The Chapman Lab has a longstanding interest and productive history in the field of tissue remodeling, particularly as it relates to lung disease. For many years our work primarily focused on proteolytic enzymes. My group cloned and characterized several new members of the cathepsin family and elucidated their roles in bone, lung, and immune disorders. I also pursued basic mechanisms by which proteases and adhesion receptors coordinate cell invasion and extracellular matrix remodeling. At UCSF I have focused my lab on pulmonary fibrosis as a disorder of unmet medical need and a logical extension of my prior work in matrix biology. I led in vivo investigation of the role of epithelial mesenchymal transition (EMT) in pulmonary fibrosis and in the course of studying epithelial plasticity we discovered a population of lung distal epithelial progenitors expressing the integrin capable of regenerative activity in vitro and in vivo in response to major injury. Follow-up studies led to the discovery that the actual lung stem/progenitor cells are relatively rare epithelial subpopulations devoid of mature lineage markers but capable of rapid proliferation and pluripotent differentiation in vivo. Their fates in vivo were recently found to be regulated by local lung hypoxia via its impact on Notch signaling. Follow-up studies led to the discovery that the actual stem/progenitor cells are relatively rare epithelial subpopulations devoid of mature lineage markers but capable of rapid proliferation and pluripotent differentiation in vivo. Their fates in vivo were recently found to be regulated by local lung hypoxia via its impact on Notch signaling.

Dr. Fragiadakis is the director of the Data Science CoLab, a collaboration-based research lab with an emphasis on complex data analysis and computational methods development. Our research program focuses on understanding immune state across disease contexts using high-dimensional immune profiling methods including single-cell RNAseq and CyTOF. In addition, we are passionate about data science training for biologists who want to better engage with their data. We also build tools for biologists to store and interact with their data, including our data library project. Our philosophy is that successful data-heavy projects happen by integrating biological understanding and intuition with advanced skills in data science. This can happen by facilitating close collaborations between experimental and computational biologists, as well as by empowering biologists to work with their own data.

The Schjerven lab studies normal and malignant immune cell development with a focus on transcriptional regulation, and the molecular mechanisms underlying how mutations in key regulatory factors can cause disease. The transcription factor Ikaros, encoded by the IKZF1 gene, is a major focus of ongoing work. Due to the many roles of Ikaros in blood cell development and function, our lab has several diverse and complementary research projects.

The Collisson Lab works on mouse models and translational science in pancreatic and lung cancer. We are regularly building immunocompetent mouse models on these diseases.

The Goldberg lab studies how crosstalk between the immune and metabolic systems coordinates immune function, inflammation, and chronic disease. Specifically, they propose a bi-directional circuit in which (a) immune cell activation and inflammatory potential is dictated by the metabolic environment, and (b) immune cells modify metabolic organ function to impact systemic metabolic health.

The Blackburn Lab is focused on the role of telomere maintenance in human diseases and risk factors, focusing on how inflammation and oxidative stress act as mediators in human diseases and interventions.

The Erle Lab's primary research goal is a deeper understanding of the molecular mechanisms underlying airway epithelial dysfunction in asthma. We study the mechanisms of gene regulation in the airway epithelium and determine the contributions of specific gene expression changes to changes in airway epithelial function. We use a variety of approaches from cell and molecular biology, genomics, and computational biology. We have adapted powerful new methods, including single cell RNA-seq (scRNA-seq), ChIP-seq, and CRISPR, for use with HBE cells as well as with cells obtained directly from individuals with asthma. We collaborate extensively with experts in asthma clinical studies, genetics and genomics, and computational biology.

The Nedelcu Lab's primary focus is cellular therapies and transfusion medicine. Our current project in clinical transfusion medicine is to elucidate the mechanism of allergic transfusion reactions.

