Recursos de colección

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Biological Engineering - Ph.D. / Sc.D.

Mostrando recursos 1 - 20 de 299

  1. Microfluidic synthesis, characterization, and applications of bioinspired deformable microparticles

    Chen, Lynna
    Polymeric microparticles have a wide variety of uses, ranging from traditional applications in paints and coatings, to specialized applications in medical therapeutics and diagnostics. For biological applications - including drug delivery, analytical assays, and tissue engineering - it is important to tailor the interactions between the microparticles and their external environment. To do this, it is necessary to precisely control the physical and chemical properties of the engineered microparticles. Recently, it has become apparent that in addition to particle chemistry, the physical properties of a particle - for example, size, shape, internal structure, and mechanical deformability - play an important...

  2. Utilizing viruses to probe the material process - structure - property relationship : controlling catalytic properties via protein engineering and nanoscale synthesis

    Ohmura, Jacqueline (Jacqueline Frances)
    From the fabrication of fine chemicals, to the increasing attainability of a non-petrochemical based energy infrastructure, catalysts play an important role in meeting the increasing energy and consumable demands of today without compromising the global health of tomorrow. Development of these catalysts relies on the fundamental understanding of the effects individual catalyst properties have on catalytic function. Unfortunately, control, and therefore deconvolution of individual parameter effects, can be quite challenging. Due to the nanoscale formfactor and wide range of available surface chemistries, biological catalyst fabrication affords one solution to this challenge. To this end, this work details the processing of...

  3. Novel applications and methods for the computer-aided understanding and design of enzyme activity

    Bonk, Brian M
    Despite great progress over the past several decades in the development and application of computer-aided tools for engineering enzymes for a vast array of industrial applications. rational enzyme design remains an ongoing challenge in biotechnology. This thesis presents a set of novel applications and methods for the computer-aided understanding and design of enzyme activity. In the first part. we apply biophysical modeling approaches in order to design non-native substrate specificity in a key enzymatic step (the thiolase-catalyzed condensation of two acyl-CoA substrates) of an industrially useful de novo metabolic pathway. We present a model-guided. rational design study of ordered substrate...

  4. Exploring the mutagenic consequences of inflammation and DNA damage

    Kay, Jennifer Elizabeth, Ph. D. Massachusetts Institute of Technology
    Inflammation is a major risk factor for many types of cancer, and the physiological processes involved in inflammation can contribute to many aspects of cancer development. Inflammation entails reprogramming of cell behaviors that resemble cancer, such as increased proliferation and signals for survival and migration, and it also entails production of reactive chemical species, which can damage DNA to promote genetic instability, another hallmark of cancer. While much research has been dedicated to studying the relationships between inflammation and cancer, it has been difficult to distinguish the relative contributions of modified cell behavior and de novo mutagenesis to the development...

  5. The role of megakaryocytes and platelets in infection and immunothrombosis

    Frydman, Galit Hocsman
    Megakaryocytes (MKs), one of the largest and rarest hematopoietic stem cells in the bone marrow, have traditionally played a primary role in hemostasis as precursors to platelets, which are importantly, one of the most abundant cell types in the peripheral circulation. While platelets are studied for their various roles in inflammation, the role of MKs within the innate immune system has not been explored. In a series of comprehensive in vitro experiments, we have demonstrated that both cord blood-derived MKs and MKs from a megakaryoblastic lineage have innate immune cell functions, including: phagocytosis, formation of extracellular traps, and chemotaxis towards...

  6. Leveraging cell micropatterning technology for rapid cell-based assessment of chemical toxicity and population variation in toxicity susceptibility

    Ngo, Le Phuong
    With the advent of combinatorial chemistry, the number of novel synthetic chemicals has skyrocketed over the past three decades, bringing about tremendous advances in medicine and material science. At the same time, the massive libraries of existing chemicals coupled with the unprecedented rate of new chemical generation presents a unique and costly challenge to toxicity testing in the 21 st century. In recent years, the United States has seen large coordinated efforts across governmental agencies to shift from expensive and slow traditional in vivo tests to more affordable and higher throughput in vitro methods. For each human cell, about 100,000...

  7. Illuminating epithelial-stromal communication using engineered synthetic matrix microenvironments

    Cook, Christi Dionne
    Mucosal barrier tissues are prominent targets for drugs against infection and chronic inflammatory disorders. One such mucosal barrier tissue, the endometrium, undergoes monthly cyclic remodeling via hormone-mediated growth, immune cell recruitment and proteolytic breakdown. Hormone response disruption has been associated with numerous endometrial pathologies, including endometriosis, adenomyosis, and infertility, which impacts upwards of 10% of women during their reproductive years. Currently, our understanding of endometrial biology is limited by the ability to replicate complex 3D physiology in vitro. Our ability to parse disease mechanisms and test efficacy of therapeutic interventions relies on development of reproducible models, adaptable to the limited...

