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Xinxia Peng

Assoc Professor

CVM Research Building 492

Publications

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Grants

Date: 09/01/21 - 8/31/23
Amount: $532,000.00
Funding Agencies: National Institutes of Health (NIH)

The cerebral cortex critically relies on balanced production of neurons and glia during embryonic and early postnatal development. Recently developed clonal lineage analysis has revealed the behavior of neural stem cells (NSCs) giving rise to neurons in the cerebral cortex with unprecedented single-cell resolution. However, the formation of glia by NSCs remains unclear and has yet to be systematically investigated using these new technologies. Gliogenesis is critical for proper neuronal functions and when disrupted, it can result in various neurological diseases. Reconstructing how glia are generated from individual NSCs and organized in the cortex during development is essential to understand the structure-function relationships and how they can be modulated by clone-specific factors. We have established a genetically-based single-cell lineage tracing technique utilizing MADM (Mosaic Analysis with Double Markers) mice to label NSCs in the developing cortex and begin to address this knowledge gap. The goal of the proposed research is to reconstruct, quantify, and mathematically model the behavior of individually labeled NSCs in vivo. We will use the power of this labeling method to also screen for gene expression of glial clones at single cell resolution, which all together will help us decipher the general principles organizing glial clones in the cortex, and define how clonal siblings interact with each other. Using some of the identified genes that we have already identified, we will test their role in generation of glial clones in the cortex, which will further help define the biological system underlying clonal rules and principles of gliogenesis. Successful completion of our study will result in a comprehensive map of single NSCs and their glial progeny in various cortical regions. Our approach will also establish a platform for detailed quantitative and computational analysis of gliogenesis, glial diversity, and their potential for regenerative approaches in the cortex. Potential for Broader Impact Our approaches to understand how important constituents of the brain, the glial cells, develop have wide implications. Disruption of glial development is the root of a range of pathological conditions in the brain. Therefore, understanding the basic principles and cellular mechanisms that control gliogenesis is critical to appreciate not only how healthy development may be controlled by systematic production of glial cells, but also how abnormalities in gliogenesis may lead to devastating neurodevelopmental disorders.

Date: 05/01/20 - 4/30/23
Amount: $93,664.00
Funding Agencies: National Institutes of Health (NIH)

Dr. Peng and members of his laboratory will conduct Total RNA transcriptome deep sequencing (Total RNA-seq) analysis of cervical samples provided by the UNC team. Dr. Peng and his group will use the generated Total RNA-seq data to identify consistently and abundantly expressed Chlamydial genes for antigen discovery. His group will process the raw RNA-seq data including quality control and provide the management and dissemination of the generated large scale RNA-seq data.

Date: 05/01/20 - 4/30/23
Amount: $131,237.00
Funding Agencies: National Institutes of Health (NIH)

Dr. Peng and members of his laboratory will conduct 16S rRNA based microbiome analysis of vaginal samples provided by the UNC team. Dr. Peng and his group will use the generated 16S data to identify microbes related to the ascending infection of Chlamydia. His group will process the raw 16S data including quality control and provide the management and dissemination of the generated 16S sequencing data.

Date: 05/04/19 - 4/30/23
Amount: $2,073,862.00
Funding Agencies: National Institutes of Health (NIH)

Voice impairment is the most common communication disorder with nearly 20 million people in the US reporting symptoms of dysphonia annually. The cost of treatment and lost wages for this disorder is approaching $13 billion. The etiology of these disorders is diverse, but given their anatomic location, the vocal folds (VFs) are susceptible to a multitude of injurious stimuli, including reflux of gastric contents, iatrogenic injury, and the inherent trauma associated with voice production. Injury can result in altered lamina propria (LP) architecture resulting in aberrant phonatory physiology. To date, no treatment restores the native VF extracellular matrix (ECM) composition, structure, and function following VF injury which likely underlies suboptimal outcomes for patients with VF scar. ECM scaffolds, if appropriately processed, can be used as resorbable and naturally derived biomaterials with a safe record of clinical use that promote tissue remodeling while reducing fibrosis. Tissue-specific ECM hydrogels are ideal for clinical application, particularly given the emerging practice and distinct advantages of in-office procedures using minimally invasive approaches. Work from our group and others provide promising data regarding the role of decellularized vocal fold lamina propria (VFLP-ECM) as a therapeutic scaffold. We broadly hypothesize that VFLP-ECM will evolve into clinical practice to provide a scaffold that promotes functional repair of the VFs. Specifically, we seek to develop an injectable vocal fold lamina propria hydrogel (VFLP-ECMh) that will degrade over time while harnessing the stimulatory effects of the ECM to drive vocal fold tissue remodeling

