Awarded: Aug 04, 2003
$1.07 million over 3 years (full grant)<br />$400,000 over 18 months (planning grants)
In 2003, one full grant of $1.07 million and five planning grants of $80,000 each were awarded to multi-disciplinary teams of investigators working to catalyze activity at the interface of clinical and other research disciplines.
2003 CIAP Grantees
Full Grant
Genomics-based Approaches to New Pathogen Discovery in Chronic Human Diseases
Team Leader:
Donald E. Ganem, M.D., Howard Hughes Medical Institute/ University of California, San Francisco
Key Investigators:
Joseph R. DeRisi, Ph.D.,
University of California, San Francisco
Homer A. Boushey, M.D.,
University of California, San Francisco
Team Disciplines:
Virology, Infectious Diseases, Genomics/ Informatics, Pulmonology
Abstract:
In the past 2 decades, great strides have been made in identifying infectious agents that cause human disease. Particularly important has been the recognition that many chronic diseases once thought to be genetic, metabolic or degenerative in origin are in fact precipitated by infection. (Examples: peptic ulcer disease, Lyme arthritis and cervical cancer). Suspicion is now growing that other disease processes - chronic inflammatory states, autoimmune diseases, and some degenerative disorders - may likewise have infectious precipitants or cofactors. However, our ability to identify new pathogens has been strongly impaired by the inadequacy of currently available techniques for identifying infectious agents. The emerging science of genomics provides new opportunities to advance this area of research. Rather than attempting to identify new pathogens by their growth properties in culture, genomic methods allow pathogens to be sought by directly attempting to detect their DNA in a clinical specimen. We have developed a new, genomics-based method for the detection of viral genomes in such specimens, using DNA microarrays bearing the conserved sequences of all known viruses. Several short fragments of DNA from each known virus are deposited on a glass slide; the DNA or RNA from the patient sample is biochemically labelled and then tested for its ability to recognize the spots of known viral DNA that are on this lside. The subsequent pattern of reactions is analyzed by computer to yield the identity of the pathogen present in the sample. In this way, in a single test we can search for nearly 1000 known viruses; in addition, the test has the potential to identify new viruses that are only partially related to presently known agents. Using this test, we are searching for new agents implicated in asthma, pneumonitis, hepatitis and other chronic diseases.
Planning Grants
Development of the First Test for Common Cancer Risk in the General Population
Progenitor Cell Based Therapeutic Strategies for Atherosclerosis
A Humanoid Robot as an Interactive Diagnostic Device in Autism
Fluorescent Probes for the Detection and Evaluation of Occult Ovarian Cancer
A Multidisciplinary Approach to Understanding the Role of Social, Economic, and Immunological Factors in Cervical Cancer: Defining Parameters for an Innovative Cancer Control Strategy
Team Leader:
Sue J. Goldie, M.D., M.P.H.,
Harvard School of Public Health
Key Investigators:
Paul Farmer, M.D., Ph.D., Harvard University
Thomas C. Wright, Jr., M.D.,
Columbia University College of Physicians & Surgeons
Team Disciplines:
Decision Science, Gynecology-Pathology, Anthropology
Abstract:
Haiti has among the highest rates of cervical cancer in the world. While screening for cervical cancer has been one of the most successful public health interventions in countries with sufficient resources to implement Pap smear programs, it has not been feasible in developing countries such as Haiti where more than 90% of cervical cancer deaths now occur. New screening options as well as vaccination against human papillomavirus (HPV), which is now recognized to cause cervical cancer, may eventually impact cervical cancer rates in these countries. However, in order for these interventions to be effective we need to have a better understanding of the immunobiology of HPV in disadvantaged women at highest risk for developing cancer, identify the impact of modifiable factors on expression of disease, and create an analytic framework in which this information can be formally synthesized, translated, and applied to the development of community-based interventions to reduce morbidity and mortality from cervical cancer. We propose to use a cross-disciplinary approach incorporating experts from the fields of clinical medicine, anthropology, and decision science to accomplish the following specific aims:
To evaluate rates of persistent and incident high-risk types of HPV infection in a cohort of Haitian women between the ages of 30 and 65;
To evaluate possible variables associated with HPV persistence by assessing biological parameters, socioeconomic factors, and clinical characteristics in this cohort of older Haitian women; and
To develop a comprehensive epidemiologic model and decision-analytic policy model to assist in the design of the intervention trial, operational planning, and assessment of appropriate clinical study endpoints, operational planning, programmatic evaluation, and extrapolation of results to other populations.
Ultimately, this model will serve as a durable tool with which to evaluate the cost-effectiveness of novel multi-component interventions to reduce the persistence of HPV and project the long-term population-based benefits on cervical cancer reduction. Integration of an anthropological and ethnographic approach into this planning grant will allow us to assess the impact of sexual behavior on HPV persistence and insure that a culturally acceptable and ethical design is developed for the subsequent randomized intervention trial. A better understanding of the biologic, clinical and social determinants of HPV persistence will be relevant for scientists and clinical researchers involved in a wide range of cervical cancer activities, ranging from planning for cervical cancer screening programs to the development of an effective HPV vaccination.
