Word (http://tools.niehs.nih.gov/portfolio/sc/list_doc.cfm?ext=.doc)
|
Excel (http://tools.niehs.nih.gov/portfolio/sc/list_xls.cfm?ext=.xls)
|
PDF (http://tools.niehs.nih.gov/portfolio/sc/list_doc.cfm?pdf=1&ext=.pdf)
Record Count: 3
To sort columns alphabetically or numerically, click on the column
header (Title, Principal Investigator, Institution, City, ST, Award Code, or
Pubs).
DESCRIPTION (provided by applicant):
Epidemiological evidence indicates that acute pulmonary exposure to airborne pollutants such as particulate matter (PM) increases the risk of pulmonary and cardiovascular morbidity and mortality. This implies that PM affects extra-pulmonary tissues, as evidenced by the occurrence of cardiovascular dysfunction on high pollution days. Furthermore, Federal Criteria Documents for PM have provided a wealth of evidence demonstrating PM dependent effects on the cardiovascular system. However, despite its obvious importance in regulating the delivery of cells and molecules to all tissues, and in the etiology of most cardiovascular diseases, the Principal Investigator's laboratory conducts the lone investigations that explore how systemic microvascular function is affected by pulmonary PM exposure. The overall aim of this project is to determine if there is a true causal link between the inflammatory events that follow PM exposure and the disruption of endothelium-dependent dilation. The central hypothesis is: Inflammatory mechanisms govern the systemic microvascular dysfunction that follows ultrafine PM exposure, and the severity of this dysfunction is augmented in clinically relevant populations. Intravital microscopy and isolated vessels will be used to test this hypothesis in the spinotrapezius muscle, bone marrow, and subendocardial circulations of rats and mice exposed to diesel exhaust particles (DEPs) or ultrafine titanium dioxide. The role of gender and age in determining the severity of these effects will also be studied. Various in vivo and in vitro techniques will be used to measure microvascular reactivity after PM exposure, and to characterize pathological changes at this crucial level of the circulation. DEPs are mobile source emission air pollutants representative of particles that humans are exposed to on a regular basis. Ultrafine titanium dioxide is a commonly used nanoparticle found in cosmetics, paints and various protective coatings. A better understanding of how these particles affect remote microvascular function will provide mechanistic insight into pathologic changes that contribute to cardiovascular morbidity and mortality. Moreover, these studies may provide a biological basis for the epidemiological associations between air pollution and cardiovascular dysfunction. A fundamental understanding of these mechanisms is vital to the prevention and treatment of life-threatening cardiovascular events, and will contribute to control strategy development.
DESCRIPTION (provided by applicant): Sonic Hedgehog (SHh), an important signaling molecule that helps orchestrate embryonic development, has recently been shown to also function in the renewal of immune cells during adult life as well as during fetal development. Cadmium (Cd) is a heavy metal that is both an environmental contaminant as well as a significant component of cigarette smoke. Cd is also a known mammalian teratogen that causes forelimb ectrodactyly in rodents. Although extensively studied as a teratogen, only very recent evidence provides a mechanism for this teratological effect, that is, that Sonic Hedgehog (sHh) signaling is altered in the offspring of Cd treated dams. This application requests funds to collect preliminary data to connect the potential of Cd to alter the development of thymocytes during fetal development. The importance of this work is both to develop a valuable probe to understand the role of SHh in fetal thymic development as well as determine the potential risk for the offspring exposed to Cd in utero. One specific aim is proposed: Establish that prenatal Cd disruption of SHh signaling alters T cell development in the mouse fetus. This specific aim is to test the hypothesis that prenatal Cd exposure will lower SHh levels resulting in a lower percentage of double positive thymocytes in the newborn.
DESCRIPTION (provided by applicant): The goal of this project is to elucidate changes in neural mechanisms induced by exposure to environmental tobacco smoke (ETS) during critical developmental windows in early life and which lead to increased susceptibility and occurrence of adult asthma. Exposure to ETS in utero or during early postnatal development increases the incidence of respiratory illnesses later in life. The mechanisms of enhanced susceptibility in early life and the basis for defining critical windows of vulnerability are not well understood. The nervous system is highly susceptible to environmental influences during development, including the nerves supplying the airways. Airway innervation develops rapidly during fetal and early postnatal life in parallel with the developing lung. Given the dynamic and vulnerable nature of developmental processes, this period of morphogenesis is likely to be exquisitely sensitive to environmental insults. Substance P (SP), a neurotransmitter synthesized and released from airway sensory nerve, plays an important role in antigen or irritant-induced asthma. SP can trigger symptoms of bronchial asthma including airway smooth muscle constriction and acute inflammation. Interestingly, recent studies in our laboratory showed that nerve growth factor (NGF) generated by irritant exposure mediated the changes in SP phenotype and neuronal responses. Thus, we hypothesize that the levels of SP in the airway neurons and airway wall are permanently altered by exposure to ETS in early life. Further, we hypothesize that these changes are mediated through NGF and are manifest as increased neural responsiveness that in turn promotes airway hyperreactivity and increased susceptibility to asthma in later life. The specific aims are to 1). identify critical windows of susceptibility to ETS by measuring SP in neurons innervating the airway and dynamic changes in lung function, 2). determine the effects of NGF limitation during critical developmental periods in the ETS-induced modulation of SP regulating airway hyperreactivity. If our hypotheses are correct, the study will show that growth factor expression is responsible for altered neurotransmitter regulation in adults during critical exposure windows. The findings will provide new understanding about the mechanisms of ETS susceptibility during early life.
|