2002 — 2003 |
Silverman, Daniel H |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Evaluation of Presynaptic Calcium Channels in Vivo @ University of California Los Angeles
Presynaptic calcium channels play a critical role in the communication of neurons with other tissues, and with each other. These molecular complexes, by undergoing voltage-dependent conformational changes, serve as literal gatekeepers to the final common biochemical pathway of neurotransmission for a wide variety of transmitters. They have also been implicated in pathologic processes ranging from paraneoplastic disease to neurologic injury secondary to cerebral ischemia. In light of the importance of the channels to normal neurophysiology and to neuropathologic conditions, a method to evaluate then in vivo could provide a valuable window into synaptic events that regulate and alter neurotransmission. The goal of this project is to study the feasibility of quantitatively assessing regional synaptic density in the living brain, while helping to lay the basic groundwork necessary to achieving quantitative imaging of presynaptic calcium channels in vivo. In addressing those problems, this proposal relates to the purpose of the Exploratory/Developmental (R21) Grant Program in several ways, including undertaking innovative research directions requiring preliminary testing, as well as developing new techniques and methods, to create tools with which to examine functional and dysfunctional brain tissue. A specific aim of this proposal is to test the feasibility of what would be an almost immediate area of practical application for this work - the use of radioligands of N-type and P/Q-type calcium channels, coupled with high-resolution imaging technology, to noninvasively quantify the distribution of synaptic density in humans and animals undergoing synaptic loss associated with neurodegeneration. Our longer-term goal is to make ligands with affinities dependent upon whether the channels are in opened or closed conformation, thus serving as a molecular handle by which to directly visualize, and eventually modulate, synaptic activity. Another specific aim is prompted by the understanding that the likelihood of these goals being satisfactorily accomplished will be enhanced by developing methods to increase transport of the channel ligands across the blood-brain barrier. A possible peripheral benefit of this work lies in its potential to bring us closer to an effective CNS delivery system for calcium channel antagonists which are under clinical development as therapeutic agents.
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0.934 |
2011 — 2012 |
Silverman, Daniel H |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Acute and Long-Term Effects of Chemotherapy On Regional Cerebral Metabolism @ University of California Los Angeles
DESCRIPTION (provided by applicant): A substantial body of evidence has accumulated over the past decade that prior exposure to cytotoxic chemotherapy as well as anti-estrogenic or estrogen-based therapies, is associated with altered regional brain metabolism, as observed by a number of groups, including our own. The mechanisms, by which these changes occur, however, remain obscure. While it has been demonstrated in tissue culture that at least some of the cytotoxic chemotherapy agents commonly used in the treatment of breast and other cancers have substantial direct neurotoxic effects, one of the issues of contention relates to what extent chemotherapy agents have access to brain tissue in vivo. While it appears that most cytotoxic agents do not enter most areas of the brain in high concentrations when the layers of tissue comprising the blood-brain barrier are healthy, diseases such as cancer, as well as therapies for those diseases can clearly alter blood-brain barrier permeability. It is less clear to what degree systemic chemotherapies themselves may diminish the functional and/or structural integrity of the barrier. As an example of one such mechanism, by which that could occur, key components of this barrier are the ATP-binding cassette transporters such as the glycoprotein exporter P-gp, which pumps a variety of molecules away from the intracerebral side of the barrier, and is involved in some forms of chemoresistance of tumors. For chemotherapy agents that serve as substrates for this or other exporters, it is feasible for the high concentrations typically used in achieving therapeutic efficacy to sufficiently saturate the transporter, such that the blood-brain barrier would be functionally compromised, permitting entry of not only that particular agent, but also other cytotoxic agents that are commonly given in multi-drug regimens to treat breast and other cancers. Our first two specific aims involve directly assessing what effects that chemotherapy agents commonly used in the treatment of breast and other cancers, including use in human studies that have pointed to long-term neuropsychological sequelae, may have upon regional cerebral metabolism, in both short-term (Aim 1) and long-term (Aim 2) time-frames. Our last set of experiments (Aim 3) involve measuring the permeability of the blood-brain barrier to an [F-18]-labeled common chemotherapy agent using small animal dynamic PET imaging, when that chemotherapy agent is co-administered with vehicle only, and with relatively small and large concentrations of multi-drug regimens, typical of those used in chemotherapy regimens for human patients. Results of these studies may help to define the basis for alterations in cerebral metabolism that have been observed in patients undergoing treatment for cancer with various chemotherapy regimens, by identifying the specific agents that demonstrate toxicity in vivo in this regard, under a variety of dose and time conditions, and quantitatively assessing the extent to which direct exposure of brain tissue to the chemotherapy agents may be occurring under each of those conditions. PUBLIC HEALTH RELEVANCE: Chemotherapy regimens commonly used in the treatment of cancer may change aspects of brain function, and alterations in brain metabolism identified with neuroimaging have provided sensitive measures of those changes. Since treatment of cancer patients in whom this has been studied has been with chemotherapy regimens comprised of multiple drugs, the relative roles of specific chemotherapy agents, and their underlying mechanisms of action, are not yet known. The controlled animal studies proposed here will help to clarify the basis for alterations in cerebral metabolism that have been observed in patients undergoing treatment for cancer with various chemotherapy regimens, and thereby be useful in formulating strategies to minimize or prevent associated impairment of brain function in the future.
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0.934 |