PDF电子书：Target Discovery and Validation Reviews and Protocols—2

lifescience1

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Preface, V/ ~% k* {" N) d
During the last few years we have seen fundamental changes in the way2 h$ Y! D0 M; h' ]- V4 f
scientists approach the identification and validation of new drug targets. These
3 I& |  b4 I' a/ d- dnovel strategies for target validation are expected to maximize the likelihood! m+ C8 A& r# b' j) g. W0 d; a
of achieving target-selective inhibition with minimal in vivo side effects. For
3 Y7 L8 f8 W9 l3 Q1 j; Rexample, by the use of small interfering RNAs (siRNAs) to down regulate
% F/ {: f( Q+ W2 p* dexpression of known genes, a number of therapeutic targets have been validated2 O6 {! u* A9 y
both in vitro and in vivo. The technologies developed to do this have not only9 o8 r+ T' h- A# t  h4 p& @
yielded a significant number of drug targets but have influenced our understanding) U  L0 D" i$ J6 s4 `  z2 d4 B, j
of gene function, the molecular mechanisms of diseases, and the
# U: m+ d3 ]7 _( N' b" ~design of new therapeutic interventions. Specific gene and protein targets—on
; e9 N, B0 C2 G1 h4 }which, for example, cancer cells depend—can now be identified, along with
( f& x/ Q  l4 k( Uthe therapeutic agents directed against them. Several relevant examples that
) C% \7 |! R! z' |have been validated, and some that have reached the clinic, are featured in
, V( D9 M8 U( p8 d' \: tVolume 2, Emerging Molecular Drug Targets and Treatment Options, of
2 g% p  ?7 a" Y- q5 W9 xTarget Discovery and Validation Reviews and Protocols.
( r" E: H0 ?/ z+ }Despite knowing the molecular mechanisms of most drugs, patients vary in
2 h3 Y7 C/ {: K" F  c5 ctheir responses to a medication’s efficacy and side effects. Indeed, the sequence
% v7 N( F: z+ t* qof the human genome has shown that there is extensive genetic variation among
$ x  k* j& {% Vindividuals that would be expected to affect the response to medication. Thus,
; @' R" x- j2 l# P  @a better understanding of the molecular mechanisms that lead to an improved
3 O! x, u8 x2 a1 C$ a$ Btreatment response should play an important role in the development of
. Z# N6 K, Y0 o8 Jindividualized medicine. DNA sequence alterations and the expression profiles# J7 ]( _9 b& q) Q
of mRNA molecules and proteins can be used to predict drug response. These4 m2 I+ Q0 E/ b# z
genetic and epigenetic changes may be used in turn to develop treatment: L3 `: G6 d- C) g9 T' J+ c3 P1 v
algorithms adjusted for use in individual patients. Several examples of such
; N* c$ w! T5 V2 J1 ~individualized treatment, aimed at increasing drug efficacy as well as
. Y( ]" x# r% l2 r7 ^/ u0 `3 w4 c" j- Tdecreasing toxicity, are discussed in this edition.) H" L( H( E1 c
In systemic autoimmune diseases, current clinical practice calls for
# o8 B2 @7 B% s6 d, Ximmunosuppressive drug therapy. However, some drugs are not target-specific. H6 F* z& J. O* Q/ w
and some carry a high risk of side effects. New immunosuppressive strategies,; z/ k7 ]) X- E- ^. p
such as monoclonal antibodies and receptor antagonists, are now emerging as
5 ~4 E1 c2 Y4 q, |* F: d+ Rpotentially valuable discriminating agents for use in innovative combinations.
( Z5 E1 i) o* p  m# ]Such novel opportunities for therapeutic targeting in systemic autoimmune" U! `/ u, g& k0 O
diseases are described in Volume 2." A1 V) o+ z& q4 r* j) e
MicroRNAs (miRNAs) are a family of short noncoding regulatory RNA# K# f! i0 ~$ @$ y9 H8 \
molecules expressed in a variety of different cell types. These tiny RNAs have8 C" w  V4 l* ]" @; _% R7 ]. i( d+ Q
been shown to play important biological functions and may regulate the* g4 f  ~$ t! g9 \: W' G& E
expression of more than 30% of human genes. Presently, evidence is emerging
; B8 H7 G& N4 e) B, A8 Y- Qthat particular miRNAs may play a role in human cancer pathogenesis. Thus,0 ^2 Z1 b  Z9 B) q1 f! U( r
the identification of miRNA expression signatures in patients with cancer may% ?$ e, X* t- F# q
help to identify subjects who are at high risk of developing cancer or those who3 l: q' Z8 G( M" N) p
have an early stage of cancer. In order to interfere with miRNA expression,8 x; Z  J; G$ g+ S- F: u
modified antisense oligonucleotides targeting individual miRNAs have been) ~) ~, K% ]6 U0 b
developed and these agents have the potential to eventually progress into a
8 m4 i7 }* S- A$ G2 Mnew class of therapeutic agents.
4 f4 X9 D1 l$ e0 u. F" f, |( nVolume II, Emerging Molecular Drug Targets and Treatment Options, was  X  _/ P9 @2 b# f2 r9 r' {2 Q
written by leading experts in the field and presents a unique source of current( e* t) D0 x' }) Q- W6 P3 B
information. Along with Volume I, Emerging Strategies in Drug Targets and
/ K- Y0 s5 A$ m% }7 ABiomarker Discovery, this work will be of interest to researchers, pharmaceutical
# M) l, H) V/ `% w$ x! Icompanies, clinicians, and students of biology, medicine, or pharmacy.
- f3 z. R# I/ `2 y& S( M4 l: SI would like to thank the authors for their contributions, Anne Dybwad for5 j4 o& p- [) t0 ]# |# Q5 u
critical reading of the manuscripts, and all those involved in the production of
, S5 N5 Q$ L' ?- r" E8 W1 Gthe book.
* j8 v" r, {1 RMouldy Sioud
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