Peng Jiang - US grants

0744879
Jiang
Photonic crystals and plasmonics are two key techniques that will ultimately enable alloptical integrated circuits and quantum information processing. Unfortunately, the development and implementation of these techniques have been greatly impeded by expensive and painstaking topdown nanofabrication (e.g., electron-beam lithography), which limit the available sample size to less than 1 mm2. By contrast, bottom-up colloidal self-assembly and templating nanofabrication provide a much simpler, faster, and inexpensive alternative to nanolithography in creating highly ordered photonic crystals and plasmonic nanostructures. However, the traditional colloidal self-assembly and templating approach suffers from low throughput, incompatibility with standard microfabrication, and limited crystal structures which greatly hamper the mass-production and on-chip integration of practical nanooptical devices.

Intellectual Merit. This proposal aims to develop understanding and control of a robust spin-coating technology that combines the simplicity and cost benefits of bottom-up self-assembly with the scalability and compatibility of top-down microfabrication. This will enable the creation of wafer-scale photonic crystals and a large variety of functional subwavelength-structured materials. The research plan has four specific objectives: (1) elucidate the basic crystallization mechanisms by which unusual nonclose-packed colloidal crystals form during spin-coating, (2) determine the photonic band gap properties of shear-aligned colloidal photonic crystals, (3) investigate the surface plasmon properties of templated periodic metallic nanostructures, including enhanced optical transmission through subwavelength nanohole arrays and surface-enhanced Raman scattering (SERS) on nanovoid gratings, and (4) develop biomimetic subwavelength-structured antireflection coatings for high-efficiency solar cells.
The proposed experimental and theoretical investigation will lead to significant breakthroughs in a wide spectrum of fields ranging from all-optical integrated circuits to plasmonic sensors to sustainable energy. Improved fundamental understanding of flow-induced crystallization and melting within non-uniform shear flows, a topic that has received little or no examination, will also result. The creative and original components of the research plan rely on the integration of the above four objectives. Insights gained into basic mechanisms facilitate better control over the crucial crystalline parameters for tailoring the optical properties in the later objectives. Most importantly, the periodic plasmonic nanostructures and subwavelength-structured antireflection coatings are indeed 2-D photonic crystals, and are thus studied with similar experimental (optical spectroscopy) and modeling (rigorous coupled-wave analysis) techniques as photonic crystals. The unification of these apparently different but intrinsically interconnected fields under one umbrella ? the spin-coating platform could lead to new optical features that are interesting fundamentally and technologically.

Broader Impacts. In conjunction with student mentorship and curriculum development activities, the closely integrated educational plan focuses on developing several outreach activities to educate K-12 students and teachers as well as the general public on nanooptics and self-assembly. An educational display for the Florida Museum of Natural History?s ?Butterfly Rainforest Center? will be created to disseminate the nanooptical mechanisms of the striking blue colors of morpho butterfly wings and the antireflection properties of butterfly eyes, along with how to mimic these natural photonic crystals and antireflection coatings using colloidal self-assembly. Direct participation of high school students from underrepresented groups in the research program and development of educational modules on making brilliant artificial opals through collaboration with high school teachers will be sought through several successful programs at the university.
The spin-coating platform will advance many other areas that depend on the creation of large-area periodic nanostructures not covered by this proposal, ranging from high-density magnetic recording to bio-microanalysis. The integrated educational program will impact students at all education levels. Outreach efforts through a local museum will bring modern nanooptics to young students and adults through a fun learning experience and participation of high school students in the research program will benefit the students and their larger communities. Collaborative efforts with high school teachers to develop colorful demonstration modules will favorably impact hundreds of students per year at the secondary level with a low annual cost ($1,000) and help the program to spread outside the State of Florida.

Solar energy is clean, abundant, and renewable, but faces challenges mainly due to the high manufacturing and installation costs of photovoltaic modules. Finding novel fabrication techniques for solar energy conversion that could increase efficiency and lower manufacturing cost is a primary challenge in meeting the world's future energy needs in a renewable fashion. This project aims to conduct research on a scalable bottom-up nanofabrication platform that enables industrial-scale production of self-cleaning, broadband antireflection coatings on a large variety of photovoltaics-relevant substrates, such as single-crystalline and multicrystalline silicon, glass, GaAs, and GaSb. This platform combines the simplicity and cost benefits of bottom-up colloidal self-assembly with the scalability and compatibility of top-down microfabrication. The proposed activity is aimed at enabling less expensive and more efficient crystalline silicon solar cells.

The proposed activity, if successful, may lead to reduced manufacturing cost and increased conversion efficiency of crystalline silicon solar cells. Improving the conversion efficiency of solar cells facilitates to reduce the environmental impact and the consumption of oil, natural gas, and fossil fuels-generated electricity. Improved fundamental understanding of subwavelength-grating diffraction may also result from the proposed research. Besides renewable energy, the scalable bottom-up nanofabrication platform has the potential to advance many other areas that depend on the creation of large-area periodic nanostructures, ranging from all-optical integrated circuits to high-efficiency light emitting diodes.

