Transcript bantam breed

Animal Models for Human Diseases
Y. Henry Sun 孫以瀚
Institute of Molecular Biology
Academia Sinica
中研院分生所
Animal models of human diseases
•Closely mimic the human disease
•Study pathogenic mechanisms
•Identify disease markers and drug targets
•Screen for drugs for prevention and therapy
常用模式生物
線蟲 (nematode Caenorhabditis elegans) http://elegans.swmed.edu/
果蠅 (fruit fly Drosophila melanogaster) http://flybase.org/
斑馬魚 (zebrafish Danio rerio) http://zfin.org
小鼠 (mouse Mus musculus)
（狗）(Canis lupus familiaris)
•Experimental advantages
•Genetically homogeneous
Animal model of diseases have defined cause(s)
Mutation
Disease model
Transgenic
簡化、模擬、參考
衛生署公佈 98年十大主要死因
（占總死亡人數的75.4%）
惡性腫瘤
心臟疾病
腦血管疾病
肺炎
糖尿病
事故傷害
慢性下呼吸道疾病
慢性肝病及肝硬化
自殺
腎炎、腎徵候群及腎性病變
28.1%
10.6%
7.3%
5.9%
5.8%
5.2%
3.5%
3.5%
2.9%
2.8%
Cancer, Obesity, Neurodegeneration
Cardiovascular diseases, Hair
癌症: 細胞分裂失控
沙皮
shar-pei = salvador (sav)
沙皮
Identifying tumor suppressors in genetic mosaics: the
Drosophila lats gene encodes a putative protein kinase
許田
Development 121, 1053-1063 (1995)
The Hippo pathway
Pan (2010) Dev Cell
19:491-505
Science 302:1227- 1231 (2003)
細胞遷移 (migration)
•離鄉背井
•殺出血路
•定居
Drosophila border cell migration
Montell (2003) Nature Revi Mol Cell Biol 4, 13-24
Obesity
2010 Albert Lasker award
Douglas Coleman
WT
Jeffrey M. Friedman
ob
•食慾的控制 (瘦體素 leptin）
•熱量的吸收、運用、儲存
•脂肪細胞的發育、數目
For the discovery of leptin, a hormone
that regulates appetite and body
weight—a breakthrough that opened
obesity research to molecular
exploration.
Effects of parabiosis of obese with diabetes and normal mice
Coleman (1973) Diabetologia 9:294-8
db overproduce a
blood-borne satiety
factor, but unresponsive
(defect in leptin
ob lacks a bloodborne satiety factor
(leptin)
Coleman (2010) Nature Med. 16:1097-1099
Therapy by leptin
Farooqi and O’Rahilly (2006) Endocr. Rev.
Body fat distribution
不患「多」而患不均
Masuzaki et al. (2001) Science 294:2166 -2170
Nature Genetics 24:66-70 (2000)
Spinal muscular atrophy (SMA) is an autosomal recessive disease
characterized by degeneration of the anterior horn cells of the spinal
cord, leading to muscular paralysis with muscular atrophy. No effective
treatment of this disorder is presently available.
Histological analysis of SMA-like mice
PNAS 98: 9808-9813 (2001)
Assay based on ratio of Exon 7 splice isoforms
=> Screen/test of drugs in in vitro system: more efficient
=> Test on animal model (in vivo)
HDAC inhibitor
Neurobiology of Disease (2006) 24:286–295
Human Molecular Genetics (2007)16: 499–514
Molecular mechanism
=> Rational search for drug target
Therapeutic approaches in SMA
Completed or ongoing clinical trials in SMA
Summer (2006) NeuroRx 3:235-245
Neurodegeneration due to loss-of-function mutations in fly
Lessing & Bonini (2009) Nature Rev Gent 10:359-370
Observing neurodegeneration in Drosophila
WT
mutant
WT
mutant
Transgenic models of neurodegeneration
Studying genetic interactions
Screen for modifier mutations
(additional genes with functional interaction)
Sang & Jackson (2005) NeuroRx 2:438-446
果蠅的酒測
對酒精的耐受性
成癮（酒精、藥物）
Wolf & Heberlein (03) J Neurobiol. 54:161-78
心臟血管的發育、疾病 （斑馬魚）
透明，可看活體
心臟血管發育
心臟跳動
血液流動
A novel mouse model of cerebral cavernous
malformations based on the twohit mutation
hypothesis recapitulates the human disease
腦海綿狀血管瘤
Cerebral cavernous malformations (CCMs) are vascular lesions of the central
nervous system appearing as multicavernous, blood-filled capillaries, leading to
headache, seizure and hemorrhagic stroke. CCM occurs either sporadically or as
an autosomal dominant disorder caused by germline mutation of one of three
genes: CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. Surgically-resected
human CCM lesions have provided molecular and immunohistochemical evidence
for a two-hit (germline plus somatic) mutation mechanism. In contrast to the
equivalent human genotype, mice heterozygous for a Ccm1- or Ccm2-null allele
do not develop CCM lesions. Based on the two-hit hypothesis, we attempted to
improve the penetrance of the model by crossing Ccm1 and Ccm2 heterozygotes
into a mismatch repairdeficient Msh2-/- background. Ccm1+/-Msh2-/- mice
exhibit CCM lesions with high penetrance as shown by MRI and histology. … The
late-stage CCM lesions displayed many of the characteristics of human CCM
lesions, including hemosiderin deposits, immune cell infiltration, increased
endothelial cell proliferation, and increased Rho kinase activity. … The CCM1
mouse model provides an in vivo tool to investigate CCM pathogenesis and new
therapies.
McDonald et al, HMG Advance Access published October 11, 2010
狗與人類疾病
致心律失常性右心室心肌病
•A single species
•Many highly inbred breeds (>1000)
•Selected for certain traits
•Other traits also fixed (~ 350 human disease)
Coat Variation in the Domestic Dog Is
Governed by Variants in Three Genes
Cadieu et al. (2009) Science 326, 150-153
Combinations of alleles at three genes
create seven different coat phenotypes
Cadieu et al. (2009) Science 326, 150-153
人類毛髮的生長
• Life quality
•無窮商機
A model is for reference!
Needs to be validated in human.
不得已也 !
黑色素原細胞 (melanoblasts) 的遷移
Waardenburg syndrome
•hearing loss
•white forelock
Defect in migration of
neural crest cells
belted
KitWLacZ/+
piebald
Pax3Spl/+
Baxter et al (04) Pigment Cell Res. 17:215-22
Mouse mutants
Steel (Sl)
Dominant White Spotting (W)
Defects in migration and proliferation
White spotting (Melanocyte)
Sterile (Germ cells)
Anemia (hematopoietic stem cells)
Transplantation experiments
Sl affected the environment (non-autonomous)
W affected these cells (cell-autonomous)
W = Kit (receptor tyrosine kinase) (Kit)
Sl (Steel) = Kit ligand (Kitl): survival factor
黑色素原細胞的遷移： 失去路障
絲羽烏骨雞 Silkie bantam
中興鄭旭辰老師
台灣畜產種原知識庫