the academic institutions and biopharmaceutical companies that create biomedical discoveries and advances. These activities will continue to strengthen California’s leadership position at the forefront of the stem cell and regenerative medical revolution of the 21st century.

Grant Type: 
Basic Biology II
Grant Number: 
RB2-01637
Investigator: 
ICOC Funds Committed: 
$1 522 800
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
oldStatus: 
Active
Public Abstract: 

Approaches to repair the injured brain or even prevent age-related neurodegeneration are in their infancy but there is growing interest in the role of neural stem cells in these conditions. Indeed, there is hope that some day stem cells can be used for the treatment of spinal cord injury, stroke, or Parkinson’s disease and stem cells are even mentioned in the public with respect to Alzheimer’s disease. To utilize stem cells for these conditions and, equally important to avoid potential adverse events in premature clinical trials, we need to understand the environment that supports and controls neural stem cell survival, proliferation, and functional integration into the brain. This “neurogenic” environment is controlled by local cues in the neurogenic niche, by cell-intrinsic factors, and by soluble factors which can act as mitogens or inhibitory factors potentially over longer distances. While some of these factors are starting to be identified very little is known why neurogenesis decreases so dramatically with age and what factors might mediate these changes. Because exercise or diet can increase stem cell activity even in old animals and lead to the formation of new neurons there is hope that neurogenesis in the aged brain could be restored to that seen in younger brains and that stem cell transplants could survive in an old brain given the right “young” environmental factors. Indeed, our preliminary data demonstrate that systemic factors circulating in the blood are potent regulators of neurogenesis. By studying how the most promising of these factors influence key aspects of the neurogenic niche in vitro and in vivo we hope to gain an understanding about the molecular interactions that support stem cell activity and the generation of new neurons in the brain. The experiments supported under this grant will help us to identify and understand the minimal signals required to regulate adult neurogenesis. These findings could be highly significant for human health and biomedical applications if they ultimately allow us to stimulate neurogenesis in a controlled way to repair, augment, or replace neural networks that are damaged or lost due to injury and degeneration.

Statement of Benefit to California: 

In California there are hundreds of thousands of elderly individuals with age-related debilitating brain injuries, ranging from stroke to Alzheimer’s and Parkinson’s disease. Approaches to repair the injured brain or even prevent age-related neurodegeneration are in their infancy but there is growing interest in the role of neural stem cells in these conditions. However, to potentially utilize such stem cells we need to understand the basic mechanisms that control their activity in the aging brain. The proposed research will start to address this problem using a novel and innovative approach and characterize protein factors in blood that regulate stem cell activity in the old brain. Such factors could be used in the future to support stem cell transplants into the brain or to increase the activity of the brain’s own stem cells.

Grant Type: 
Basic Biology II
Grant Number: 
RB2-01602
Investigator: 
ICOC Funds Committed: 
$1 387 800
Disease Focus: 
Epilepsy
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 

There are now viable experimental approaches to elucidate the genetic and molecular mechanisms that underlie severe brain disorders through the generation of stem cells, called iPS cells, from the skin of patients. Scientists are now challenged to develop methods to program iPS cells to become the specific types of brain cells that are most relevant to each specific brain disease. For instance, there is evidence that defects in cortical interneurons contribute to epilepsy, autism and schizophrenia. The experiments proposed in this grant application aim to understand basic mechanisms that underlie the development of cortical interneurons. We are discovering regulatory elements (called enhancers) in the human genome that control gene expression in developing interneurons. We have three experimental Aims. In Aim 1, we will study when and where these enhancers are expressed during mouse brain development. We will concentrate on identifying enhancers that control gene expression during development of specific types of cortical interneurons, although we hope to use this approach for additional cell types. Once we identify and characterize where and when these enhancers are active, in Aim 2 we will use the enhancers as tools in human stem cells to produce specific types of cortical interneurons in the test tube. The enhancers will be used to express proteins in the stem cells that will enable us purify only those cells that have specific properties (e.g. properties of cortical interneurons). In Aim 3 we will explore whether the human brain produces cortical interneurons in the same way as the mouse brain; this information is essential to identify molecular markers on the developing interneurons that could be used for further characterization and purification of the interneurons that we care generating in Aim 2. We want to emphasize that while the experiments focus on cortical interneuron subtypes, our work has general implications for the other types of brain cells our labs study, such as cortical and striatal neurons. In sum, the basic science mechanisms that we will discover will provide novel insights into how to generate specific types of neurons that can be used to study and treat brain diseases.

Statement of Benefit to California: 

Large numbers of California residents are stricken with severe medical disorders affecting the function of their brain. These include epilepsy, Parkinson’s Disease, Alzheimer’s Disease, Huntington’s Disease, Autism and Schizophrenia. For instance, a recent report from the Center for Disease Control and Prevention [www.cdc.gov/epilepsy/] estimates that 1 out of 100 adults have epilepsy. In California, epilepsy is one of the most common disabling neurological conditions, with approximately 140,000 affected individuals. The annual cost estimates to treat epilepsy range from $12 to $16 billion in the U.S. Currenlty up to one-third of these patients are not receiving adequate treatment, and may benefit from a cell-based transplantation therapy that we are currently exploring with our work in mice.
There are now viable experimental approaches to elucidate the genetic and molecular mechanisms that underlie these neuropsychiatric disorders through the generation a stem cells, called iPS cells, from the skin of patients. Scientists are now challenged to develop methods to program iPS cells to become the specific types of brain cells that are most relevant to each specific brain disease. For instance, there is evidence that defects in cortical interneurons contribute to epilepsy, autism and schizophrenia. The experiments proposed in this grant application aim to understand basic mechanisms that underlie the development of cortical interneurons. We are discovering regulatory elements (called enhancers) in the human genome that control gene expression in developing interneurons. Our experiments will help us understand fundamental mechanisms that govern development of these cells. Furthermore, we have designed experiments that harness these enhancers to drive the production of specific subtypes of these cells from human stem cells. This will open the door to making these types of neurons from iPS cells to study human disease, and potentially to the production of these neurons for transplantation into patients whose interneurons are deficient in regulating their brain function. Furthermore, the approach we describe is general and readily applicable to the generation of other brain cells. Thus, the results from these studies will provide essential and novel basic information for understanding and potentially treating severe brain disorders.

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