  8. Synthetic biology approaches for engineering diverse bacterial species

    Brophy, Jennifer Ann Noelani
    When engineers control gene expression, cells can be re-programmed to create living therapeutics or materials by initiating expression of biosynthetic pathways in response to specific signals. In this thesis, two new genetic tools were developed to aid the construction of genetic circuits and facilitate their delivery to bacteria isolated from diverse environments. First, antisense transcription was explored as a new tool for tuning gene expression in Escherichia coli. Antisense transcription was found to reliably repress gene expression and was applied tune simple genetic circuits. Second, an integrative conjugative element from Bacillus subtilis, ICEBsJ, was engineered to deliver exogenous DNA to...

  9. Regulatory systems for the robust control of engineered genetic programs

    Segall-Shapiro, Thomas Hale
    The ability to engineer complex genetic programs could have a huge impact on many industries, yielding organisms that can respond to their environment and perform functions relevant to manufacturing, agriculture, and medicine. However, such engineering efforts have proven difficult, in part because these programs often require precise levels of gene expression for proper function. It is especially tough to build programs that have robust activity, as any changes to the host cells can perturb the context of the genetic system and disrupt carefully tuned expression levels. Additionally, genetic programs often place high demands on host resources, which can adversely affect...

  10. A multiplexed approach for quantitative profiling of the translatome using bioorthogonal non-canonical amino acids

    Rothenberg, Daniel Abram
    One of the major goals of systems biology is understanding how a cell changes from a healthy state to a diseased state. Entire fields of cell biology have been built around studying how changes in the type and abundance of specific biomolecules affect disease status. However, one major knowledge gap in systems biology is the quantification of protein synthesis rate at any given time (i.e the Translatome). At this time, measurements of protein synthesis rates are limited to methods that use mRNA abundance as a proxy; however, there are regulatory steps on the level of translation that can confound correlation...

  11. Bioimage informatics for understanding the effects of chemotherapy on cellular signaling, structure, and function

    Gordonov, Simon
    Chemotherapy is widely used in the treatment of solid tumors, but its effects are often associated with cancer relapse, metastasis, and drug resistance. The biological mechanisms that drive the structural and functional changes in cancer cells associated with these features of disease progression remain poorly understood. Consequently, quantitative characterization of molecular signaling pathways and changes in cancer cell phenotypes induced by chemotherapy through the use of in vitro model systems would expand our understanding of drug mechanisms and provide for putative strategies to counteract drug-induced cancer progression. Toward this end, I develop bioimage informatics tools to characterize changes in signaling,...

  12. Engineering immunity : enhancing T Cell vaccines and combination immunotherapies for the treatment of cancer

    Moynihan, Kelly D. (Kelly Dare)
    Checkpoint blockade with antibodies against CTLA-4 or PD-1 has demonstrated that an endogenous adaptive immune response can be stimulated to elicit durable tumor regressions in metastatic cancer, but these dramatic responses are confined to a minority of patients¹-³. This outcome is likely due in part to the complex network of immunosuppressive pathways present in advanced tumors, which necessitates the development of novel therapeutics and combination immunotherapies to generate a counter-directed network of pro-immunity signals⁴-⁸. In Chapters 2 and 3 of this thesis, we describe methods for enhancing T cell priming against tumor antigens via covalent modification of molecular vaccines to...

  13. Understanding biological hydrogel function through design of simplified peptides and polymers

    Chen, Wesley George
    Biological hydrogels exhibit complex properties that cannot be recapitulated by current synthetic materials. Examples include mucus, which acts as a barrier against toxins and pathogens while simultaneously hosting trillions of microbes within the gut; cartilage which resists repetitive compressive forces while maintaining highly lubricated layers for efficient movement; and nuclear pore matrices which act as selective barriers in the transport of proteins and nucleic acids. An underlying theme that gives biological hydrogels their unique mechanical and biological functions is the presence of long polymeric molecules. These polymers are typically comprised of repeating subunits that are essential for correct polymer function,...

  14. Understanding biological hydrogel function through design of simplified peptides and polymers

    Chen, Wesley George
    Biological hydrogels exhibit complex properties that cannot be recapitulated by current synthetic materials. Examples include mucus, which acts as a barrier against toxins and pathogens while simultaneously hosting trillions of microbes within the gut; cartilage which resists repetitive compressive forces while maintaining highly lubricated layers for efficient movement; and nuclear pore matrices which act as selective barriers in the transport of proteins and nucleic acids. An underlying theme that gives biological hydrogels their unique mechanical and biological functions is the presence of long polymeric molecules. These polymers are typically comprised of repeating subunits that are essential for correct polymer function,...

