[转帖]系统生物学在免疫系统研究中的应用

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系统生物学在免疫系统研究中的应用
  
Macrophages are found throughout the human body
Several decades of intensive study have revealed thousands of proteins that play important roles in the encounters between the immune system and pathogenic organisms. With the volumes of genomic information (both human and microbial) that are rapidly becoming available and the development of high-throughput analysis of mRNA and protein expression, protein modifications and protein-protein interactions, the field is at a turning point where major advances are likely to come from studies into how a multitude of proteins in many pathways interact with each other to coordinate our defense against infection. The innate immune system also initiates local and sometimes systemic inflammatory responses that alert the body to the presence of potential threats and guides the development of subsequent adaptive immune responses that evolve in the weeks following infection. The inflammatory process is a double-edged sword; while on one hand inflammation is usually helpful and protective, it sometimes can become deregulated and result in tissue destruction and physiological changes that endanger the health of a person. Septic shock, a life-threatening systemic inflammatory response to bacterial infection, is a major problem in hospitals around the world, and inflammatory processes cause damage in a broad range of diseases including atherosclerosis, arthritis, and cancer. Phagocytes such as macrophages, neutrophils, dendritic cells and monocytes are central effector cells of the innate immune system (see box). These cells constantly survey the body and recognize, internalize, kill and degrade foreign microbes. These cells also secrete inflammatory chemokines and cytokines and process antigens that train the adaptive immune response. The Aderem laboratory is focused on understanding the molecular and genetic factors that regulate these functions of phagocytes. How do macrophages detect microbes and identify infectious agents? A remarkable feature of the innate immune system is its capacity to recognize so many different types of microbes. Phagocytes use receptors belonging to several different genes families to bind microbes (see Figure 1 and Figure 2).These receptors permit the phagocyte to engulf and destroy the microbes. Some of the receptors are involved in the uptake/engulfment process, and others are involved in initiating the signals that announce to the immune system that microbes have been encountered. How do immune cells internalize and kill microbes? Phagocytosis is an ancient process by which phagocytes such as monocytes, macrophages, neutrophils and dendritic cells internalize large particles like bacteria or fungi and kill them. After recognition of a particle as foreign and potentially dangerous, signals are delivered into the phagocyte that cause reorganization of the actin cytoskeleton and recruitment and extrusion of membrane leading ultimately to complete enclosure of the particle within the phagocytes membranes. This newly formed compartment in the cell then matures into an acidic compartment where enzymes cause death and degradation of the potentially harmful organism. In addition to the central importance of phagocytosis to defense, internalization of dead cells and debris is also an important role of phagocytes in normal tissue maintenance and wound healing. Immunity Links: Aderem Lab Immunity Diseases
Infectious Diseases
Disease in the Developing World
Autoimmunity and Inflammation
Diabetes
Heart Disease Cancer  

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At the ISB we are studying systems related to understanding, curing, and preventing cancer. Our approach will allow us to accurately identify different types and stages of cancer early in the transformation process, and to understand the interplay between genetic and environmental networks operating in these different cancers. Ultimately, these studies may point the way to personalized treatment and early diagnosis of people at risk. These projects include: Prostate Cancer The National Cancer Institute (NCI) is providing $23.5 million to support collaborations between the University of Washington (UW), the Fred Hutchinson Cancer Research Center (FHCRC) and the Institute for Systems Biology (ISB) to study of the prevention and treatment of prostate cancer. This funding provides area researchers with unprecedented opportunities in their ongoing efforts to better understand prostate cancer and develop improved therapies, particularly for men with recurrent or advanced disease. In the United States, prostate cancer is the second most common cancer in men. Because prostate cancers are extremely heterogeneous in their progression, speed, and capacity for growth, there are several major challenges in prostate cancer diagnosis and therapy. Some early prostatic carcinomas may behave as indolent, asymptomatic conditions and remain as such until detected during autopsy, whereas others may progress aggressively and metastasize to other organs, eventually becoming the cause of death. Because we cannot distinguish between aggressive and slow growing prostate carcinomas, after diagnosis there are two options for treatment: watchful waiting or radical prostatectomy followed by chemo- or radiation therapy. The choice is a difficult one; undergo the radical treatment or take a chance that the cancer is a slow growing variety? Researchers are unable to distinguish the aggressive tumors from the indolent, but one clue may lie in the fact that prostate carcinomas initially grow in an androgen-dependent manner. Here, the therapeutic strategy is based on androgen ablation, including chemical and surgical castration. However, in those carcinomas that follow the aggressive course, this strategy fails because prostate carcinomas eventually lose their androgen dependence and gain the ability to grow in the absence of androgens (become androgen-independent). The mechanism for the transition from androgen dependence to independence is not known, but a complete elucidation of androgen-regulated networks and alternative pathways will help us to understand the mechanism of this transition and assist in the distinction between aggressive and indolent carcinomas. Additionally, we are developing a three-dimensional cell culture system to study cell differentiation and carcinogenesis. In this system, we are using epithelial progenitor cells together with factors derived from prostatic stromal mesenchyme [SCL1] cells and extra-cellular matrix to produce gland-like structures. Gene expression perturbations can then be used to identify genes involved with differentiation and transformation. This will help define the molecular interactions between epithelial and stromal cells. As the functioning of epithelial cells is determined by their neighboring stromal mesenchyme cells, a perturbation in this interaction may be a major epigenetic cause of cancer. Experiments using CD immuno-phenotyping have shown that cancer-associated stromal cells are different from those of normal tissue. In this multi-pronged approach to prostate cancer, we have set our goals t
Identify markers for prostate cancer stratification;
Identify and characterize novel genes as diagnostic markers and therapeutic targets; and
Understand the androgen-regulated networks in prostate cancer.
We are using tools including monoclonal antibody production, microarray gene expression analysis, comparative proteomics using mass spectrometry, and animal models to achieve our goals. Ovarian Cancer In collaboration with the University of Washington and the Fred Hutchinson Cancer Research Center, the ISB is using patient samples to determine whether pre-neoplastic cells are genetically altered and whether they are the precursor cells for malignant ovarian cancer. Evidence from our investigations suggests that primary carcinomas can be stratified into distinct categories of clinical behavior based upon profiles of their expressed genes. These studies will help determine whether specific alterations in gene expression patterns correlate with loss of the wild-type alleles of genes important in the control of the cell cycle, cell proliferation, or cellular maturation. The Institute for Systems Biology is developing new tools and techniques for SNP detection, mRNA expression, and proteome analysis that could aid in early identification of the genetic alterations which lead to ovarian cancer. Another goal of the ISB is to develop the tools and protocols that bring this early detection ability into the offices of primary care physicians. The delineation of the early molecular events involved in the development of ovarian cancer will improve the overall management and outcome of the disease and be invaluable for the accurate assessment of the risk factors and genetic predisposition. Ultimately, these discoveries will aid in diagnosis, identification of personalized targets for drug therapy, and even prevention of this form of cancer.

