“Probing the functional heterogeneity of high-density lipoprotein using physiological biomimicry”
Funded by NIH Director's New Innovator Award
Therapeutic strategies raising plasma high-density lipoprotein (HDL) levels failed to demonstrate reduced cardiovascular events in patients with coronary artery disease (CAD). Recent studies have provided insight into the possible mechanisms by which compositional alterations of HDL in patients with CAD leads to the functional heterogeneity. This continuous remodeling generates a heterogeneous population of circulating HDL, which can have distinct effects on endothelium. Due to the overwhelming number of HDL component combinations, the mechanisms of the altered effects on endothelial function remain poorly understood. Moreover, recent genetic studies suggest that bare measurements of plasma HDL levels are insufficient to accurately capture the functional variations caused by dynamic remodeling of HDL compositions. Furthermore, the inability of conventional experimental models to create a disease-relevant state underscores the development of an in vitro model that reconstitutes pathophysiological conditions of vascular ECs in atherosclerosis. We propose to comprehensively investigate the endothelial effects of a wide-ranging library of engineered HDL-based nanoparticles (eHNPs) with representative functional proteins in pathophysiologically relevant microenvironments. We will create a novel in vitro surrogate model that replicates the structural and functional complexity of the human coronary artery and study the heterogeneous endothelial effects of various eHNPs for the treatment of atherosclerosis. The successful outcomes will provide a better understanding of the mechanisms leading to altered endothelial effects of HDL, improve the outcomes of the clinical studies by determining effects of alterations in the HDL proteome, and potentially lead to novel therapeutic measures capable of preventing the progression of atherosclerosis.
"Advanced CNS delivery of microglial Kv1.3 channel inhibitor for attenuation of neuroinflammation in Alzheimer's disease"
In collaboration with Dr. Srikant Rangaraju at Emory
Microglia are the innate immune cells of the CNS that mediate opposing deleterious pro-inflammatory and protective anti-inflammatory functions in Alzheimer’s Disease (AD). Specific inhibitors of pro-inflammatory microglial functions with high CNS bioavailability are desperately needed as disease-modifying treatments for AD are lacking. Kv1.3 is a microglial potassium channel that regulates membrane potential and pro-inflammatory functions and is highly expressed by amyloid beta plaque-associated microglia in human AD brains. We engineer a nanoparticle platform capable of BBB-crossing delivery of Kv1.3 inhibitor that selectively blocks Kv1.3 potassium channels on activated microglia in neuroinflammation, and to examine its delivery efficacy using both an in vitro BBB model of neuroinflammation and an in vivo mouse model of AD. Our approach may be able to attenuate amyloid-associated neuroinflammation and create the possibility of altering the course of AD. The successful outcomes will serve as a foundation for translating the basic research and technology to the clinics, with particular pertinence to accelerating advanced CNS delivery of therapeutic and diagnostic agents.
"Microengineered vascularized 3D glial network for the development of a neurovascular unit"
In collaboration with Dr. Allan Levey at Emory
Alzheimer's disease (AD) is hypothesized to be caused by imbalanced production and clearance of amyloid beta (Aβ) that leads to Aβ accumulation in the central nervous system. Impaired Aβ clearance appears to be the primary mechanism in the commonly occurring form of late-onset sporadic AD. With no effective treatment available for AD, a better understanding of mechanisms that enhance Aβ clearance is critical to the development of new therapeutics to mitigate Aβ burden in AD patients. The overall goal of this project is to engineer a human neurovascular unit on a chip that can recapitulate the structure and function of the BBB with a neural network. Our approach will present a representative example of a cost-effective platform for accelerating the translation from animal to clinical studies, and our ultimate vision is to leverage these technological advances to develop new therapeutics for the treatment of CNS diseases.
"Microengineering of vascularized muscle stem cell niche on a chip"
In collaboration with Dr. Young Jang at Georgia Tech
Aging muscles exhibit significant deficits in repair capacity, leading to the slow and incomplete recovery process. To maintain skeletal muscle homeostasis and repair damaged muscle, a population of dedicated MuSC, or satellite cell, activate, express myogenic transcription factors, migrate, proliferate, and fuse with existing myofibers or form de novo myofibers to complete regeneration. Skeletal muscle microenvironment is composed of myofibers, extracellular matrix, and cellular components including MuSCs, FAPs, MNs, and ECs in the microvascular network. A growing body of recent data highlights that the intricate biophysical and biochemical interactions between MuSCs and their microenvironment dictate cell-fate decision and are vital for proper regenerative function. We engineer a novel vascularized muscle-on-a-chip (vMOC) platform that mimics the physiologically relevant microenvironment of skeletal muscle.