The Sheppard Lab's research focuses on the in vivo roles of members of the integrin family, the biologic and therapeutic significance of integrin-mediated activation of transforming growth factor beta, and the molecular mechanisms underlying tissue fibrosis. One aim of the research is to identify new therapeutic targets to improve the treatment of common disorders including tissue fibrosis, cancer and asthma. The work begins with basic investigation of how cells use members of the integrin family to detect, modify and respond to spatially restricted extracellular clues and how these responses contribute to the development of common diseases.

The Allen Lab is interested in the cellular communication and differentiation programs in allergic immune responses, particularly in asthma. We are applying sophisticated imaging, flow cytometry, mouse genetics, and other techniques to uncover novel paradigms underlying allergic inflammation. As a major area of emphasis, we are studying the generation and function of IgE antibodies that initiate allergic inflammation. We have developed innovative techniques to study rare IgE-producing B cells in vivo, including the generation of fluorescent IgE reporter mice. We have established that IgE B cell responses are controlled by the cytokine IL-21 and distinct signaling properties of the IgE B cell receptor. We are imaging the lungs and associated lymphoid tissues by two-photon laser scanning microscopy to directly visualize cellular interactions in situ. Using this approach, we achieved the first in vivo analysis of the interactions of CD4 T cells with basophils, which are rare IgE effector cells. We are analyzing the interactions of basophils with other cell types during secondary immune responses to further elucidate the functions of these cells. We have also established a role for macrophages associated with the bronchial airways in the elicitation of allergic inflammation in the lung.

The Lowell Lab studies tyrosine kinase based signal transduction in innate immune cells. Our general approach involves examination of innate immune function in knockout mice lacking various members of the Src-family or Syk family of tyrosine kinases. Many of these studies also involve use of mice lacking these kinases in specific hematopoietic lineages, such as neutrophils, macrophages or DCs, generated through Cre/Lox technology. We have also used this approach to study other tyrosine kinases (Pyk2/Fak) and intracellular signaling molecules (WASp, STIM1) in innate immune cells. Our major findings have illuminated the function of Src-family and Syk kinases in leukocyte integrin signaling ��������� loss of these kinases results in significant defects in inflammatory and host defense functions mediated by integrins. We have found that leukocyte integrin signaling utilizes the same intracellular pathways initiated by classical immunoreceptors (such as Fc?Rs) by co-opting ITAM-containing adapterdemonstrated the important ways these kinases regulate innate immune cells in the setting of autoimmune and inflammatory diseases, using the Lyn kinase-deficient model. Ongoing studies also involve examination of tyrosine phosphatases (mainly SHP-1) in the counter regulation tyrosine kinases, especially in the setting of hematopoietic malignancy, as well as studies of calcium signaling proteins, using mice lacking these genes specifically in myeloid lineage cells.

The Wilder Lab's goal is to understand how innate immune functions of lung epithelial cells regulate the development and progression of lung immunopathogenesis. Specifically, they are interested in investigating distinct immune gene expression and cellular responses controlled by interferon-specific dynamic control of the transcription factor ISGF3.

The Graham lab's field of research is the study of how host immunity drives pulmonary vascular disease, focusing on the disease schistosomiasis-associated pulmonary hypertension (PH). Schistosomiasis is a major cause of PH worldwide, but how this parasitic infection causes the disease is unclear. We think that some of the pathways that we are uncovering are relevant to other forms of PH more common in developed settings. Our primary approach is using a mouse model of this disease, which lends itself well to investigating how innate and adaptive immunity, and the cross-talk between the two, mechanistically drive pulmonary vascular disease. The pathway we have uncovered includes conventional dendritic cells, CD4 T cells, classical monocytes, and interstitial pulmonary macrophages, expressing cytokines including IL-4/IL-13, CCL2, TSP-1, and TGF-beta. We are now starting to develop protocols for screening humans for this disease in endemic settings, and studying biospecimens from these individuals. We are also studying the role of inflammation in hypoxic-PH and other forms of PH.