Yan Yang - US grants

This basic research project will develop new statistical techniques that will provide more robust estimates of the Value-Added Models (VAM). Multivariate response value-added models will be developed to include continuous and categorical responses and nested data structures, and address missing data problems. These models will employ latent-class mixture models, and will use classification trees and random forest methods for data analyses. The new techniques will allow the models to be used not only with continuous response data, such as test scores, but also categorical response data such as completion of a STEM degree. The techniques will also allow researchers to investigate the effects of missing data on value added models, as can occur when students drop out of STEM degree programs during college. The models will improve upon the current VAM models in three aspects: 1) incorporating the various missing data structures, 2) considering both continuous and categorical outcomes, and 3) taking into account complex relationships among subgroups of students and program characteristics.

The potential benefits of developing such value added statistical models will be for informing educational policy and practice. These benefits will include better decisions based on more precise estimates of teacher effects and the effects of other inputs on student outcomes in STEM. The researchers propose to address limitations of current value-added models to provide stronger models for assessing STEM program effectiveness and measure teacher or school effects on student achievement.

DESCRIPTION (provided by applicant): Oligodendrocyte precursors (OPCs) differentiate into oligodendrocytes that are the myelinating cells of the vertebrate CNS. Myelin sheaths wrap axons in the brain and spinal cord and maintain axonal function and promote rapid conduction of electrical impulses. Any damage to myelin sheaths, such as occurs in multiple sclerosis, results in loss of axonal conduction and ultimately axonal degeneration and irreversible neural disability leading to serious physical or mental impairments. Multiple sclerosis is a devastating disease that affects more than 300,000 individuals in the United States. Current therapies are directed towards regulating the inflammatory aspects of the disease, however long term functional recovery will depend upon successful myelin repair in the CNS. Recent studies suggest that many areas of demyelination in the brains of MS patients contain OPCs but the ability of these cells to repair damage is limited because they fail to differentiate for reasons tat are currently unknown. A detailed understanding of the mechanisms controlling OPC maturation and myelination will therefore provide new insights and novel therapeutic strategies for enhancing myelin repair in MS. The experiments described in this proposal will explore the roles of the intracellular signaling molecule cyclin dependent kinase 5 (Cdk5) and its co-activators p35/p39, in regulating the development of OPCs, myelination and remyelination. Cdk5 is known to be involved in various signaling pathways that are key for CNS development. Our preliminary data has revealed novel functions of Cdk5 in controlling the development of OPC and myelination. The proposed study will explore whether Cdk5 within cells of the oligodendrocyte lineage regulates their development and myelination in vitro and in vivo using molecular and genetic approaches. We will identify the roles p35/p39 play in mediating Cdk5 modulation of OPC maturation and myelination. To determine whether the Cdk5 pathway is a novel potential target for therapeutic development we will test whether Cdk5 is essential for remyelination in adult CNS after the induction of focal demyelinating lesions. To accomplish this we will selectively delete Cdk5 from OPCs in the adult CNS during demyelination. Successful completion of the proposed studies will provide critical insights into the signaling mechanisms regulating OPC maturation and myelination and provide novel targets to promote myelin repair. PUBLIC HEALTH RELEVANCE: Multiple sclerosis is a devastating, irreversible and progressive disease that result from failure of myelin repair and degeneration of demyelinated axons. Unfortunately, no effective therapeutics are currently available to promote myelin repair. Understanding OPC differentiation and myelination is critical for developing new strategies for promoting repair of myelin lesions in MS patients. We have identified Cdk5 as an important regulator of oligodendrocyte development and the current studies will define the role of Cdk5 and its activators, p35 and p39 in myelination and myelin repair. Results of our studies will provide critical insights into the signaling mechanisms regulating OPC maturation and myelination and provide novel targets to promote myelin repair.

? DESCRIPTION (provided by applicant): The goal of this SBIR Phase II proposal is to conduct the advanced development of the 3rd-gen Thermoresponsive NanoVelcro assay in order to achieve rapid purification of circulating tumor cells (CTCs) from non-small cell lung cancer (NSCLC) patient blood samples, paving the way for CTC-derived molecular signatures and functional readouts. This project is led by Dr. Garcia (PI), who has extensive experience in early-stage development of the technology and has a background in surface chemistry, microfluidics, and in vitro diagnostic technologies. He is supported by an interdisciplinary team comprising business development, FDA expertise, QC/QA management, nanotechnology support, lung cancer, clinical utility, genetic analysis, biostatistics, industrial collaborators, nd downstream potential customers. NSCLC accounts for >70% of lung cancer cases. Since NSCLCs are usually not very sensitive to chemotherapy and/or radiation, the advent of targeted therapy by epidermal growth factor receptor (EGFR) inhibitors offer a great treatment options to a sub-population of NSCLC patients who carry oncogenic driver mutations in their EGFR genes. To guide the implementation of targeted therapy, invasive biopsy or surgery is employed to sample NSCLC tissues for determining the presence of these EGFR mutations. However, these invasive sampling procedures impose significant risk to the patients. As an alternative, CTCs can be captured repetitively and analyzed in a minimally invasive manner thus providing a systemic picture of the malignant clones that possess high metastatic capacity. The proposed Thermoresponsive NanoVelcro assay is composed of two individual components: i) a digital fluidic handler with an embedded temperature control module, and ii) a custom-designed chip holder, in which a clamp-down design allows instant assembly of a NanoVelcro substrate with an overlaid PDMS component, will be designed and fabricated at CytoLumina. To highlight the significance of our downstream studies, we will gather serial blood samples from lung cancer patients. We will collect the purified CTCs and subject them to mutational analysis for eight genes, including EGFR., Further, the purified CTCs will be introduced to a variety of in vitro cell culture systems (i.e., microfluidic and 3D cell-culture platforms) established by our joint team (UCLA and CytoLumina) to create viable CTC cell lines. The personalized cell lines will be used to study patterns in drug susceptibility, which is linked to the underlying genetic driver mutation.