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Nanosystems Biology Alliance and Cancer
The Institute for Systems Biology, Caltech and the University of California Los Angeles have recently established a NanoSystems Biology Alliance (NSBA). The goals of the Alliance are to attack challenges in cancer and immunology and ultra-rapid disease diagnostics by integrating newly developed nanotechnology and microfluidics tools with modern cancer biology and immunology. Modern science has generated a picture of cancer that has at its foundation specific molecular errors that instruct healthy cells to become those of disease. Virtually all cancers arise from a series of DNA mutations (errors) that accumulate in a single cell. One error may be genetically passed from parent to child, while others arise from external sources, such as environmental toxins, smoking, viruses or simply from mistakes in DNA repair that occur with aging. Consider a patient diagnosed today with breast cancer. A molecular-based analysis of that same patient might be “breast cancer type 32 resulting from mutations in the Her2 oncogene and the PTEN tumor suppressor gene.” In other words, different breast cancer patients may have common clinical presentations, but different diseases. Thus, clinically treating breast cancer as a single disease is incorrect. The development and testing of new cancer drugs is similarly misguided without an informed diagnosis --the molecular description of the malignant cells and identification of vulnerable therapeutic DNA, RNA and protein targets. As a result, non-specific chemotherapy drugs (i.e. cis-Plat) or radiation are still the primary weapons used by oncologists, even after a 32 year-old and very expensive war on cancer. Why, then, are breast cancers, prostate cancers, etc., all treated as single diseases? Cancer diagnostic tools (mammograms, CT, MRI imaging, etc.) are based on identifying disease lesions (i.e. tumors), but not the molecular causes. PET molecular imaging can examine the molecular basis of disease in patients, but it needs guidance that establishes the molecular diagnostic criteria. An informative diagnostic description of disease requires the means to examine hundreds to thousands of molecular species – a concept beyond the scope of current clinical practice. Modern systems biology techniques (the coordinated measurement of the molecular signatures of genes and proteins that are the biological language of health and disease) provide a foundation for such measurements. Unfortunately, those techniques now require a large surgical tissue sample, are costly, are limited in the diversity of molecular species that can be examined, and are tedious. Thus, a combination of inadequate knowledge, antiquated clinical practices and inefficiencies in current tools of molecular diagnostics has kept an informed molecular diagnosis of disease – and from this the development of effective molecular therapeutics – a dream, rather than a reality. This picture is changing, and a new wave of nanotechnologies are being developed that will revolutionize virtually every aspect of medicine – cancer is just one example. Imagine that a full molecular-based cancer diagnosis could be accomplished using just a few cells, at low cost, within seconds. With a drop of blood or with a low risk outpatient biopsy procedure, a cancer patient could be correctly diagnosed, even in the very early stages of the disease, within minutes. This would revolutionize drug discovery and clinical treatment:
First, it would allow for the identification of the combinations of molecular errors that result in the various cancers;
Second, it would hasten the development of drugs targeted to the critical and vulnerable molecular errors causing the cancer;
Third, clinical trials to test those drugs, by targeting the appropriate patient pool, could be completed with smaller numbers of patients and lead to rapid approval by the FDA. The goal of the Nanosystems Biology Alliance is to make this vision a reality.