In order to fully exploit knowledge garnered from sequencing the human genome, there is a dire need to deliver biologically active drugs and biopharmaceuticals into the CNS for stroke therapies and the treatment of neurodegenerative disease. The goal of this exploratory R21 feasibility research proposal is to identify peptides capable of targeting the choroid plexus (CP) so that they can be evaluated for their capacity to deliver drugs to the CP or across the CP into cerebrospinal fluid (CSF). The anatomical and therapeutic rationale for the proposed research originates with the observation that the CP is a structurally unique interface between blood and CSF that acts as a heretofore unrecognized focal gateway that can deliver naturally occurring agents like ascorbic acid into the brain, and specifically into CSF. Accordingly, in addition to drug targeting the CNS, CP-targeting would also open the possibility of creating new CP-based neurotherapeutics that either (1) modify CP drug transport functions directly, (2) alter its capacity to secrete CSF or (3) modulate the composition and concentration of factors (e.g. growth factors) that it places into CSF. Rather then apply rational design to create drug delivery agents for CP and CSF therapeutics however, we propose to exploit the power of combinatorial biology and genetic selection to mine libraries of peptides for those capable of targeting CP. Specifically, we propose to identify (1) peptides that target CP endothelial and stromal cells (2) peptides that target CP epithelial cells and (3) peptides that can translocate across the CP and into CSF. At the conclusion of this project, we will have identified 3 classes of peptides capable of specifically targeting the blood (basolateral) and CSF (apical) interfaces of the CP for CP and CSF-targeted for drug delivery to the brain during neurodegeneratrive disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Exploratory/Developmental Grants (R21)
Project #
3R21EY018479-02S2
Application #
7996282
Study Section
Special Emphasis Panel (ZRG1-GGG-S (52))
Program Officer
Steinmetz, Michael A
Project Start
2007-09-30
Project End
2010-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
2
Fiscal Year
2010
Total Cost
$159,408
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Pharmacy
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Podvin, Sonia; Miller, Miles C; Rossi, Ryan et al. (2016) The Orphan C2orf40 Gene is a Neuroimmune Factor in Alzheimer's Disease. JSM Alzheimers Dis Relat Dement 3:
Torbett, Bruce E; Baird, Andrew; Eliceiri, Brian P (2015) Understanding the rules of the road: proteomic approaches to interrogate the blood brain barrier. Front Neurosci 9:70
Podvin, Sonia; Dang, Xitong; Meads, Morgan et al. (2015) Esophageal cancer-related gene-4 (ECRG4) interactions with the innate immunity receptor complex. Inflamm Res 64:107-18
Baird, Andrew; Lee, Jisook; Podvin, Sonia et al. (2014) Esophageal cancer-related gene 4 at the interface of injury, inflammation, infection, and malignancy. Gastrointest Cancer 2014:131-142
Lee, Jisook; Baird, Andrew; Eliceiri, Brian P (2014) Vascular normalization in cerebral angiogenesis: friend or foe? Methods Mol Biol 1135:25-34
Shaterian, Ashkaun; Kao, Steven; Chen, Lin et al. (2013) The candidate tumor suppressor gene Ecrg4 as a wound terminating factor in cutaneous injury. Arch Dermatol Res 305:141-9
Baird, Andrew; Coimbra, Raul; Dang, Xitong et al. (2012) Cell surface localization and release of the candidate tumor suppressor Ecrg4 from polymorphonuclear cells and monocytes activate macrophages. J Leukoc Biol 91:773-81
Costantini, Todd W; Eliceiri, Brian P; Putnam, James G et al. (2012) Intravenous phage display identifies peptide sequences that target the burn-injured intestine. Peptides 38:94-9
Dang, Xitong; Podvin, Sonia; Coimbra, Raul et al. (2012) Cell-specific processing and release of the hormone-like precursor and candidate tumor suppressor gene product, Ecrg4. Cell Tissue Res 348:505-14
Podvin, Sonia; Gonzalez, Ana-Maria; Miller, Miles C et al. (2011) Esophageal cancer related gene-4 is a choroid plexus-derived injury response gene: evidence for a biphasic response in early and late brain injury. PLoS One 6:e24609

Showing the most recent 10 out of 12 publications