“Integrated microfluidic systems for scalable manufacturing of multicomponent nanoparticles”
Funded by NSF (CAREER AWARD)
The low success rate in the bench to bedside translation of theranostics is mainly due to large batch-to-batch variations and low reproducibility of nanoparticle properties in scaled-up production. We do fundamental research for the design and development of parallelized microfluidic systems and integration with high-precision feedback control enabling a nanoparticle manufacturing platform that is robust and reliable. Successful large-scale, controlled microfluidic synthesis of multicomponent nanoparticles will have the potential to improve the success rate in the clinical translation of a broad range of theranostic nanoparticles, in particular, and enhance the manufacturing ability of various complex nanomaterials, in general. Furthermore, parallelizable microfluidic systems lend themselves to the latest advances in the application of high-performance computing for a variety of manufacturing operations, including reconfigurable operations for rapid product generation. This study will impact the basic science of various scientific fields as nanoparticles are involved in a myriad of physical and chemical processes in a wide range of applications spanning life science, health, and energy.
“Targeted delivery of a sonic hedgehog inhibitor for the study of medulloblastoma therapeutics”
Funded by NIH, NINDS
In collaboration with Dr. Tobey MacDonald at Emory
Most brain tumor treatments involve radiation and chemotherapy, which cause serious adverse effects. However, the development of new drugs is a costly, time-consuming process; only one in ten thousand drug candidates makes it to market, taking fifteen years and one billion dollars to develop. Although continuous progress has been made in developing site-specific nanocarriers, it remains challenging to achieve successful drug treatment of brain tumors without side effect due to the defense of the blood-brain barrier (BBB) and the lack of site-specific nanocarriers stable in circulation. We engineer a new nanocarrier that can cross the BBB, transport a sonic hedgehog (SHH) inhibitor, and target stage-specific embryonic antigen-1 for a SHH-driven brain tumor in the mouse. The BBB-crossing performance of the nanocarrier will be probed in an in vitro microchip model of the BBB, and the targeted delivery and inhibiting efficacy will be examined in a SmoA1/Math1-GFP mouse model of SHH-type medulloblastoma. The successful outcomes of this project will demonstrate advanced approaches to the development of new BBB-crossing nanocarriers and in vitro model BBB systems for treating MB and other brain tumors.
"Advanced CNS Drug Delivery via Lipoprotein-Polymer Nanocomplexes in Experimental Alzheimer’s Disease"
Funded by Coins for Alzheimer's Research Trust (CART)
Disruption of the blood-brain barrier (BBB) during the aging process results in inappropriate traffic of peripheral immune cells to the central nervous system and activation of microglia resulting in chronic neuroinflammation and increased vulnerability to age-related neurodegenerative disorders, including Alzheimer’s disease (AD). Neuroinflammation has long been recognized as a prominent manifestation of the AD brain. With no current effective treatment available for AD, there is a large unmet need to develop new therapeutics that can improve the prognosis and quality of life for AD patients. However, it remains challenging to achieve successful and stable delivery of potential therapeutic agents across the BBB, underscoring the need for the development of novel nanocarriers capable of effectively crossing the BBB and delivering therapeutic agents in sufficient amounts to the brain with sustained stability. We engineer a multifunctional nanocomplex that transports a novel anti-inflammatory biologic across the BBB and to examine its therapeutic properties in an in vivo mouse model of AD.
"Engineering of anti-miRNA transporting HDL for treating endothelial inflammation in experimental atherosclerosis"
Funded by American Heart Association
In Collaboration with Dr. Hanjoong Jo at Emory
Atherosclerosis is a progressive disease with a chronic inflammation of the large arteries, and its major clinical manifestation, coronary artery disease, is the leading cause of death in the Western world. The inflamed endothelium plays a crucial role in the atherosclerotic process from lesion formation to progression and thrombotic complications. High-density lipoprotein (HDL) has recently been reported to transport endogenous microRNAs (miRNAs) to recipient cells with functional targeting capabilities. While silencing a miRNA that induces endothelial inflammation prevents atherosclerosis in a murine model, effective delivery of naked miRNA silencers (anti-miRs) remains limited due to the inefficient incorporation and low targeting efficacy. HDL-mimicking nanomaterials capable of targeting cells and transporting anti-miRs, therefore, have the potential to improve the delivery for effective regulation of targeted gene expressions. We engineer HDL-based nanomaterials that transport an anti-miR and target the inflamed endothelium and evaluate the targeted delivery and silencing efficacy in a mouse model for treating endothelial inflammation in experimental atherosclerosis. This study will provide a better understanding of the role of HDL-based nanomaterials for improved delivery of anti-miRs, contributing to a novel therapeutic and diagnostic paradigm for treating atherosclerosis.