Molecular processor

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A molecular processor is a processor that is based on a molecular [1] [2] platform rather than on an inorganic semiconductor in integrated circuit format.

Contents

Current technology

Molecular processors are currently in their infancy and currently only a few exist. At present a basic molecular processor is any biological or chemical system that uses a complementary DNA (cDNA) template to form a long chain amino acid molecule. A key factor that differentiates molecular processors is "the ability to control output" of protein or peptide concentration as a function of time. Simple formation of a molecule becomes the task of a chemical reaction, bioreactor or other polymerization technology. Current molecular processors take advantage of cellular processes to produce amino acid based proteins and peptides. The formation of a molecular processor currently involves integrating cDNA into the genome and should not replicate and re-insert, or be defined as a virus after insertion. Current molecular processors are replication incompetent, non-communicable and cannot be transmitted from cell to cell, animal to animal or human to human. All must have a method to terminate if implanted. The most effective methodology for insertion of cDNA (template with control mechanism) uses capsid technology to insert a payload into the genome. A viable molecular processor is one that dominates cellular function by re-task and or reassignment but does not terminate the cell. It will continuously produce protein or produce on demand and have method to regulate dosage if qualifying as a "drug delivery" molecular processor. Potential applications range from up-regulation of functional CFTR in cystic fibrosis and hemoglobin in sickle cell anemia to angiogenesis in cardiovascular stenosis to account for protein deficiency (used in gene therapy.)

Example

A vector inserted to form a molecular processor is described in part. The objective was to promote angiogenesis, blood vessel formation and improve cardiovasculature. Vascular endothelial growth factor (VEGF) [3] and enhanced green fluorescent protein (EGFP) cDNA was ligated to either side of an internal ribosomal re-entry site (IRES) to produce inline production of both the VEGF and EGFP proteins. After in vitro insertion and quantification [4] of integrating units (IUs), engineered cells produce a bioluminescent marker and a chemotactic growth factor. In this instance, increased fluorescence of EGFP is used to show VEGF production in individual cells with active molecular processors. The production was exponential in nature and regulated through use of an integrating promoter, cell numbers, the number of integrated units (IUs) of molecular processors and or cell numbers. The measure the molecular processors efficacy was performed by FC/FACS to indirectly measure VEGF through fluorescence intensity. Proof of functional molecular processing was quantified by ELISA to show VEGF effect through chemotactic and angiogenesis models. The result involved directed assembly and coordination of endothelial cells for tubule formation [5] by engineered cells on endothelial cells. The research goes on to show implantation and VEGF with dosage capabilities to promote revascularization, validating mechanisms of molecular processor control. [6]

See also

Related Research Articles

Angiogenesis

Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting. Vasculogenesis is the embryonic formation of endothelial cells from mesoderm cell precursors, and from neovascularization, although discussions are not always precise. The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.

Endothelium Cells that line the Inner surface of blood vessels

Endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels, and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel wall. Endothelial cells form the barrier between vessels and tissue and control the flow of substances and fluid into and out of a tissue.

Platelet-derived growth factor Signaling glycoprotein regulating cell proliferation

Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing blood vessel tissue, mitogenesis, i.e. proliferation, of mesenchymal cells such as fibroblasts, osteoblasts, tenocytes, vascular smooth muscle cells and mesenchymal stem cells as well as chemotaxis, the directed migration, of mesenchymal cells. Platelet-derived growth factor is a dimeric glycoprotein that can be composed of two A subunits (PDGF-AA), two B subunits (PDGF-BB), or one of each (PDGF-AB).

Vascular endothelial growth factor (VEGF), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis and angiogenesis.

Angiomotin

Angiomotin (AMOT) is a protein that in humans is encoded by the AMOT gene. It belongs to the motin family of angiostatin binding proteins, which includes angiomotin, angiomotin-like 1 (AMOTL1) and angiomotin-like 2 (AMOTL2) characterized by coiled-coil domains at N-terminus and consensus PDZ-binding domain at the C-terminus. Angiomotin is expressed predominantly in endothelial cells of capillaries as well as angiogenic tissues such as placenta and solid tumor.

An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained exogenously through pharmaceutical drugs or diet.

Endostatin

Endostatin is a naturally occurring, 20-kDa C-terminal fragment derived from type XVIII collagen. It is reported to serve as an anti-angiogenic agent, similar to angiostatin and thrombospondin.

Angiogenin

Angiogenin (Ang) also known as ribonuclease 5 is a small 123 amino acid protein that in humans is encoded by the ANG gene. Angiogenin is a potent stimulator of new blood vessels through the process of angiogenesis. Ang hydrolyzes cellular RNA, resulting in modulated levels of protein synthesis and interacts with DNA causing a promoter-like increase in the expression of rRNA. Ang is associated with cancer and neurological disease through angiogenesis and through activating gene expression that suppresses apoptosis.

