Isaac Skromne, Ph.D. - US grants

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).

A neural progenitor cell encounters numerous cues during its development, but acquires a distinct fate from hundreds of possible fates. The PI is interested in understanding how neural progenitor cells choose the cues to respond to during their development. For example, his previous work demonstrated that a cell's decision to become brain or spinal cord was controlled by Caudal/Cdx genes. This project examines the role the Fibroblast Growth Factors (FGFs) signaling in regulating Caudal/Cdx activity during the cell?s decision. He will address this issue by altering Caudal/Cdx and FGF gene expression at different times and places during zebra fish development. He expects to uncover the conditions where FGF signaling promotes proliferation and differentiation of brain and spinal cord progenitor cells and where these processes are prevented from occurring. These studies should provide new insights into the mechanisms governing the ability of cells to respond to environmental factors during the development and adult life of an organism. In particular, this research should have broad intellectual implications in the fields of immunology, neurobiology, developmental and cancer biology. This research program is also designed to foster inquiry-based research and communication skills and advance knowledge among graduate and undergraduate students, particularly those from underrepresented minorities.

Project Summary Traditional methods to deliver drugs to bones for the treatment of mineralization diseases, such as Osteoporosis, can also disrupt homeostasis in other tissues. To overcome this important problem it is critical to develop novel drug delivery methods that precisely deliver drugs exclusively to the bones. One novel method of drug delivery uses Carbon nanodots (C-dots), an emerging class of nanoparticles with high stability and excellent biocompatibility. Our work in zebrafish has identified a particular class of C-dots that bind with high affinity and specificity to larval and adult bones, without binding to other tissues. Based on this and additional preliminary evidence, here we seek to develop C-dots as a novel method for the precise delivery of drugs exclusively to bones. By systematically defining the chemical properties of C-dots that are essential for bone binding and drug delivery, we will determine the mechanism of C-dot's binding specificity and affinity to bones, while developing a novel and versatile set of carriers for delivering drugs precisely to bones. As proof of principle that C-dots can be used as novel therapeutic drug delivery system, we are targeting the Retinoic Acid signaling pathway involved in the homeostatic regulation of bone mineralization. Rare mutations in humans have identified Retinoic Acid as a key regulator of bone mineralization. These mutations, which can be faithfully recapitulated in the zebrafish, cause excessive Retinoic Acid accumulation, promote excessive osteocyte cell differentiation, and trigger bone fusions. Thus, recruiting the Retinoic Acid signaling pathway to regulate osteocyte production represents a novel and largely unexplored approach to regulating bone mineralization for disease treatment. We are combining our expertise in carbon-based material chemistry and Retinoic Acid signaling in zebrafish to determine the mechanisms of C-dots binding to bones, and improve their efficiency as a bone-specific drug delivery system. The aims of this project are: 1) to determine C-dots' range of function as bone-specific, drug delivery agents; by loading C-dots with a variety of Retinoic Acid activator and inhibitor drugs and measuring changes in osteocyte cell differentiation and bone mineralization in developing, mature, and regenerating bones; 2) to increase the repertoire of drugs that C-dots can deliver to bones; by chemically changing the linkers and functional groups on the C-dots surface and testing their activity in our osteocyte cell differentiation and bone mineralization paradigm. The development of C-dots as tools for the study and precise treatment of bone mineralization diseases will help increase our understanding of the function of cell signaling in promoting and preventing osteocyte differentiation. By expanding the repertoire of drugs that C-dots can carry, this novel drug-delivery platform will also allow, in future work, to target other processes altering bone homeostasis, including cancer. Thus, cellular and molecular data emerging from the use of C-dot-based reagents will lead to new biological insights and the development of innovative bone therapies.

NON-TECHNICAL ABSTRACT

This project advances our understanding of Carbon dots (C-dots) physical and chemical properties for their application in biological systems. Size, morphology, surface chemistry and method of preparation govern how C-dots interact with biological tissues. C-dots derived from carbon powder are unique in that they bind to mineralized bones with high affinity and specificity. By characterizing the physical and chemical properties that confer these C-dots their unique bone-binding properties, this project will advance our understanding of the interactions between C-dots and mineralized tissues. This is an essential step towards developing C-dots as tools for bone imaging and diagnostic tools, and for the treatment and repair of bone fractures and degenerative diseases (e.g., osteoporosis) that would impact US health. Additionally, this work will support the training of graduate and undergraduate students, fostering inquiry-based research and scientific collaboration essential to develop the skills needed in a thriving US scientific workforce.

TECHNICAL ABSTRACT

The goal of this work is to understand the physical and chemical properties of Carbon nanoparticles (C-dots) for their development as bone-specific drug carriers. C-dots are a new emerging class of nanomaterials whose biological applications in imaging, diagnostics and therapeutics critically depend on their size, molecular structure and material of origin. One particular class of C-dots synthesized from carbon powder have the unique property of binding to mineralized bones in vivo. To advance our understanding of the interactions between C-dots and mineralized tissues this project will (1) determine the intrinsic chemical and physical properties of C-dots that are related to their high affinity and specificity towards mineralized bones, (2) determine how different surface functionalities influence the interactions between C-dots and mineralized bones, and (3) functionally test the ability of C-dots to deliver drugs to bones. By characterizing C-dots' unique bone binding properties, this work will not only uncover the physicochemical principles that allow C-dots binding to bones, but will also discern the molecular principles need to target new nanomaterials to mineralized tissue at the exclusion of other tissues. Thus, the findings of this work will have broad intellectual implications for nanomaterial chemistry and engineering, as well as advancing the development of bone imaging and diagnostic tools for the repair and treatment of bone fractures and degenerative diseases.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.