  15. Systems modeling of quantitative kinetic data identifies receptor tyrosine kinase-specific resistance mechanisms to MAPK pathway inhibition in cancer

    Claas, Allison
    Targeted cancer therapeutics have seen constraint in clinical efficacy due to resistance. Indicators for resistance may include genetic mutations or protein-level overexpression of targeted or bypass receptor tyrosine kinases (RTKs). While the latter is often attributed to gene amplification, genetic characterization of tumor biopsies has failed to explain substantial proportions of resistance. We hypothesize that post-synthesis mechanisms governing RTK levels may represent underappreciated contributors to drug resistance. We have developed an experimental and computational model for the simultaneous analysis of synthesis and post-synthesis mechanisms contributing to protein level changes. The experimental component quantitatively measures processes operating on multiple time scales...

  16. RNA tools for optimization of multi-protein genetic systems

    Ghodasara, Amar
    Balancing protein expression is critical when optimizing genetic systems. Typically, this requires construction of a library where variants of parts (e.g. promoters) are tried for each gene, which can be expensive and time-consuming. Here, we present an approach that leverages transacting RNA regulators to explore large gene expression spaces without de novo library construction. First, we developed six sRNAs whose strengths have been optimized against a set of 15nt "target" sequences that can be inserted upstream of a ribosome-binding site to generate up to 175-fold repression when maximally expressed. By controlling sRNA expression, the targeted gene can be tunably repressed...

  17. The molecular basis for tumor growth suppression by tRNA methyltransferase 9-like (TRM9L)

    Chen, Gu, Ph. D. Massachusetts Institute of Technology
    The human tRNA methyltransferase 9-like (TRM9L) gene is a homolog of yeast Trm9 and human ALKBH8 and it has an important function in suppressing tumor growth in colorectal cancer. Loss of heterozygosity events on the Chromosome 8p22 loci, where TRM9L is located, are overrepresented in a wide variety of cancers, including prostate cancer, breast carcinoma, and hepatocellular carcinoma; downregulation of TRM9L expression is also observed in many different types of cancer. These findings implicate a general role potentially played by TRM9L in tumor suppression. A mechanistic understanding of TRM9L would have a broad impact in oncology. The broad objective of...

  18. The molecular basis for tumor growth suppression by tRNA methyltransferase 9-like (TRM9L)

    Gu, Chen, Ph. D. Massachusetts Institute of Technology
    The human tRNA methyltransferase 9-like (TRM9L) gene is a homolog of yeast Trm9 and human ALKBH8 and it has an important function in suppressing tumor growth in colorectal cancer. Loss of heterozygosity events on the Chromosome 8p22 loci, where TRM9L is located, are overrepresented in a wide variety of cancers, including prostate cancer, breast carcinoma, and hepatocellular carcinoma; downregulation of TRM9L expression is also observed in many different types of cancer. These findings implicate a general role potentially played by TRM9L in tumor suppression. A mechanistic understanding of TRM9L would have a broad impact in oncology. The broad objective of...

  19. Dynamic regulation of bacterial metabolic pathways using autonomous, pathway-independent control strategies

    Gupta, Apoorv
    Metabolic engineering efforts have so far focused on strain optimization through careful metabolic modeling and tinkering with host genomes, through gene knockouts or knockins, to direct flux in desired channels. These efforts have borne fruit with the development of large manufacturing processes for numerous chemicals. The next challenge for metabolic engineering, however, lies in tackling issues associated with construction of more complex pathways, such as those that directly interfere with host metabolism, have branchpoints with promiscuous enzymes, or synthesize toxic intermediates or products. Dynamic metabolic engineering has emerged as a new frontier for tool development to allow regulation and control...

  20. Quantitative analysis of proteotoxicity associated with neurodegenerative disease

    Hesse, William R. (William Reichard)
    Neurodegenerative diseases are a costly burden, both economically and in terms of human suffering. A common feature of neurodegenerative diseases is that they stem from problems with protein folding, but the underlying biology that leads to neuron death is not well understood. Due to this lack of mechanistic information there are currently no therapeutics that treat underlying mechanisms that lead to cell loss. This thesis explores the link between complications in protein folding and cell death. In the first part of this thesis, I combined modeling of the proteotoxicity of polyglutamine (as exemplified in Huntington's Disease) in Saccharomyces cerevisiae with...

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