2006 — 2007 |
Taylor, Michael Robert [⬀] Taylor, Michael Robert [⬀] |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Analysis of Tuberous Sclerosis Complex in Zebrafish @ University of California San Francisco
[unreadable] DESCRIPTION (provided by applicant): Tuberous sclerosis complex (TSC) is a genetic disease afflicting nearly 50,000 Americans and at least one million individuals worldwide. TSC is a devastating multi-organ disease that results in benign tumors and severe neurological manifestations. Epilepsy is a common feature of TSC, with at least 90% of affected individuals generating seizures ranging from infantile spasms to complex partial seizures. While there currently is no cure for this disease, improved therapies may be developed from a more thorough understanding of the molecular basis of epilepsy in TSC. To gain insight into this health problem, a zebrafish model of this disease has been developed by knocking-down TSC gene function using morpholino oligonucleotides. In this proposal, electrophysiological recordings and behavioral monitoring will be used to examine the hyperexcitable in TSC-deficient morphants. A comprehensive analysis of brain morphology will be performed to uncover the developmental effects of TSC deficiency. Finally, pharmacological agents, known to affect the TSC signaling pathway, will be tested for therapeutic efficacy. This proposal may provide clues into the causes of epilepsy in TSC and identify biochemical targets for treating this disease. [unreadable] [unreadable] [unreadable]
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0.958 |
2020 — 2021 |
Taylor, Michael Robert [⬀] Taylor, Michael Robert [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Regulation of Cns Angiogenesis and Barriergenesis @ University of Wisconsin-Madison
The blood-brain barrier (BBB) plays a vital role in diseases of the central nervous system (CNS). Dysfunction of the BBB is common to several neurological disorders, including stroke, epilepsy, Alzheimer?s disease, and brain tumors, where brain endothelial cells (BECs) lose barrier properties, gain fenestrations, and increase permeability. Significantly, the BBB prevents the free exchange of many therapeutic agents, presenting a challenging problem for the treatment of many neurological diseases. Conversely, when the BBB is compromised in diseases such as neurodegenerative disorders, brain tumors, stroke, and multiple sclerosis, inflammatory conditions often result in the infiltration of peripheral immune cells, contributing to the pathology of the disease. Therefore, a fundamental understanding of BBB formation is essential to provide therapeutic insights into treating these diseases. During BBB development, there is a coordinated effort between CNS angiogenesis and barriergenesis (i.e. the acquisition of BBB properties). While both processes are dependent upon signals within the developing CNS, the precise molecular and cellular mechanisms that drive BBB formation are only beginning to be elucidated. Our overall objective is to bridge the gap in this knowledge. Our proposal is innovative because we: 1) identified zebrafish mutants with defective brain vasculature; 2) demonstrated that canonical Wnt signaling is sufficient for barriergenesis in the absence of Vegf signaling; 3) determined that activated canonical Wnt signaling in neural progenitor cells inhibits CNS angiogenesis; and 4) identified regulatory elements that may suppress fenestrations in BECs. Based upon our compelling preliminary studies, our central hypothesis is that canonical Wnt signaling regulates Vegf signaling and the acquisition of barrier properties in BECs using both cell autonomous and cell non-autonomous mechanisms. Our specific aims will test the following hypotheses: (Aim 1) canonical Wnt signaling regulates cell autonomous Vegf signaling in BECs, but that Vegf signaling can drive CNS angiogenesis in the absence of canonical Wnt signaling; (Aim 2) activated canonical Wnt signaling in neural progenitor cells inhibits the development of the BBB; and (Aim 3) regulatory elements within the plvap promoter suppress fenestrations in BECs, but not peripheral endothelial cells. Our proposed studies establish an innovative approach to discover new insights into the molecular and cellular mechanisms that regulate CNS angiogenesis and barriergenesis. Our long-term goals are to use this information to develop new strategies that permit the controlled access of therapeutic agents into the CNS and repair damaged or dysfunctional barriers associated with the pathology of neurological diseases.
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