The microelectronics revolution sparked by the invention and the very-large-scale integration of transistors has affected almost every aspect of our daily lives. As the 50-year-old Moore's law is approaching its limits, scientists are now turning to light as the information carrier. Unfortunately, our ability to control light in nanoscopic volumes is in many ways in its infancy, compared with how we can manipulate electrons. A new class of optical materials known as photonic crystals may hold the key to continued progress towards all-optical integrated circuits. However, traditional nanomanufacturing technologies for producing photonic crystals with three-dimensionally ordered nanostructures suffer from low throughput, small sample areas, and high cost. By integrating a simple, fast, and inexpensive colloidal self-assembly methodology with a new type of shape memory polymer, this project will explore a novel scalable nanomanufacturing approach for wafer-scale production of photonic crystals with reconfigurable optical properties. This interdisciplinary research will be closely integrated into curriculum development, new demonstration module design, and training of underrepresented high school and undergraduate students through a few successful programs at the university.

Although various colloidal self-assembly technologies have been developed, most of these bottom-up approaches are only favorable for low volume, laboratory-scale production of photonic crystals. Moreover, self-assembled photonic crystals with fixed microstructures are only appropriate for fabricating passive nanooptical devices. Smart shape memory polymers that can memorize and recover their permanent shapes from structurally stable temporary sates are promising for developing active photonic crystal devices. Unfortunately, most of the existing shape memory polymers are thermoresponsive, and they suffer from heat-demanding shape memory cycles. The research team aims to conduct simultaneous experimental and theoretical investigations to address the key scientific and engineering barriers faced by the current colloidal self-assembly and shape memory polymer technologies. In-situ nanoscopic mechanical and mechanochromic tests, along with multiphysics mechanical finite element analysis simulations will facilitate the basic understanding of the unusual shape recovery mechanisms of the new type of shape memory polymer that enables unconventional all-room-temperature shape memory cycles. The stimuli-responsive microstructure-optical property relationship of the self-assembled photonic crystals will be elucidated by optical characterization and finite element optical simulations. Large-area macroporous polymer photonic crystals with optimal crystal structures and multiple memorizable optical states will be fabricated by the scalable bottom-up nanomanufacturing technology.

Project Summary Background: Drug resistance is a major limit of anti-cancer therapy effectiveness. To identify biomarkers and regulators of drug resistance, many genomics technologies have been applied to identify alterations in patient samples and tumor models. Recent years have seen the rapid growth of cancer genomics data; however, a major gap in the field is a lack of computational frameworks that integrate diverse types of data related with cancer drug resistance to develop response biomarkers and understand resistance mechanisms. To overcome this problem, I have developed prototype computational methods to predict response biomarkers for both targeted therapies and immune checkpoint blockade (ICB), and conducted cell line experiments to validate regulator genes in targeted therapy resistance. In this proposal, I aim to develop novel data-driven methods to overcome the data-to-knowledge challenge in drug resistance research and facilitate precision cancer medicine using a combination of computational and experimental approaches, with a melanoma disease focus. Research: In aim 1 (K99 phase), I will develop a network inference framework to identify regulators of targeted therapy resistance through integrating the molecular profiles of drug resistant cells with gene interaction and regulation networks. The performance of my algorithm will be systematically validated through both public and in-house CRISPR or shRNA screens. In aim 2 (R00 phase), I will create gene biomarkers to predict ICB response and decompose ICB resistance causes, through modeling the gene expression signatures of T cell dysfunction and exclusion in tumor. In aim 3 (R00 phase), I will identify the regulators of ICB resistance through a combination of network-based gene prioritization and mini-pool CRISPR screen on tumor models in syngeneic recipient mice. My extensive background in computational biology and training in experimental biology puts me in a unique position to accomplish this proposal, which requires a seamless integration between data science and functional genomics approaches. Career and Training: I received my PhD in Computer Science at Princeton University, and started postdoc research in the Lab of Prof. X. Shirley Liu at Dana-Farber Cancer Institute and Harvard School of Public Health. During the K99 phase, I will continue to be mentored by Prof. Liu to conduct research. Under the supervision of co-mentors Prof. Kai Wucherpfennig and Myles Brown, I will acquire trainings on CRISPR screening, customized screen library construction, and tumor models in syngeneic recipient mice. This proposed plan would prepare myself as an independent scientist in translational cancer research.

