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

lifescience1

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1 U$ ^5 b% h" R, u, M8 a" C" _Preface4 j! ?4 x# o  Y# w
During the last few years we have seen fundamental changes in the way
# D' g& Z6 L5 S- A* H/ O7 qscientists approach the identification and validation of new drug targets. These
* e; g& ~; j' [, znovel strategies for target validation are expected to maximize the likelihood
/ }6 s2 a/ N7 v9 |+ rof achieving target-selective inhibition with minimal in vivo side effects. For  t# L- Y4 F. J& V* }7 V9 E
example, by the use of small interfering RNAs (siRNAs) to down regulate
' l" w8 l0 x1 w+ y! E2 S5 t$ |" @expression of known genes, a number of therapeutic targets have been validated
: W( p& L  [2 }9 w+ t9 vboth in vitro and in vivo. The technologies developed to do this have not only
8 W/ ^3 w7 }2 R0 S; yyielded a significant number of drug targets but have influenced our understanding& K; z# ^' k' L
of gene function, the molecular mechanisms of diseases, and the) M9 D) H8 F1 T. K( {
design of new therapeutic interventions. Specific gene and protein targets—on. i# n7 N9 Z$ H, Q) q7 G, S' e
which, for example, cancer cells depend—can now be identified, along with1 j5 F+ ^2 @6 H: z; m3 _# A
the therapeutic agents directed against them. Several relevant examples that% k" `0 c& y; |5 l5 d7 R
have been validated, and some that have reached the clinic, are featured in7 B  p" L% w; R
Volume 2, Emerging Molecular Drug Targets and Treatment Options, of7 i0 u9 x) ]4 P
Target Discovery and Validation Reviews and Protocols.5 G" D( g2 x( @- v$ p
Despite knowing the molecular mechanisms of most drugs, patients vary in
. E' f+ t" a; G# V( Ytheir responses to a medication’s efficacy and side effects. Indeed, the sequence
* U# @! p5 y/ V% d/ `: b! v* ^of the human genome has shown that there is extensive genetic variation among
* n' `0 d  N( B1 m& l% Z+ `. n* uindividuals that would be expected to affect the response to medication. Thus,3 a" m! R- I' h' }/ M4 l
a better understanding of the molecular mechanisms that lead to an improved! y4 U1 }$ U4 [- ]5 N$ D
treatment response should play an important role in the development of) q' n/ O' ]! h8 z7 G: X& r& n
individualized medicine. DNA sequence alterations and the expression profiles4 k3 _6 u/ I. t. C
of mRNA molecules and proteins can be used to predict drug response. These' Q, y3 x8 `( Y' a. u0 \( t
genetic and epigenetic changes may be used in turn to develop treatment
  g6 h3 E' B% S2 j2 Malgorithms adjusted for use in individual patients. Several examples of such
; B8 ^+ w+ y' ]6 x3 Rindividualized treatment, aimed at increasing drug efficacy as well as, j6 t: K* u5 P. R
decreasing toxicity, are discussed in this edition.% k+ s, V7 r9 o* ^  d
In systemic autoimmune diseases, current clinical practice calls for4 ?- Y9 s$ y& ^# t. o' ~( ^( N
immunosuppressive drug therapy. However, some drugs are not target-specific& z, g+ f* e3 u7 j! d% h  L1 d
and some carry a high risk of side effects. New immunosuppressive strategies,
) ^7 y' r, @1 {: y9 i2 ~such as monoclonal antibodies and receptor antagonists, are now emerging as) F1 t, g9 l0 A6 s1 a7 W! L3 D, K
potentially valuable discriminating agents for use in innovative combinations./ Q+ M8 v6 a  h  A- l* o/ \2 d
Such novel opportunities for therapeutic targeting in systemic autoimmune
) P2 r9 A& m/ B* Wdiseases are described in Volume 2.
* U/ @6 \' f) f% S) |# Y6 xMicroRNAs (miRNAs) are a family of short noncoding regulatory RNA" _" c. A& ^& j' Q
molecules expressed in a variety of different cell types. These tiny RNAs have: R2 s- I6 ?2 r* s' f
been shown to play important biological functions and may regulate the( y, s& T8 U3 j) F8 w
expression of more than 30% of human genes. Presently, evidence is emerging
& u" u  n  U. C7 lthat particular miRNAs may play a role in human cancer pathogenesis. Thus,
1 y( j* D; {$ d6 ^+ ?. k% V9 ~# C8 _: Jthe identification of miRNA expression signatures in patients with cancer may1 c- D) U6 R' Q: B( M$ k) [! O
help to identify subjects who are at high risk of developing cancer or those who0 F" h: i! _1 R/ M. B
have an early stage of cancer. In order to interfere with miRNA expression,
# `) R, r; V4 O3 a# qmodified antisense oligonucleotides targeting individual miRNAs have been
3 B5 G# q6 }- pdeveloped and these agents have the potential to eventually progress into a" f' R& t5 O& ^/ E3 }5 k& t& Y6 o8 X# c
new class of therapeutic agents.
& {' w: l: Y" ^8 \. S& r) P  AVolume II, Emerging Molecular Drug Targets and Treatment Options, was; P( k9 y7 r8 S9 l1 @0 J! U" c) f
written by leading experts in the field and presents a unique source of current
% G7 e, S$ _$ ^; i/ ]information. Along with Volume I, Emerging Strategies in Drug Targets and
! |! y4 b1 ~/ r# z1 x! q' p6 BBiomarker Discovery, this work will be of interest to researchers, pharmaceutical6 c' {7 h' d" @, t& ?
companies, clinicians, and students of biology, medicine, or pharmacy.
  S2 Z3 v5 k' V4 p5 J: oI would like to thank the authors for their contributions, Anne Dybwad for
, `0 k6 n& S3 ~critical reading of the manuscripts, and all those involved in the production of  N. r2 W- W! {) H" Z
the book.
! t, L5 b& g0 }7 T$ W2 fMouldy Sioud
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