Neurodegenerative disorders, including Alzheimer's Disease and Parkinson's Disease, have become an increasingly important concern due to the expanding elderly people. The cost to society is immense, and successful new drug or cell therapies would result in an enormous savings to society, in addition to alleviating patient suffering. Neural damage as a result of stroke or trauma to the brain or spinal cord is also a leading cause of death and disability, and neuronal death is an important cause of some of the most intractable forms of epilepsy. Few therapies are available for these neurological disorders. Providing a supply of new, functional neural cells at the site of the lesion, including new neurons, astrocytes and glial cells, have been proposed as means to ameliorate neural degeneration or damage. One proposed strategy for achieving this goal is to transplant neural stem and progenitor cells into the brain or spinal cord, such that they develop into specialized neural cells. An alternative strategy is to boost or initiate endogenous neurogenesis by delivering biologically active molecules to the brain or spinal cord, so as to stimulate the proliferation, differentiation and migration of endogenous neural stem or progenitor cells. Ideally, with either approach, the new cells will correctly reconstruct neuronal circuits, produce neurochemically active substances, and integrate into existing functional neural circuity. However, the development of effective therapies for treating neural repair is currently limited by the lack of understanding of the mechanisms that control neurogenesis. To develop improved therapies will thus require the identification of signal transduction pathways involved in neurogenesis and the regulators of these pathways. By identifying such pathways and regulators, new drugs can be developed that modulate neurogenesis in either ex vivo or in vivo applications. Thus, there exists a need to identify signal transduction pathways for modulating neurogenesis. Identification of extrinsic factors coordinating the proliferation and maturation of neural stem cells and progenitors in normal brain as well as after brain injury may lead to novel drug candidates and/or therapeutic targets for neural repair.
Statement of Benefit to California:
Neurodegenerative disorders, including Alzheimer's Disease, Parkinson's Disease, have become an increasingly health concern due to the expanding elderly population. Neural damage as a result of stroke or trauma to the brain or spinal cord is also a leading cause of death and disability. No adequate therapy is available for these delabiliting neurological disorders. California, with one of highest ratio of retired population, has increasing number of people suffer from these debilitating neurological disorders, sometimes for many years. The cost is immense, and progress at prevention and new drug or cell treatment would result in an enormous savings to our state, in addition to alleviating patient suffering. Here we propose to study the effect of a newly discovered molecule on the differentiation of cultured human neural stem cell. We will also study whether the delivery of this molecule into brain can ameliorate the neural damage caused by stroke. The successful completion of these aims may lead to validation of a potential novel drug therapy or new drug target for treating stroke and other neurological disorders. This grant application will also benefit the State of California and its citizens by creating intellectual properties, and help the training of next generation scientists of neural repair and neural regeneration.
This proposal is based on the recent discovery that a secreted protein, prokineticin 2 (PK2), functions as a chemical guide for the migration of progenitor cells of the subventricular zone. PK2 also promotes the differentiation of adult mouse neural stem cells (NSCs) along the neural (not the glial) pathway. The long-term goals of this proposal are to gain insight into the role and signaling mechanisms of PK2 in the differentiation of NSC, to understand the role of PK2 in neurogenesis under normal and diseased conditions; and to evaluate the possible use of PK2 and/or its receptor as possible therapeutic targets for neural repair. The specific aims are: to study the effect of recombinant PK2 on the differentiation of cultured human NSC; 2) to investigate whether infusion of PK2 in to the cerebral ventricles will boost ischemia-induced neurogenesit; and 3) to determine whether ischemia-stimulated neurogenesis is altered in PK2-deficient mice. SIGNIFICANCE AND INNOVATION: This proposal has limited significance and originality with respect to the use of hES cells. Two of the three aims do not use ES cells at all. STRENGTHS: The PI has interesting findings indicating important effects of PK2 on neuroblast migration and differentiation. WEAKNESSES: This proposal is only marginally related to the RFA, which was directed toward the study of human embryonic stem cells. Two of the three aims involve important and interesting studies on the effect of PK2 on ischemia-induced neurogenesis in rodent models, and do not involve hESCs at all. The third aim, which is related to the other two only by the use of PK2, intends to investigate the hypothesis that expression of PK2, which has recently been shown to be a functional target gene of pro-neural HLH transcription factors, is related to the change from of hESCs from pluripotency to neural progenitor cells. No clear rationale is provided for why these experiments are being done with hESCs rather than mESCs.