Date: 06/01/20 - 3/31/23
Amount: $1,140,000.00
Funding Agencies: National Institutes of Health (NIH)

The emotion of fear is a powerful trigger for memory storage, helping us avoid cues associated with aversive outcomes. However, fear memories become maladaptive and trigger inappropriate emotional responses in common psychiatric diseases such as post-traumatic stress disorder (PTSD), generalized anxiety disorder, and panic disorder. Women are twice as likely as men to experience fear-based psychiatric conditions, and greater symptom severity leads to poorer quality of life in women with these illnesses. Unfortunately, the neurobiological mechanisms underpinning this sex difference in susceptibility remain poorly understood due to a lack of female subjects in preclinical research. By understanding how females encode and express fear memories differently than males, we will pinpoint sex-specific mechanisms and treatment strategies for fear-based psychiatric disease. The purpose of this project is to identify the molecular-, cellular-, and circuit-based mechanisms underlying female susceptibility to fear-based mental illness. Based on preliminary experiments, this work will focus on the lateral septum (LS), a sexually dimorphic hub of the limbic system known to gate maladaptive emotional behaviors. We show that the LS is robustly activated during cued threat (also known as fear) memory formation in females but not males, that this sex-specific activation is causally linked to the strength of the threat memory, and that neurons of the female LS threat memory ensemble directly project to regions that drive cue-evoked emotional responses. The experiments proposed in this application will expand upon these initial findings to test the central hypothesis that female-specific engagement and subsequent synaptic strengthening of a hitherto unrecognized LS circuit enhances cued threat memory in females versus males. In Aim 1, we will test the hypothesis that selective recruitment of threat-related LS neurons enhance threat memory encoding and expression in females versus males through disinhibition of projection neurons of the hypothalamus, ventral hippocampus, and periaqueductal gray. In Aim 2, we will test the hypothesis that excitatory projections from the medial prefrontal cortex are necessary and sufficient for LS memory ensemble recruitment and enhanced memory encoding in females versus males. Finally, in Aim 3, we will test the hypothesis that sex differences in the molecular architecture of LS neurons drive sex-specific memory allocation. These experiments have the potential to transform our understanding of how basic brain circuits for fear memory storage and expression differ between the sexes. Our long-term objective of this work is to help clinicians uncover novel gender-specific therapeutic targets for fear-based psychiatric disease.

Date: 04/01/20 - 3/31/23
Amount: $2,125,528.00
Funding Agencies: National Institutes of Health (NIH)