Development of the First Test for Common Cancer Risk in the General Population
Team Leader:
Andrew P. Feinberg, M.D., M.P.H,
Johns Hopkins University School of Medicine
Key Investigators:
Francis M. Giardiello, M.D., M.B.A.,
Johns Hopkins University School of Medicine
Elizabeth A. Platz, Sc.D., M.P.H.,
Johns Hopkins Bloomberg School of Public Health
Marcia R. Cruz-Correa, M.D, Ph.D.,
Cleveland Clinic Foundation & Johns Hopkins University School of Medicine
Ruth R. Faden, Ph.D., M.P.H.,
Johns Hopkins Bloomberg School of Public Health
Team Disciplines:
Molecular Genetics, Gastroenterology, Epidemiology, Community Medicine, Bioethics
Abstract:
Each year, 147,000 Americans are newly afflicted with colorectal cancer (CRC), of whom 57,000 do not survive. Although several genes have been identified that contribute to the cause of CRC, they are almost always mutated (altered) in the cancers of patients but not in their normal cells. That means that molecular tests for cancer would not work in identifying patients at risk of cancer before they develop cancer, in contrast to the way that tests for heart disease do work in identifying patients at risk of heart disease before they become ill. The same limitation is true for breast and other cancer tests, where genes have been found that are important in the disease, but these genes are only rarely altered in normal cells in the general population. The goal of this project is to develop the first test in normal cells suitable for common cancer risk assessment in the general population. It is based on a discovery from our team of a novel type of genetic change involving "genomic imprinting" in colon cancer. Imprinting is a genetic process that involves the silencing of one of the two parental copies each person inherits from one's parents. The gene we are focusing on is termed insulin-like growth factor II (IGF2), and normally only the copy from one's father is active; the copy from the mother is normally inactivated. We discovered that in about 10% of the population, IGF2 undergoes loss of imprinting (LOI), with activation of the normally maternal copy of IGF2 and a double dose of this important growth factor, that can lead to increased cell growth. LOI was present about 5 times more frequently in patients with a family history of CRC, and 20 times more frequently in patients who had a past history of colon tumors. We now want to develop a study to determine how we can identify healthy individuals without a family or personal history of cancer, but at risk of developing colon cancer, and intervene to prevent their developing colon cancer. One of our goals is to demonstrate the feasibility of our test on community-based samples. Our original work was done on a hospital clinic-based population, but for it to work we must know whether it is equally valid in patients of differing ethnic and racial backgrounds. Our second goal is to attempt to use a set of samples and data that was collected on a community-based population over the past 12 years. Since samples were collected in the past, we can determine whether LOI predicts later development of colon tumors. In this planning grant, we will determine the feasibility of testing these samples over time and validating our previous observation on recently obtained specimens. Our third goal is to develop a model for interdisciplinary research on a molecular test for common colorectal cancer risk, and to see if it can be applied to a community-based population. This will involve the integration of geneticists, gastroenterologists, epidemiologists, and bioethicists. As we are the first group developing a test for common cancer risk, we wish to make sure it is done in the most effective way with the most significant public health impact, without compromising patients' privacy or causing undue anxiety to families. This study embodies a high degree of novelty, including the novelty of a common cancer risk test itself, its highly interdisciplinary nature, its strong ethics component, and its emphasis on community-based populations. We hope that these attributes should maximize the potential of this work to have a major impact on cancer mortality in the general population, leading eventually to a full study based on the results of this planning grant.
Progenitor Cell Based Therapeutic Strategies for Atherosclerosis
Team Leader:
Pascal J. Goldschmidt, M.D.,
Duke University Medical Center
Key Investigators:
Joanne Kurtzberg, M.D., Duke University
Jeremy Sugarman, M.D., M.P.H., M.A.,
Duke University Medical Center
Kenneth C. Land, Ph.D., Duke University
Team Disciplines:
Medicine/ Cardiology, Pediatrics, Bioethics, Sociology
Abstract:
Atherosclerosis is the underlying disease process that causes major health problems in our society, including heart attacks, sudden deaths and strokes. It consists of a progressive, time-dependent, degeneration of the arterial blood conduits that bring blood to all areas of the human body. Younger individuals are much less susceptible to atherosclerosis and its complications than elderly individuals. Yet, for a long time, it was unclear why that would be the case. The cells (cells are the little bricks of life that constitute most tissues of the human organism) that have the capacity to repair and rejuvenate arterial conduits arise from a particular area of many bones called the marrow. We have discovered that these marrow-derived cells, called vascular progenitor cells, become progressively exhausted with aging in the presence of risk factors that injure the arterial conduits, such as abnormal blood cholesterol or hypertension. As a consequence, repair and rejuvenation of arterial conduits become impaired. The arterial conduits respond to such lack of repair by developing an inflammatory reaction quite similar to that found in many injured tissues. This inflammatory process is responsible for the narrowing and, at times total closure, of certain arterial conduits leading to heart attack, sudden cardiac death, and stroke.
