Research Activities
To effectively organize and run the Center, participants will be broadly categorized into three groups on the basis of research activities, namely, those focusing on (1) development and interplay of inflammation-related cells, (2) regulation of inflammatory responses, and (3) infection and inflammation. It should be emphasized, however, that these groups are interconnected and complementary to each other, constantly sharing ideas, information and technologies, and commonly aiming at establishing the field of integrative inflammology, wherein the Center will take the initiative of coordinating all activities. Furthermore, the participants of all groups will commonly seek to better our understanding of various inflammation-associated diseases as well as develop new strategies for the diagnosis, prevention, and treatment of these diseases. The Center will also coordinate an effective exchange of relevant materials and information for stimulating cooperation. A participant may be involved in more than one of these groups as cooperator. A more detailed research plan of each group is described below.
(1) Development and interplay of inflammation-related cells
Members of this group will study the origin and dynamic function of cells that critically mediate inflammatory responses. Cells of the immune system cannot respond to a threat unless they can cross blood vessels. Indeed, inflammatory responses represent the body's stereotypical reaction to tissue damage, involving rapid delivery of soluble elements and leukocytes from the blood to the site of injury. Leucocytes are recruited to the site of inflammation in a series of adhesion steps, followed by transversion of the endothelium and migration through the interstitial tissues. This group will study the regulatory events at the interface of leukocytes and the endothelium, including vascular progenitor cells and other endothelial cells, with the aim of understanding how the breakdown of the vascular regulation results in pathological inflammation such as rheumatoid arthritis, osteoarthritis and multiple sclerosis. The study will also extend to mechanisms underlying the regulation of angiogenesis and lymphangiogenesis, as well as development of cell culture-based models of endothelialized organs/tissues.
T and B cells are critical for the evocation and regulation of inflammatory responses; hence, their development and function need to be tightly regulated to prevent autoimmune or allergic inflammatory responses. We will study how the differentiation of T and B cells is regulated, with the aim of elucidating the genetic basis of T and B cell development as well as the acquisition and maintenance of central and peripheral tolerance. In the context of inflammation-associated diseases, genetic analysis of connective tissue diseases resulting from the breakdown of T cell tolerance, will also be investigated.
(2) Regulation of inflammatory responses
Numerous factors that promote or inhibit inflammation have been identified, but an integrated view of how these molecules orchestrate their activities into protective and pathological inflammatory responses remains vague. Members of this group, drawn from different research backgrounds, will coordinate to study the function and interplay of general and tissue- or organ-specific molecules involved in acute or chronic inflammation. The group will also aim to clarify the molecular basis of inflammation-associated diseases regulated by these molecules. For instance, cytokines are major determinants of cellular responses during inflammation such as cell infiltration, activation and differentiation, while lipid mediators, chemical messengers released in response to tissue injury, can also positively or negatively regulate cells involved in the inflammatory responses. In addition to these soluble mediators, equally important are adhesion molecules that mediate the firm arrest of leukocytes on the inflamed endothelium and coordinate transmigration through the basement membrane to allow the homing to the site of infection or inflammation. How lipid mediators, cytokines, and adhesion molecules work in concert with other factors such as neurotransmitters, and hormones remain an important but unresolved issue. Hence, we aim at gaining a better understanding of the cooperation of these distinct classes of molecules.
In addition, by coordinating the above research activities, the group will also focus on molecules associated with chronic inflammatory diseases, specifically, diabetes, atherosclerosis, multiple sclerosis, and osteoarthritis. In particular, the group will focus on molecules that regulate obesity and insulin resistance, two key features of metabolic syndrome that are closely associated with the state of chronic, low-grade inflammation characterized by abnormal macrophage infiltration into adipose tissues. It is becoming increasingly clear that tuberculosis and type 2 diabetes/obesity are strongly correlated. Thus, patients suffering from diabetes and/or obesity are at highly increased risk of developing active tuberculosis. Moreover, it has been speculated that the etiologic agent of tuberculosis, Mycobacterium tuberculosis, misuses adipocytes as a safe niche and that macrophages and adipocytes in fat tissue downregulate protective immunity against tuberculosis. Additionally, systems biology approaches will be used in an attempt to establish a cell-based model for metabolic diseases. The group will also study the normal and abnormal metabolism of cholesterol and glucose in blood vessels, with the hope of developing drugs for highly prevalent diseases associated with the pathologies of these metabolic pathways. Moreover, this group will study aspects of inflammatory autoimmune diseases of the brain, such as multiple sclerosis, wherein immunology and neurobiology will be integrated in the context of inflammology. Finally, the group will introduce and exploit new technologies, such as animal models of osteoarthritis and anti-inflammatory cell coating, wherever possible, in the hopes of achieving breakthroughs for these diseases.
(3) Infection and inflammation
While inflammation is a well-known hallmark of bacterial and viral infections, it paradoxically underlies the development and/or exacerbation of various infection-associated diseases. Since infection is a consequence of specific interactions between a given pathogen and the host, we will study the underlying molecular mechanisms operating during host-pathogen interactions and the subsequent evocation of inflammatory responses. In particular, the group will focus on well-established microbes including Helicobacter pylori, Mycobacterium tuberculosis, herpes viruses, and influenza virus. The focus will be on the cross-talk mechanisms of molecules, cells, and tissues that occur during infection with the goal of determining how such mechanisms help or hinder immune responses. This group will also aim to understand various infection-associated diseases such as tuberculosis, cancer, intestinal infectious diseases, polymicrobial diseases, sepsis, asthma, and autoimmune diseases. Moreover, crosstalk between immune cells in coinfections, such as pulmonary infections with M. tuberculosis and influenza virus and comorbidities such as tuberculosis and type 2 diabetes, will be analyzed and harnessed for novel intervention measures.
(4) Inflammation-associated diseases
Integrative inflammology pursued by the Center will amalgamate the study of seemingly unrelated diseases, as described above, so as to identify key molecules and regulatory pathways that are distinct or common to these diseases. As such, the research activities of the Center by all participants will converge toward a common understanding of these diseases in the context of inflammation. The Center will coordinate the entire research activities for the common endeavor and integrate them so as to generate a new view of how diseases should be systematically analyzed, diagnosed, treated , and prevented. Thus, the diseases that will be touched upon in the Center will include the following: infectious diseases, allergy and autoimmune diseases, cancers, diabetes, cardiovascular diseases, and arthritis. These diseases will not only be studied as singular entities but also in the context of comorbidities. We will strive to translate the knowledge gained and technology developed into clinical applications for the benefit of society.