Neovascularization is the natural formation of new blood vessels, usually in the form of functional microvascular networks, capable of perfusion by red blood cells, that form to serve as collateral circulation in response to local poor perfusion or ischemia.

Angiopoietin Protein family

Angiopoietin is part of a family of vascular growth factors that play a role in embryonic and postnatal angiogenesis. Angiopoietin signaling most directly corresponds with angiogenesis, the process by which new arteries and veins form from preexisting blood vessels. Angiogenesis proceeds through sprouting, endothelial cell migration, proliferation, and vessel destabilization and stabilization. They are responsible for assembling and disassembling the endothelial lining of blood vessels. Angiopoietin cytokines are involved with controlling microvascular permeability, vasodilation, and vasoconstriction by signaling smooth muscle cells surrounding vessels. There are now four identified angiopoietins: ANGPT1, ANGPT2, ANGPTL3, ANGPT4.

Neuropilin

Neuropilin is a protein receptor active in neurons.

VEGF receptor

VEGF receptors are receptors for vascular endothelial growth factor (VEGF). There are three main subtypes of VEGFR, numbered 1, 2 and 3. Also, they may be membrane-bound (mbVEGFR) or soluble (sVEGFR), depending on alternative splicing.

VEGFR1 Protein-coding gene in the species Homo sapiens

Vascular endothelial growth factor receptor 1 is a protein that in humans is encoded by the FLT1 gene.

Vascular endothelial growth factor C

Vascular endothelial growth factor C (VEGF-C) is a protein that is a member of the platelet-derived growth factor / vascular endothelial growth factor (PDGF/VEGF) family. It is encoded in humans by the VEGFC gene, which is located on chromosome 4q34.

Thymidine phosphorylase

Thymidine phosphorylase is an enzyme that is encoded by the TYMP gene and catalyzes the reaction:

PEDF

Pigment epithelium-derived factor (PEDF) also known as serpin F1 (SERPINF1), is a multifunctional secreted protein that has anti-angiogenic, anti-tumorigenic, and neurotrophic functions. Found in vertebrates, this 50 kDa protein is being researched as a therapeutic candidate for treatment of such conditions as choroidal neovascularization, heart disease, and cancer. In humans, pigment epithelium-derived factor is encoded by the SERPINF1 gene.

Placental growth factor

Placental growth factor is a protein that in humans is encoded by the PGF gene.

AGGF1

Angiogenic factor with G patch and FHA domains 1 is a protein that in humans is encoded by the AGGF1 gene.

Vascular endothelial growth factor A

Vascular endothelial growth factor A (VEGF-A) is a protein that in humans is encoded by the VEGFA gene.

Angiogenesis is the process of forming new blood vessels from existing blood vessels. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteases (MMPs), a disintegrin and metalloprotease domain (ADAM), a disintegrin and metalloprotease domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.

References

  1. ↑ Williams, Kevin Jon (2008). "Molecular processes that handle — and mishandle — dietary lipids". Journal of Clinical Investigation. 118 (10): 3247–59. doi:10.1172/JCI35206. PMC   2556568 . PMID   18830418.
  2. ↑ McBride, C; Gaupp, D; Phinney, DG (2003). "Quantifying levels of transplanted murine and human mesenchymal stem cells in vivo by real-time PCR". Cytotherapy. 5 (1): 7–18. doi:10.1080/14653240310000038. PMID   12745583.
  3. ↑ Leung, D.; Cachianes, G; Kuang, W.; Goeddel, D.; Ferrara, N (1989). "Vascular endothelial growth factor is a secreted angiogenic mitogen". Science. 246 (4935): 1306–9. Bibcode:1989Sci...246.1306L. doi:10.1126/science.2479986. PMID   2479986.
  4. ↑ Leutenegger, C; Klein, D; Hofmann-Lehmann, R; Mislin, C; Hummel, U; Böni, J; Boretti, F; Guenzburg, WH; Lutz, H (1999). "Rapid feline immunodeficiency virus provirus quantitation by polymerase chain reaction using the TaqMan fluorogenic real-time detection system". Journal of Virological Methods. 78 (1–2): 105–16. doi:10.1016/S0166-0934(98)00166-9. PMID   10204701.
  5. ↑ Vernon, RB; Sage, EH (1999). "A novel, quantitative model for study of endothelial cell migration and sprout formation within three-dimensional collagen matrices". Microvascular Research. 57 (2): 118–33. doi:10.1006/mvre.1998.2122. PMID   10049660.
  6. ↑ Russell Auger, PhD., Mesenchymal stromal cells as angiogenic cellular vectors for revascularizing the heart., 08.2006: PhD Thesis Publication available at Tulane University Library and through UMI Copyright 2006–2007.
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