Currently, ischemic damage to the heart cannot be repaired by conventional medical care therefore only palliative treatments exist. Stem cell transplantation is a promising strategy for therapeutic cardiac regeneration, but current therapies are limited by insufficient interaction between the regenerative cells and the injured tissue. In the last grant period, we have developed targeted nanoparticles (namely bispecific antibody-conjugated agents) to redirect circulating stem cells to the infarcted heart for therapeutic regeneration. Despite such initial success, we realize our system has some problems: (P1) We cannot fully reply on the stem cells (“seeds”) for cardiac repair. The post-injury heart microenvironment (“soil”) needs to be primed for the maximum outcome; (P2) Antibody targeting is quite specific but is fully dependent on the antigen, which are cardiac injury biomarkers that only expresses in a short period of time after injury. The current renewal proposal builds on the previous study, but represents a significant advancement, both technically and conceptually. To address P1, we reason one of the antibodies needs to be therapeutic, to combat the excessive inflammation in the heart. To address P2, we seek for agents that have broad spectrum affinity with cardiac injury. To those ends, we developed anti-IL-1 platelet mimetic (IL1-PM). The mode of action for IL1-PM is as follows: platelet vesicles serve as the carrier of our system and they have innate ability to find cardiac injury (replying on the binding motifs on platelet membranes); anti-IL-1 antibodies are currently in Phase 3 clinical trials and have demonstrated ability to neutralize inflammation and promote cardiac repair; platelet vesicles can be further loaded with stem cell-derived growth factors to aid the repair process. AIM 1: Fabricate IL1-PM and characterize its physicochemical and biological properties. We will generate IL1-PM agents by conjugating anti IL-1 antibodies onto platelet membrane nanovesicles; binding/engaging ability, toxicity, pharmacokinetics of IL1-PM will be examined in cultured cells and in healthy animals. AIM 2: Determine the therapeutic potential of mesenchymal stem cell (MSC) secretome-loaded IL1-PM in a mouse model of myocardial infarction. MI will be induced by ischemia-reperfusion. After that, MSC-IL1-PM, along with various control agents, will be delivered intravenously. Therapeutic safety and efficacy will be determined. In addition,the underlying mechanisms of such treatment will be explored. AIM 3: Translate the findings into a clinically-relevant large animal model of myocardial infarction. MI will be induced in swine via a balloon-occlusion procedure. The safety and efficacy of MSC-IL1-PM treatment will be evaluated. Our therapeutic system combines stem cell therapy (component 1) and anti-IL1 therapy (component 2), both of which have been rigorously tested and verified in clinical trials for cardiac repair. Moreover, the therapeutics will be delivered in a targetable fashion relying on the injury-finding ability of platelet binding motifs (component 3). All 3 components have been supported by strong preliminary data from our group.

Date: 12/01/18 - 11/30/22
Amount: $2,110,002.00
Funding Agencies: National Institutes of Health (NIH)

Voice impairment is the most common communication disorder with nearly 20 million people in the US reporting symptoms of dysphonia annually. The cost of treatment and lost wages for this disorder is approaching $13 billion. The etiology of these disorders is diverse, but given their anatomic location, the vocal folds (VFs) are susceptible to a multitude of injurious stimuli, including reflux of gastric contents, iatrogenic injury, and the inherent trauma associated with voice production. Injury can result in altered lamina propria (LP) architecture resulting in aberrant phonatory physiology. To date, no treatment restores the native VF extracellular matrix (ECM) composition, structure, and function following VF injury which likely underlies suboptimal outcomes for patients with VF scar. ECMs, if appropriately processed, can be used as resorbable and naturally derived biomaterials with a safe record of clinical use that promote tissue remodeling while reducing fibrosis. Injectable hydrogels are ideal for clinical application and cell delivery, particularly given the emerging practice and distinct advantages of in-office procedures using minimally invasive approaches. Work from our group and others provide promising data regarding the role of decellularized vocal fold lamina propria (VFLP-ECM) as an injectable agent or as a delivery vehicle for therapeutic cells such as mesenchymal stem cells. We broadly hypothesize that VFLP-ECM hydrogels (with or without stem cells) will evolve into clinical practice to provide a scaffold that promotes functional repair of the VFs. Specifically, we seek to develop an injectable vocal fold lamina propria hydrogel (VFLP-ECM-H) that will degrade over time while harnessing the stimulatory effects of the ECM to drive vocal fold tissue remodeling.

