Daniel Marenda - US grants

DESCRIPTION (provided by applicant): Mitogen-activated protein kinases (MAPKs) are a highly conserved family of protein serine/ threonine kinases involved in signal transduction pathways in yeast, flies, and mammals, and are activated in response to a variety of signals. In mammals, MARK proteins p42/p44 (also called ERK 1/2) phosphorylate and activate a number of targets in both the cytoplasm and the nucleus, and in cell culture systems, a strong correlation exists between the subcellular localization of MAPK and the subsequent cellular responses elicited. However, preliminary data from our lab suggests that MAPK can function to promote cell proliferation after translocation to the nucleus even when it does not become phosphorylated. I therefore plan to test this suggestion directly, with the following two specific aims: 1) Is MAPK phosphorylation required for MAPK nuclear translocation and cell cycle progression?, and 2) What are the factors mediating MAPK hold in the cyoplasm vs. translocation to the nucleus in cell cycle regulation? As alterations in the Ras/MAPK pathway are associated with approximately 25% of human tumors, a deeper understanding of how MAPK nuclear translocation affects this process could enhance our understanding of human cancers.

DESCRIPTION (provided by applicant): CHARGE Syndrome (CS) is a rare, autosomal dominant disorder that is characterized by a variety of clinical symptoms. The most common of these include Coloboma, Choanal atresia, abnormal semicircular canals, heart defects, mental retardation, retardation of growth, and genital and ear anomalies, making CS a common cause of congenital anomalies. It is prevalent in approximately 1 in every 10,000 live births, and is caused in large part by loss of function mutations in the human Chd7 gene (haploinsufficiency in Chd7). Mutations in Chd7 account for some 2/3 of all patients diagnosed with CS, though little is known about the genes (and cellular processes) this protein regulates. The long term goal of this project is a deeper understanding of the mechanism(s) of pathogenesis of CS through characterization and application of a novel Drosophila model of the disease. Our hope is that research proposed here will ultimately lead to new diagnostic tools and/or therapeutic targets for treatment in patients with CS. Attempts to understand the complex etiology of many human diseases have been improved through the study of model organisms. The fruit fly, Drosophila melanogaster, has been tremendously important and influential in furthering our understanding of the mechanisms of a variety of human diseases. Using an RNA-interference (RNAi) gene knockdown strategy, we have created the first Drosophila model for CS in adult flies. Because kis, and its human homolog Chd7, encode transcription factors, the identification of biologically relevant target genes whose expression is regulated by these transcription factors, and whose function also contributes towards disease pathology will be critically required for a better understanding of this disease's pathogenesis, as well as a better rational design towards therapeutic intervention and/or diagnostic and prognostic indicators. As a model organism, Drosophila are unsurpassed as a tool of gene discovery and functional gene analysis. Using both genetic screening and microarray analysis in Drosophila, we have identified a number of target genes whose expression is regulated by kis function. Many of these target genes have the potential to contribute to one or more aspects of disease pathology. We wish to further test which of the genes that we have identified might contribute to specific aspects of disease pathology in CS through the following specific aim: to employ genetic, behavioral, and cell biological methods to further characterize which Kismet target genes may be biologically relevant to the disease symptoms observed in CS. We will specifically focus our analysis on gross motor dysfunction, intellectual disability, and defects in neuronal morphology. PUBLIC HEALTH RELEVANCE: The fruit fly, Drosophila melanogaster, has been tremendously important and influential in furthering our understanding of the mechanisms of a variety of human diseases, including neurodegenerative diseases, and forms of hereditary mental retardation (MR). Thus, we have created the first Drosophila model for CHARGE Syndrome, an uncommon autosomal dominant form of mental retardation. Using our new model, we will determine what genes functionally contribute to CHARGE Syndrome in flies, with the hope that the research proposed will lead to novel diagnostic tools and/or therapeutic targets for patients with CHARGE Syndrome.

The proper regulation of gene expression is critical for the normal development and function of the nervous system. "Chromatin remodeling", or the alteration of DNA structure, is a key step in gene regulation and is an important process in nervous system development and function. In mammals, the amino acid glutamate mediates the majority of signaling in the nervous system, and regulates processes that underlie learning, memory, and neurodegeneration. Factors that control the development and function of glutamatergic neurons (neurons that use glutamate) are of considerable and broad interest. Yet, these factors are largely unknown. The objective of this project is to better understand the function of the chromatin remodeling protein Kismet in the development and function of glutamatergic neurons. This proposal will utilize both genetics and molecular biology to accomplish this goal. This project will determine which signals activate Kismet, and subsequently, which genes Kismet activates in glutamatergic neurons to regulate their function.

The broader impacts of this project are manifold. First, though these studies are particular to Kismet function in glutamatergic neurons, the results from this research will help us understand how chromatin remodeling factors regulate the function of other cells as well. Second, this project will provide research opportunities for undergraduate students to perform directed research in the Marenda laboratory. Third, this award will support a hybrid class for undergraduate students that will addresses a significant problem in multiple universities: accommodating the large number of undergraduate students who want to participate in undergraduate research, but can not due to limited faculty to student ratios. Importantly, the outcome of this hybrid class is assessed through pre- and post-class surveys. Therefore, this project not only addresses important questions in neural development, but also addresses important concerns in science education and training.

NRT-IGE: Pedagogical Readiness Oversight for Future Educators in STEM Subjects (PROFESS)

Faculty careers are desirable to many graduate students in science, technology, engineering, and mathematics (STEM), yet few STEM graduate trainees are provided with formal opportunities for career development related to academic or other career outcomes. However, it has been demonstrated that engaging in teaching in conjunction with research can promote graduate students? skills relevant to research, without increasing the time to graduation. This National Science Foundation Research Traineeship (NRT) award in Innovations in Graduate Education (IGE) to Drexel University is a pilot to address the need to develop mechanisms to train STEM graduate students to effectively teach undergraduate students. This project will develop and test a new model of graduate education that will enable students to train in educational methods as part of their graduate career and earn an additional advanced degree in STEM education.

The project will support the professional development of STEM graduate students as educators through four targeted goals to (1) train graduate students in evidence-based pedagogical approaches, (2) provide a mechanism for STEM graduate students to earn an MS in Undergraduate STEM Education in addition to their chosen technical PhD, (3) maintain student interest in diverse careers in the professoriate, and (4) support faculty development. The program will leverage the national UTeach program model, currently being replicated at the undergraduate level at Drexel University through the DragonsTeach program. The new courses, including a capstone internship, mentoring activities, and the new degree program will be developed as a cross-university collaboration among STEM education and content faculty and will emphasize the importance of deep content knowledge and research-based pedagogy. To evaluate this pilot, data will be collected on student outcomes and perceptions, faculty perceptions, as well as the value and costs of the pedagogical training as part of a graduate program to determine whether this model is sustainable and transferrable to other institutions.

The NSF Research Traineeship (NRT) Program is designed to encourage the development and implementation of bold, new, potentially transformative, and scalable models for STEM graduate education training. The Innovations in Graduate Education Track is dedicated solely to piloting, testing, and evaluating novel, innovative, and potentially transformative approaches to graduate education.