Project Summary The goal of our study is to better understand the pathogenic role of human microglia in Alzheimer?s disease (AD) in Down syndrome (DS) and develop new therapeutic avenues for the treatment of AD in DS as well as AD in general population. Our studies are in line with the goals of RFA-OD-20-005 because we will focus on evaluating the genetic factors associated with trisomy 21 and their impacts on neurodegeneration using human tissue and a novel human-mouse chimeric brain model and we will also use gene editing to remove triplicated genes. The foundation of our studies is that recent genome-wide association studies have shown that many AD risk genes are highly and sometimes exclusively expressed by the brain-resident macrophage, microglia. Recent transcriptomic studies have also clearly demonstrated that human vs. mouse microglia exhibit distinct gene expression profiles, and more importantly, they age differently under both normal and diseased conditions. These findings argue for the utilization of species-specific research tools to investigate microglial functions in human brain aging and degeneration. We propose to use a novel human induced pluripotent stem cell (hiPSC)-based microglial chimeric mouse model that can recapitulate features of adult and aging human microglia to investigate the role of human microglia in AD in DS. While the aggregation of amyloid-beta (Ab) precedes that of tau, tau protein pathology commences in humans much sooner than was previously thought. Contrary to the marked microglial activation reported in amyloidogenic transgenic mouse models, in human brain tissue derived from AD and DS patients, brain regions particularly relevant in AD development, such as the hippocampal formation, exhibit low and late Ab pathology, whereas hyperphosphorylated tau (p-tau) accumulates starting in the early stages of the disease. The preferential accumulation of p-tau over Ab plaques could induce a totally different microglial response. Here we put forward a new tau/microglial senescence hypothesis that human microglial senescence and functional changes, induced by soluble p-tau, likely occur prior to neurodegeneration and is causatively linked to the AD progression and cognitive decline in DS. We have created control and DS microglial mouse chimeras by engrafting control and DS hiPSC-derived microglia into mouse brains. We will characterize the dynamic responses of DS and control hiPSC-derived microglia to pathological soluble p-tau in human microglial chimeric mouse brains, by using newly invented robotic four-dimensional long-term imaging technology. We will determine the changes in synaptic functions by electrophysiological recordings and behavioral performance of DS microglial chimeras after exposure to pathological soluble p-tau, as compared to control microglial chimeras. Moreover, single-cell RNA-sequencing analysis of chimeric mouse brains and CRISPR/Cas9-mediated removal of triplicated genes will be performed to determine the molecular mechanisms underlying the pathogenic role of microglia. By understanding the underpinning mechanisms, we can develop new therapeutic strategies to prevent human microglial senescence to slow the progression of AD in DS.

Down syndrome (DS), caused by triplication of human chromosome 21 (HSA21), is the most common genetic origin of intellectual disability. Studying DS disease mechanism is challenging because functional human DS brain tissues are scarcely available and transgenic mouse models of DS demonstrate incomplete/inaccurate expression of HSA21 genes. The advent of human induced pluripotent stem cell (hiPSC) technology has led to the generation of DS patient-derived hiPSCs, which presents an unprecedented opportunity for studying the pathogenesis of DS with unlimited human brain cells in vitro. While using the hiPSC-based in vitro models, basic aspects of the disease phenotypes can be examined, the disruption of neural circuits in the developing brain under disease conditions remains to be studied with hiPSCs. Ultimately, specific developmental and disease mechanisms can only be modeled in live animals to identify links between cellular phenotypes and behavioral performance. Therefore, we propose to employ hiPSC-based chimeric mouse brain models to study the neuropathophysiology of DS in vivo. Microglia play critical roles in brain development and are also an active player in learning and memory processes. Surprisingly, very little information is available on how trisomy of HSA21 alters the development and functions of microglia and what roles microglia play in the abnormal brain development and cognitive deficits in DS. In addition, mounting evidence indicates that rodent microglia are not able to fully mirror the properties of human microglia in normal and disease conditions. In this study, we will use our recently created hiPSC microglial chimeric mouse model to unravel the role of microglia in DS pathogenesis in an in vivo system with intact neural networks. We hypothesize that unlike engrafted normal human microglia, engrafted diseased DS human microglia will show abnormal biological properties and functions, such as synaptic pruning function in vivo. These abnormal properties of DS microglia will result in their negative regulation of the synaptic activity and plasticity of the hippocampal neural network, critically contributing to the cognitive deficits seen in DS. This hypothesis will be tested in three specific aims. Aim 1: we will determine the differences between DS and control hiPSC-derived microglia in vivo in human microglial chimeric mouse brains. Aim 2: Using the microglial chimeric mouse model, we will further examine the impact of integration of DS microglia on synaptic plasticity of the hippocampus and learning and memory behavior of the animals. Aim 3: We will normalize the expression of the HSA21 genes by CRISPR/Cas9 to examine how this will alter the properties of DS microglia. Moreover, single-cell RNA-sequencing analysis of hiPSC microglial chimeric mouse brains will be performed to compare gene expression profiles of control and DS microglia. Findings from our study using a powerful, new hiPSC microglial chimeric mouse model will provide novel insights into the pathological roles of human microglia in DS. Identifying the potential molecules that can be targeted to improve microglial function may provide a new therapeutic avenue for the treatment of DS.