Date: 09/30/21 - 9/29/22
Amount: $402,340.00
Funding Agencies: National Institutes of Health (NIH)

Ferrets and Syrian (golden) hamsters are two leading small animal models for respiratory infections. However, a well-known challenge for both models is the overall lack of species-specific reagents and tools. In particular, immunoglobulin (Ig) and T-cell receptor (TCR) repertoire analysis is key to understand the development of antigen-specific immunity during infection and vaccination. Currently, very little is known about ferret and hamster Ig/TCR repertoires, significantly limiting the options to monitor their immune response to experimental infections and vaccinations. Dedicated efforts using special strategies are necessary to analyze complex immune loci like Ig/TCR regions. Recently we reported a novel and efficient strategy to construct complete Ig and TCR reference sequences for rhesus macaque, which has been plagued by a lack of similar immune resources. We also successfully designed rhesus-specific single cell level Ig and TCR repertoire assays, which are completely comparable to those available for human and mouse. Here, we propose using the same approach to develop public resources and assays to enable Ig and TCR repertoire analysis in both ferrets and hamsters. This project includes two Specific Aims. In Aim 1, we will obtain a large number of high-quality, full-length Ig and TCR transcript sequences using an established long read transcriptome sequencing protocol for both hamsters and ferrets. We will apply custom bioinformatics methods to identify full-length species-specific Ig/TCR transcript sequences and variable region genes and to curate constant region reference sequences for both species. In Aim 2, we will use the reference sequences obtained in Aim 1 to design species-specific single cell B- and T-cell V(D)J assays, similar to our design for rhesus macaque. We will experimentally validate these species-specific V(D)J assays using hamster and ferret samples. These resources and assays will provide the ability to perform single-cell sequencing and Ig and TCR repertoire analysis in both species vaccinated against and/or infected with pathogens.

Date: 07/01/18 - 6/30/22
Amount: $369,542.00
Funding Agencies: National Institutes of Health (NIH)

Dr. Peng and members of his laboratory will conduct parallel bioinformatic studies and computational modeling of transcriptomic and microbiome data sets generated by the Nonhuman Primate Core Functional Genomics Laboratory for AIDS Vaccine Research and Development. He will apply his computational strategy for quantifying the allele-specific expression of macaque complex immune genes like MHC genes to specific data sets received from the Core. This strategy may involve the utilization of PacBio Iso-Seq data to accurately define the full-length transcripts and alternative splicing patterns for macaque MHC alleles. Additionally, when requested, he will apply advanced methods for correlating microbiome composition and infection- or vaccine-induced host transcriptional responses. Dr. Peng will oversee all activities at North Carolina State University. He will participate in monthly web conferences with other members of the Core and DAIDS representatives, submit monthly progress reports to the University of Washington, and attend annual programmatic site visits held in Seattle WA.

Date: 06/13/19 - 5/31/22
Amount: $405,448.00
Funding Agencies: National Institutes of Health (NIH)

Globally annual influenza epidemics are estimated to result in about 3 to 5 million cases of severe illness. Between 291,000 and 646,000 people worldwide die from seasonal influenza-related respiratory illnesses each year by the most recent report. The advances in sequencing technologies have led to the discovery of numerous long non-coding RNAs (lncRNAs). While the specific functions of these lncRNAs are still largely unknown, this new discovery offers an opportunity to develop novel classes of influenza interventions that target relevant lncRNAs or their interactions with other molecules. Our meta-analysis identified several lncRNAs that are predicted to be highly relevant to influenza A virus infection and host responses. Here we will extend these analyses with systematic investigations to establish their functional roles in influenza infection experimentally and to discover candidate lncRNAs as targets for influenza intervention. This project includes two Specific Aims: (1) experimentally establish how these highly ranked cellular lncRNAs affect influenza infection, and (2) identify lncRNA regulatory networks involved in influenza infection. In Aim 1, we will determine how influenza replication is altered when the expression of individual lncRNAs is knocked down or activated in human epithelial cells. For selected lncRNAs that the perturbation of their expressions affects influenza replication most effectively, we will confirm their effects on influenza infection in primary epithelial cells. In Aim 2, we will investigate: a) whether these highly ranked lncRNAs are interferon-stimulated genes; b) whether they act in cis or trans; c) the impact of selected lncRNAs on host responses to influenza infection. In particular, we will conduct an unbiased dual gene activation and knockout library screen to reconstruct the underlying lncRNA regulatory networks and uncover directional dependencies in these networks. Together, these analyses will allow us to better understand the functions of lncRNAs and their role in influenza infection, and to identify specific lncRNAs as novel targets for influenza intervention.


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