Nanomedicine

NanoMedicine Center for Mechanics in Regenerative Medicine

Major innovations in biomedicine and in our understanding of how cells work were made possible through the last decades by a series of new technologies, from biochemistry starting in the 70s, to biotechnology, and finally through the deciphering of the human genome at the end of the 90s. Although we understand many aspects of the biochemistry of cells, we have very little knowledge of the mechanical aspects of cells that enable 40 micron cells to shape an organism many meters in size. Similarly, in disease we do not understand how tissues become abnormal such as in cancers or cardiac hypertrophy. The processes whereby cells sense and shape their mechanical environment are critical. Cells respond to primary mechanical cues, force and geometry, through a series of steps that begin at the molecular (nanometer) level. Intracellular systems sense force and/or nanometer level geometry, and transduce the cues into biochemical signals that are then processed over space and time to give mechanoresponses that then cycle back to change the mechanical cues. The long-term effects of these cycles determine whether cells grow or die, the shape of the organism and whether many tissue functions are effective. Defects in mechanosensing, transduction, or responses underlie many diseases such as cancers, immune disorders, cardiac hypertrophy, genetic malformations, and neuropathies. New technologies in nanofabrication and single molecule mechanics enable us to analyze cellular mechanical processes at a molecular level. In the term of this grant, we plan to develop an understanding of cellular mechanical biology that will begin a Cell Operations Manual. With clinical information, we hope to develop a Cell Repair Manual for critical diseases of cellular mechanics.

Nanomedicine Challenges

The underlying machinery that allows cells to sense and respond to the mechanical aspects of their environments is made of intricate physically-coupled protein networks which connect cells with their environment. These networks convert mechanical stimuli into biochemical signals, they integrate mechanical cues over many length scales and ultimately regulate diverse cell functions, from differentiation to apoptosis. One of the most innovative aspects of our program is the concerted effort to build a quantitative description of the cellular machinery that eukaryotic cells possess for the sensing of force and the geometric features of their environment. In order to understand cellular processes not only based on their inventory of molecular players but also at the systems bioengineering level, we have brought together a diverse team of scientists, engineers and mathematicians to understand mechanotransduction at the cell and molecular level. At the nanoscale, we analyze these systems bringing together cutting-edge technologies developed by biologists, chemists, engineers and computational scientists in a way that differs from conventional approaches.

Understanding the roles of force and geometry in regulating cell functions requires the development of detailed quantitative pictures of this machinery at both the single molecule level, describing how single molecules respond to mechanical forces (functional changes imposed by the forced-unfolding of biomolecules), and at the nanoscale, describing how supramolecular complexes regulate each other via physical means by coupling force-generating elements (motor proteins) with force-bearing elements and force-sensitive elements that respond to the rigidity and form of the environment. Further, we will need an understanding of how forces regulate signaling pathways and gene expression. Position, force, and dynamic binding constants determined by in vitro assays may not be relevant in vivo because of mechanical aspects; therefore, in vivo dynamic measurements are critical. The tools of nanotechnology and modern cell biology now provide the means to investigate many of the physical aspects of these complex processes at the micro- and nanometer scale. For nanomedicine to become a reality, our goal is to fully understand and characterize these physical phenomena. From an understanding of the molecular mechanisms of mechanotransduction in cells, we can develop models to be tested in cell-substrate and multicellular systems. This research will provide important new approaches to stop metastases, to facilitate wound healing and many other medical problems that depend upon mechanotransduction. We believe that the only way to gain a meaningful understanding of mechanotransduction is to develop an integrated engineering approach, ranging from the individual molecular and nanoscale components all the way to learning how forces regulate cell shape, cell migration, and cell function. Generating a well-defined, and extensive knowledge base of cellular forces and employing an engineering approach allows us to view the cell as a "complex machine" that can activate highly specialized tool sets to accomplish the necessary tasks at a number of different hierarchical levels. Our macroscopic paradigms for engineering the static force-bearing junctions in buildings, cars, etc. are inapplicable at the cellular level. Understanding the transduction and generation of force in systems whose components are simultaneously undergoing assembly and disassembly, creation and decay, will require the development of new paradigms that are necessarily more complex. This is particularly true if we hope to understand these systems quantitatively. Although we have a molecular parts list, we lack the understanding at the engineering level of how tools are used in cellular mechanics from sensing to response. The goal is that our program will act as a nucleation point to collect and disseminate relevant information and technologies to the broad national and international community and complimentary to the efforts of other programs such as the Consortium on Cell Migration.

Nanomedicine: Future Perspectives and Anticipated Impact

The physiological and medical relevance of deciphering the underlying mechanisms of cellular mechanics is profound; fundamentally new insights will be obtained into how the processes of cell migration, metastasis, angiogenesis, immune function and osteogenesis are regulated by mechanical forces. Since we believe that the control of forces and force-bearing contacts at the cellular level defines the morphology of all tissues and appears to play an important role in many cell functions, it follows that the proposed research will result in new strategies for treating wound healing, hypertension, cardiovascular diseases, osteoporosis, nerve regeneration and the manipulation of the immune response. From metastases to tissue malformation, the sensing and processing of mechanical and matrix cues is abnormal. Therefore, by understanding the molecular pathways involved in determining form and function, we can develop strategies to alter the cellular level responses to correct defects. Many of our recent findings, including the observation that the mechanical unfolding of proteins inside and outside the cell transduces force into biochemical signals, are novel and suggest diagnostics and treatments that are radically different from those used for conventional enzymatic pathways. For example, because the unfolding of proteins exposes new sequences that are then phosphorylated to give focused responses, we may be able to selectively block migration (metastases) with small peptides that would also undergo phosphorylation and block normal component assembly and migration. Furthermore, as we gain fundamentally new insights into the dynamic interplay of cells with their biological and synthetic matrices, we will obtain new insights into how to engineer synthetic surfaces and tissue scaffolds (tissue engineering) for optimal function. Finally, we will define the role of mechanical force in the functional regulation of interconnected protein networks, which is crucial to systems biology.

Investigators

*Principal Investigator

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