Anshu Agrawal, Ph.D., Associate Professor, UC Irvine, Department of Medicine
Identification of Peripheral Immune Mechanisms playing a protective role in AD progression
Recent studies have highlighted the role of inflammation and the immune system in the etiology of Alzheimer’s disease (AD). However, there is a key gap in knowledge regarding the immune processes in healthy aged individuals as compared to AD patients. To address this gap we have characterized the peripheral immune response of healthy aged subjects to Amyloid beta and compared it to AD subjects. The human studies have been complemented by in vivo experiments using the 5xFAD mouse model of AD. Using a combination of flow cytometry, multiplex assays and cell culture experiments we have identified potential immune parameters which may be playing a protective role in preventing AD in healthy aged subjects.
Anshu Agrawal, Ph.D., is an Associate Professor at UC Irvine in the Department of Medicine since 2004. She was a Research Scientist in the division of immunology at the United Nations research center, International Center for Genetic Engineering and Biotechnology (ICGEB), New Delhi. Subsequently, she won a scholarship to work in Paris, France. Her research expertise lies in the area of innate immunity, inflammation and aging with focus on human samples. She studies the age-associated changes in the functions of dendritic cells and their role in age-related pathologies including neuro-degenerative and respiratory diseases.
Mathew Blurton-Jones, Ph.D., Associate Professor, UC Irvine Dept of Neurobiology and Behavior
Using iPSC-derived Microglia and Chimeric Models to Study the Interactions between Human Microglia and AD pathology
Microglia respond dynamically to A plaques, a key component of Alzheimer’s Disease (AD) neuropathology. In addition, genetic studies have further highlighted the importance of these brain-resident myeloid cells in AD. The recent development of iPSC-based models has provided a new tool to study human microglia, and yet these cells remain highly sensitive to their environment, undergoing significant transcriptional changes with cell culture. We therefore sought to develop a new approach to study the function, transcriptome, and interactions between human microglia and AD pathology in vivo. 5xfAD transgenic mice were backcrossed onto a xenotransplantation-compatible background (Rag2-/-,il2rg-/-,hCSF1) and then iPSC-derived hematopoietic progenitors (HPCs) were transplanted into P1 brains. Mice were aged for 2-8 months and then human microglia were isolated by FACS sorting for RNA-sequence analysis. HPC transplantation resulted in robust forebrain engraftment and differentiation of human cells into microglia. RNA sequencing and live imaging demonstrated that xenotransplanted microglia adopt typical ex-vivo human microglial transcriptomic signatures and rapidly responded to both systemic and localized insults. Examination of the interactions between human microglia and A plaques further revealed dramatic changes in microglial protein expression, including the adoption of a disease-associated microglial-like response. By combining patient-derived iPSCs, CRISPR gene editing, and chimeric mice we anticipate that this new model can provide new opportunities to examine the influence of AD risk genes on human microglial biology.
Mathew Blurton-Jones, Ph.D., is an Associate Professor in the Department of Neurobiology and Behavior at UC Irvine and the Director of UCI’s Alzheimer’s Disease iPS cell Core. His research uses stem cell and mouse models of Alzheimer’s Disease (AD) to examine the impact of AD risk genes on microglial function. By combining iPS-modeling and CRISPR gene editing with xenotransplantation, his group has recently established a new approach to study human microglia in vivo.
Steve W. Cole, Ph.D., Professor of Medicine (Hematology-Oncology) and Psychiatry & Biobehavioral Sciences, UCLA School of Medicine
Social regulation of human gene expression
Relationships between genes and social behavior have historically been viewed as a one-way street, with genes in control. Recent analyses have challenged this view by discovering broad alterations in the expression of human genes as a function of differing socio-environmental conditions. This talk summarizes the developing field of human social genomics, and its efforts to identity the types of genes that are subject to social regulation, the biological signaling pathways that mediate these effects, and the cellular mechanisms involved. This talk highlight the key role that flow cytometry has played in elucidating the mechanisms by which sympathetic nerve fibers regulate the circulating leukocyte transcriptome by altering hematopoiesis in the bone marrow and extramedullary tissues.
Dr. Cole’s research utilizes molecular genetics and computational bioinformatics to analyze the pathways by which social and environmental factors influence the activity of the human genome, as well as viral and tumor genomes. He pioneered the field of human social genomics (https://en.wikipedia.org/wiki/Social_genomics) and supports a world-wide array of research programs in his role as Director of the UCLA Social Genomics Core Laboratory. His research has mapped the pathways by which social factors enhance replication of cancer-associated viruses (e.g., HIV-1 and HHV-8), alter expression key cancer-related cytokines (e.g., IL6, IL8, VEGF, and IFNB), and up-regulate metastasis-related genes by breast and ovarian cancer cells. His current research focuses on development of pharmacologic and behavioral interventions to block the molecular impacts of adverse social conditions on the health and well-being of cancer patients.