With this project, we propose to study the loss of bone marrow-derived progenitor cells by looking at the blood of patients with and without atherosclerosis of the arterial conduits of the heart. Such cells can be recognized by their capacity to multiply rapidly when extracted from the blood and allowed to grow under specific conditions. Specifically, we have hypothesized that such vascular progenitor cells would be much less abundant in the blood of individuals with advanced atherosclerosis, when compared to individuals with nearly intact heart arteries (as evidenced by studying these arterial conduits with specialized X-ray techniques). Furthermore, we also plan to look at the ability of another type of progenitor cells that can be found in the cord blood of newborns, to prevent the development of atherosclerosis and consequent heart disease in children that have a particular pre-disposition for developing atherosclerosis because of what we call inherited metabolic disorders, and in particular, Hurler syndrome.
The long-term goal of our study is not only to eradicate atherosclerosis, but also and as a consequence, to prolong healthy life and perhaps life itself for many human beings. Such progress may create fundamental societal and ethical issues that we are planning to address from the start of performing these experiments. With such approach, we intend to bring our scientific breakthroughs in an environment where harmony can be maintained between science, philosophy, and spirituality.
A Humanoid Robot as an Interactive Diagnostic Device in Autism
Team Leader:
Brian M. Scassellati, Ph.D., Yale University
Key Investigators:
Ami Klin, Ph.D., Yale University School of Medicine
Fred R. Volkmar, M.D., Yale University School of Medicine
Team Disciplines:
Computer Science, Psychology, Psychiatry
Abstract:
Using eye-tracking technology, we have been able to see and measure what individuals with autism - from toddlers to adults - look at when presented with social situations on a screen. Relative to typical peers, individuals with autism look at the mouths rather than at the eyes of people, suggesting that they miss essential social cues that are conveyed through the eyes. They also focus more on objects than their peers. Because these skills emerge in the first weeks of life, we are developing this technique to identify the earliest forms of vulnerability for autism. There is a need for early detection because the earlier we identify children with autism, the more likely we are, through early intervention, to affect the natural course of the disorder and maximize a positive outcome.
In our studies to date, children watch social situations on a screen while we measure what they are looking at. To improve upon this technique, we propose to make our procedure more interactive by replacing the video screen with a humanoid robot. We have been successful in building robots that detect human social cues and respond to people in a contingent, social fashion. These robots evoke social responses in children (making it possible to measure a child's ability to attribute human qualities); they can express social cues with great control, one at a time (making it possible to measure a child's reactions to specific social cues); and they are interactive (making it possible to measure the child's visual engagement with an object that behaves like a human being). The attempt to merge eye-tracking techniques and humanoid robotics represents an effort to utilize the best technologies available in social development research and artificial intelligence to create an early detection procedure capable of identifying the largest number of children at risk for autism.
Fluorescent Probes for the Detection and Evaluation of Occult Ovarian Cancer
Team Leader:
Michael V. Seiden, M.D., Ph.D.,
Massachusetts General Hospital
Key Investigators:
Arlan Fuller, M.D., Massachusetts General Hospital
Richard Penson, M.D., Massachusetts General Hospital
Debra Bell, M.D., Massachusetts General Hospital
Neil Horowitz, M.D., Massachusetts General Hospital
Ralph Weissleder, M.D., Ph.D., Massachusetts General Hospital
Team Disciplines:
Medical Oncology, Gynecologic Oncology, Radiology, Medical Physics, Pathology
Abstract:
Standard examination for ovarian cancer involves the use of a 300mm long, 5mm diameter cylindrical lens assembly (laparoscope) projecting onto a visible spectrum charge coupled device (CCD), permitting the surgeon to image and survey the peritoneal cavity. However, sub-clinical disease goes undetected because it is not adequately imaged in the visible spectrum.
In the last several years, investigators have shown that classical imaging can be greatly enhanced by the use of reagents, which react with occult tumor and show the presence of very small tumors by signaling molecular events which are characteristic of cancer.
Essentially these molecular reagents, or molecular probes, can be made to detect several mechanisms as "markers" of cancer proliferation, such as the growth of abnormal blood vessels, the ability to subvert standard processes of cell death (apoptosis), the over-expression of growth factors and the breakdown of normal communication, or signal transduction, between elements of cell regulation.
In this work, we create a broad imaging platform by adding an infra-red channel, which is overlayed and co-registered with the standard visible optical image.
By injecting a small amount of indocyanine green (ICG), we see the notable retention of this common ophthalmic marker in abnormal tissue due to the micro-vessel density in tumor. Many similar bio-markers have been shown to specifically infer the molecular signatures of disease. ICG is made to fluoresce by near-infrared peak excitation at ~805nm using either a broadband or laser diode source. The characteristic emission at ~835_nm is captured in a secondary, devoted infra-red camera and combined and co-registered with the standard visible signal.
Biopsy guided by this method is anticipated to confirm that the combined visible and near-infrared system can locate tumor and suggest underlying causes otherwise invisible in standard practice.